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Considerations when prescribing trimethoprim-sulfamethoxazole
... The most common adverse reactions of TMP-SMX are rash, allergic reaction, gastrointestinal discomfort, hyperkalemia, nephrotoxicity, and pancytopenia (3). In rare cases, TMP-SMX can also cause severe hypoglycemia that is often overlooked, leading to fatal outcomes. ...
... Of the 19 patients measured, 15 (78.9%) had elevated serum insulin levels, with a median of 31.8 mU/mL (range 3-115.3). Cpeptide levels increased in all 13 measured patients, with a median of 7.7 ng/mL (range 2. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Renal impairment occurred in 25 of 33 patients (75.8%), and hepatitis occurred in 2 of 22 patients (9.1%). ...
Objective
Hypoglycemia is a sporadic and serious adverse reaction of trimethoprim-sulfamethoxazole (TMP-SMX) due to its sulfonylurea-like effect. This study explored the clinical characteristics, risk factors, treatment, and prognosis of TMP-SMX-induced hypoglycemia.
Methods
Case reports and series of TMP-SMX-induced hypoglycemia were systematically searched using Chinese and English databases. Primary patient and clinical information were extracted for analysis.
Results
A total of 34 patients were reported from 31 studies (16 males and 18 females). The patients had a median age of 64 years (range 0.4-91), and 75.8% had renal dysfunction. The median duration of a hypoglycemic episode was six days (range 1-20), and the median minimum glucose was 28.8 mg/dL (range 12-60). Thirty-two patients (97.0%) showed neuroglycopenic symptoms, with consciousness disturbance (30.3%) and seizure (24.2%), sweating (18.2%), confusion (15.2%), asthenia (12.1%) being the most common symptoms. Fifteen patients (44.1%) had elevated serum insulin levels, with a median of 31.8 μU/mL (range 3-115.3). C-peptide increased in 13 patients (38.2%), with a median of 7.7 ng/mL (range 2.2-20). Complete recovery from symptoms occurred in 88.2% of patients without sequelae. The duration of hypoglycemia symptoms was 8 hours to 47 days after the intervention. Interventions included discontinuation of TMP-SMX, intravenous glucose, glucagon, and octreotide.
Conclusion
Hypoglycemia is a rare and serious adverse effect of TMP-SMX. Physicians should be aware of this potential adverse effect, especially in patients with renal insufficiency, increased drug doses, and malnutrition.
... It can also reduce the creatinine clearance at renal tubules, and it can lead to dangerously low levels of thrombocytes by reducing the folic acid levels and associated bone marrow blood cell formation. 7 Therefore, pursuing new, simple, low-cost, rapid, reliable, and user-friendly analytical techniques for simultaneously quantifying trimethoprim and sulfamethoxazole involving pharmaceutical quality control and the investigation of biological samples is indispensable. ...
... It can also reduce the creatinine clearance at renal tubules, and it can lead to dangerously low levels of thrombocytes by reducing the folic acid levels and associated bone marrow blood cell formation. 7 Therefore, pursuing new, simple, low-cost, rapid, reliable, and user-friendly analytical techniques for simultaneously quantifying trimethoprim and sulfamethoxazole involving pharmaceutical quality control and the investigation of biological samples is indispensable. ...
Synthetic antibiotics known as sulfonamides suppress the synthesis of tetrahydrofolic acid, which cures respiratory tract infections and protozoal infections by preventing the creation of dihydrofolic acid. Electrochemical sensors based on tetrakis(1,10-phenanthroline)-μ-(4,4′-bipyridine) dicopper(II) chloride monohydrate ([P2Cu-Bip-CuP2]Cl4·H2O or simply Cu2P4BCl4) have been successfully applied for the determination of sulfamethoxazole (SMX) and trimethoprim (TMP) from samples. The experimental conditions and parameters were optimized to achieve the best electrode performances for simultaneous quantification of SMX and TMP. Based on the analysis of the effect of scan rate on the peak parameters, the R² for the peak current vs square root of the scan rate was greater than that of the peak current vs scan rate, indicating diffusion-controlled behavior of both species. The current intensities of both SMX and TMP were highly improved due to surface activation of the electrodes by electropolymerization. For SMX, the limit of detection was determined to be 27.94 nM, while for TMP, it was 21.56 nM, and the limit of quantifications was 71.88 nM, and the corresponding relative standard deviation for each was 0.74% and 0.11%. The constructed electrode was stored for varying durations ranging from two h to 2 days, and it was found to be above 97% stable after storing for 15 days. The real applicability of the suggested sensor for the simultaneous determination of SMX and TMP was verified by sensing clinical serum and urine samples and their spike recovery studies.
... This scenario was notably observed in elderly patients prescribed aminoglycosides, necessitating reduced treatment durations to mitigate adverse effects [175]. Additionally, as people age, the prescription of medications like antihypertensives becomes more common, and the concurrent use of certain antibiotics, such as trimethoprimsulfamethoxazole, can result in harmful drug interactions that further compromise renal function [176]. This aspect is crucial for ADPKD patients, who face heightened infection risks and frequent interventions for hypertension, potentially exacerbating side effects that harm kidney function and accelerate disease progression. ...
Understanding chronic kidney disease (CKD) through the lens of evolutionary biology highlights the mismatch between our Paleolithic-optimized genes and modern diets, which led to the dramatically increased prevalence of CKD in modern societies. In particular, the Standard American Diet (SAD), high in carbohydrates and ultra-processed foods, causes conditions like type 2 diabetes (T2D), chronic inflammation, and hypertension, leading to CKD. Autosomal dominant polycystic kidney disease (ADPKD), a genetic form of CKD, is characterized by progressive renal cystogenesis that leads to renal failure. This review challenges the fatalistic view of ADPKD as solely a genetic disease. We argue that, just like non-genetic CKD, modern dietary practices, lifestyle, and environmental exposures initiate and accelerate ADPKD progression. Evidence shows that carbohydrate overconsumption, hyperglycemia, and insulin resistance significantly impact renal health. Additionally, factors like dehydration, electrolyte imbalances, nephrotoxin exposure, gastrointestinal dysbiosis, and renal microcrystal formation exacerbate ADPKD. Conversely, carbohydrate restriction, ketogenic metabolic therapy (KMT), and antagonizing the lithogenic risk show promise in slowing ADPKD progression. Addressing disease triggers through dietary modifications and lifestyle changes offers a conservative, non-pharmacological strategy for disease modification in ADPKD. This comprehensive review underscores the urgency of integrating diet and lifestyle factors into the clinical management of ADPKD to mitigate disease progression, improve patient outcomes, and offer therapeutic choices that can be implemented worldwide at low or no cost to healthcare payers and patients.
... The trial showed that administering a double-strength TMP-SMX daily or three times weekly can prevent PJP. 10,11 However, discontinuation rates due to adverse effects were notable, reaching up to 10% in the thrice-weekly group and 20% in the daily-group, after which PJP occurred. The discontinuation of the treatment was attributed to adverse events such as acute kidney injury, leukopenia, and gastrointestinal disturbances. ...
Background
The administration of trimethoprim-sulfamethoxazole (TMP-SMX) for the prophylaxis of Pneumocystis jirovecii pneumonia (PJP) has proven to be highly efficacious in individuals who have undergone kidney transplantation. Nevertheless, the potential for severe adverse reactions associated with this treatment cannot be overlooked, and the determination of an optimal dosage regimen continues to be a matter of investigation. The current study evaluated the effectiveness of low-dose TMP-SMX for PJP prophylaxis in kidney transplant patients and conducted an analysis of the clinical characteristics and epidemiological trends in patients with PJP infection.
Methods
This retrospective analysis studied electronic medical records of 1763 kidney transplant recipients from 2017 to 2020. These patients were initially prescribed a daily half-strength TMP-SMX (40 mg/200 mg), and the efficacy of this regimen was assessed during a follow-up period of 3–51 months.
Results
Under our PJP prevention and adjustment strategy, 24 patients were infected with PJP. The overall morbidity of PJP infection in our study was 1.36%, corroborates with findings from previously published studies. Among these 24 patients, up to 87.5% had their dosage adjusted due to increased creatinine or other adverse reactions, the most frequent dose was daily quarter-strength TMP-SMX (20 mg/100 mg). TMP-SMX prophylaxis successfully postponed and distributed the onset of PJP, with the mean duration from transplantation to the occurrence of PJP being 13.50±7.11 months.
Conclusion
Daily administration of half-strength TMP-SMX can effectively prevent PJP, and prolonging prophylaxis with this medication may potentially reduce the incidence of infection.
... Trimethoprim inhibits 2C8 which is responsible for the metabolism of repaglinide, meglitinide. Several clinical studies report an increase in the plasma concentration of antidiabetics leading to increased pancreatic insulin release and symptomatic hypoglycemia [136][137][138]. ...
Antimicrobial agents are widely used, and drug interactions are challenging due to increased risk of adverse effects or reduced efficacy. Among the interactions, the most important are those affecting metabolism, although those involving drug transporters are becoming increasingly known. To make clinical decisions, it is key to know the intensity of the interaction, as well as its duration and time-dependent recovery after discontinuation of the causative agents. It is not only important to be aware of all patient treatments, but also of supplements and natural medications that may also interact. Although they can have serious consequences, most interactions can be adequately managed with a good understanding of them. Especially in patients with polipharmacy it is compulsory to check them with an electronic clinical decision support database. This article aims to conduct a narrative review focusing on the major clinically significant pharmacokinetic drug-drug interactions that can be seen in patients receiving treatment for bacterial infections.
... The anti-folate effect of cotrimoxazole, primarily due to trimethoprim, can induce megaloblastic alterations. Prolonged or high-dose administration of cotrimoxazole has been associated with macrocytic anemia, mild thrombocytopenia, and leukopenia, attributed to diminished folate levels available for hematopoiesis [54]. In our study, the changes in erythrocytes, leukocytes, neutrophils, and platelets observed after initiating treatment, upon clinical cure, were not significantly greater in those who received cotrimoxazole compared to those who received itraconazole. ...
Blood count is crucial for assessing bone marrow’s cell production and differentiation during infections, gaging disease severity, and monitoring therapeutic responses. The profile of blood count in chronic forms of paracoccidioidomycosis (PCM) has been insufficiently explored. To better understand the changes in hematological cells in different stages of the PCM chronic form, we evaluated the blood count, including immature blood cells in automated equipment, before and during the treatment follow-up of 62 chronic PCM patients. Predominantly male (96.8%) with an average age of 54.3 (standard deviation SD 6.9) years, participants exhibited pre-treatment conditions such as anemia (45.2%), monocytosis (38.7%), and leukocytosis (17.7%), which became less frequent after clinical cure. Anemia was more prevalent in severe cases. Notably, hemoglobin and reticulocyte hemoglobin content increased, while leukocytes, monocytes, neutrophils, immature granulocytes, and platelets decreased. Chronic PCM induced manageable hematological abnormalities, mainly in the red blood series. Monocytosis, indicating monocytes’ role in PCM’s immune response, was frequent. Post-treatment, especially after achieving clinical cure, significant improvements were observed in various hematological indices, including immature granulocytes and reticulocyte hemoglobin content, underscoring the impact of infection on these parameters.
... Wesolek JL et al [14] in their study had 74.9% sensitivity to Trimethoprim/sulfamethoxazole. Since the susceptibility of uropathogens to Trimethoprim/sulfamethoxazole is high and is cost effective when compared to other antibiotics and it can also be administered orally without regards to meals [15], and only barring those children with risk factors [16], Trimethoprim/sulfamethoxazole can still be considered as an empiric drug of choice especially in the developing countries in paediatric age group for acute uncomplicated cystitis. ...
Cystitis in childhood, is a common health issue causing morbidity and mortality. This study was to find out the bacterial pathogens causing cystitis in children and its susceptibility pattern. 1792 urine specimens from 1day- 18 years of age suspected of cystitis were obtained. Samples were inoculated into culture plates. Identification of the pathogens was by MALDI-ToF mass spectrometry and antimicrobial susceptibility testing by VITEX 2 system (bioMerieux,Inc, Durham, NC). 48.38% were males and 51.61% were females, 65% attended outpatient department and 35% were admitted in the hospital. Cystitis was more frequently seen in less than one year. Samples when on inoculation into the culture plates, had no organisms in 69.31% and 30.69% had significant bacteriuria. Bacteriuria among boys was more frequently seen in the age group of less than one year of age (35.06%) in the females, bacteriuria was more commonly seen in the age group of 1-5 years (28.32%). Escherichia coli 63.45% was the commonest pathogen isolated. Susceptibility to Trimethoprim/sulphamethoxazole was 84.53% and Ampicillin 45.56% .Since Trimethoprim/sulphamethoxazole is an FDA approved and cost effective drug, it could be an empirical drug of choice for treating cystitis in children of more than 6 weeks of age in the developing countries.
... 9 Trimethoprim-sulfamethoxazole was not considered in the second patient due to the potential risk of myelosuppression, hyperbilirubinemia, and kernicterus among neonates. 10 Thus, we employed a combination of vancomycin with rifampicin as vancomycin alone was not recommended especially in complicated cases. 1,2 Apart from that, we took preventive measures including thorough disinfection of the wards, isolation of the patients, strict adherence to hand hygiene practice, and mandatory wearing of personal protective equipment before examination to prevent the outbreaks of Elizabethkingia infections. ...
Elizabethkingia species are multi-drug resistant, Gram-negative bacteria that can adapt to different environmental conditions and rarely cause infections in humans but can be fatal among immunocompromised populations. We report our first experience of managing 2 pediatric patients infected with Elizabethkingia species. Over 12-months, 2 pediatric patients were infected with Elizabethkingia species in our hospital. They were both immunocompromised and were initially covered with broad spectrum antibiotics. Their conditions deteriorated and further investigations revealed the growth of Elizabethkingia species from the blood culture. Change of antibiotics was commenced and marked improvement was shown along the course of treatment. Both eventually completed the treatments and recovered remarkably well with no complications from the infections. However, colonization of the Elizabethkingia species was not identified on our environmental surveillance. Timely and appropriate anti-infectives and supportive management have shown marked improvement and disease curability in our patients who suffered from bacteremia and multiple liver abscesses.
... Although TMP/SMX has traditionally served as the agent of first choice for the treatment of SM infections, clinical data have shown no difference in outcomes for patients treated with TMP/SMX versus minocycline (12). The use of TMP/SMX is associated with several significant adverse events that may limit pathogendirected therapy, such as worsening renal function, hyperkalemia, and myelosuppression (23). Levofloxacin is less active against SM than either TMP/SMX or minocycline, and its role in treatment of minor infections is doubtful given the potential for the emergence of resistance during therapy (20). ...
Acinetobacter baumannii - calcoaceticus species complex (ACB) and Stenotrophomonas maltophilia (SM) are opportunistic, non-fermentative organisms that can cause serious hospital-acquired infections in immunocompromised patients. These pathogens are inherently resistant to several common drug classes and often acquire other resistance mechanisms, making them difficult to treat. In this study, we analyzed the susceptibility of 1,029 contemporary ACB and 1,522 SM isolates to minocycline (MIN) and levofloxacin (LEV) as well as meropenem (MER) for ACB and trimethoprim-sulfamethoxazole (TMP/SMX) for SM using the CLSI broth microdilution method. Isolates were collected as a part of the SENTRY Antimicrobial Surveillance Program from 2014 to 2021. Pneumonia in hospitalized patients was the most common infection from which ACB (57.0%) and SM (73.9%) were isolated. MIN had the highest in vitro activity for ACB (86.2%) and SM (99.5%). The activity of ACB and SM to all three agents varied over the period studied. MIN activity to ACB decreased in 2020 (80.6%) but rebounded in 2021 (86.2%). LEV and MER showed an overall trend of increasing susceptibility for ACB, with slightly lower activity in 2020–2021. MIN and TMP/SMX (>98.3% and >93.7%, respectively) activities were stable against SM isolates. LEV activity decreased from 84.3% (2015) to 69.2% (2018). The activity of MIN remained stable and higher than other agents tested for both ACB and SM, pathogens that have limited therapeutic alternatives. These in vitro data suggest that MIN is a useful treatment option for infections caused by ACB or SM.
IMPORTANCE
Acinetobacter baumannii-calcoaceticus species complex and Stenotrophomonas maltophilia are opportunistic, non-fermentative Gram-negative organisms that can cause serious hospital-acquired infections in immunocompromised patients. These pathogens are inherently resistant to several common drug classes and often acquire other resistance mechanisms, making them difficult to treat. In this study, we analyzed the trends of susceptibility of over 2,500 U.S. bacterial isolates collected from hospitalized patients over an 8-year period to minocycline, which is used to treat infections caused by these pathogens. These in vitro data suggest that minocycline is a useful treatment option for infections caused by Acinetobacter baumannii-calcoaceticus species complex or Stenotrophomonas maltophilia .
... It is used to treat urinary tract infections and skin and soft tissue infections. It is also used for the treatment of opportunistic infections, including those caused by Stenotrophomonas maltophilia (S. maltophilia), Toxoplasma gondii, and Pneumocystis jirovecii [5,6]. Stenotrophomonas maltophilia is a gram-negative bacteria that was previously known as Pseudomonas maltophilia or Xanthomonas maltophilia. ...
Background: Infections caused by Stenotrophomonas maltophilia (S. maltophilia) and Pneumocystis jirovecii (Pneumocystis jirovecii pneumonia (PJP)) require weight-based dosing for co-trimoxazole. The aim of this study is to assess the appropriateness of co-trimoxazole dosing in adult inpatients for the treatment of these infections.
Methodology: This is a single-center, cross-sectional study that included adult inpatients treated with co-trimoxazole for a weight-based dose indication (S. maltophilia and PJP). The primary outcome was the appropriateness of co-trimoxazole dosing for these infections.
Results: Forty-three patients were included in the study. Of the 43 patients, 29 (67.4%) were using co-trimoxazole for PJP treatment, and 14 (32.6%) were using it for S. maltophilia treatment. The co-trimoxazole dose was appropriate in 22 (51.2%) patients, 21 (72.4%) in the PJP treatment group, and one (7.1%) in the S. maltophilia treatment group. Underdosing was observed in 21 (48.8%) patients, of whom eight (27.6%) were in the PJP treatment group and 13 (92.9%) were in the S. maltophilia treatment group.
Conclusions: This study found a relatively high rate of underdosing of co-trimoxazole based on weight in hospitalized adults with PJP and S. maltophilia infections.
... There are a wide variety of possible TMP-SMX AR, ranging from mild nausea through to life-threatening toxic epidermal necrolysis. This highlights the importance of the correct evaluation and documentation of these reactions to guide future prescribing decisions [2]. ...
Introduction:
Trimethoprim-sulfamethoxazole (TMP-SMX) is an important antibiotic, with the most compelling indications for Pneumocystis jirovecii pneumonia prophylaxis and methicillin-resistant Staphylococcus aureus treatment. Previous adverse reactions (AR) to TMP-SMX may limit the usability of TMP-SMX. Electronic medical record (EMR) of AR for other antibiotics has previously been shown to be inaccurate; however, the extent to which this occurs for TMP-SMX is unknown.
Methods:
A multi-centre retrospective observational study was conducted for consecutive inpatient admissions over a 2.5-year period commencing 2020. Adverse reactions to TMP-SMX recorded in the EMR were collected and reviewed by two independent medical officers using pre-defined expert criteria for the classification of allergies and intolerances.
Results:
TMP-SMX AR were present in the EMR of 759 individuals (prevalence 0.6%). The majority were labelled as allergy (725, 95.5%) rather than intolerance (34, 4.5%). Most common AR were rash, vomiting, and swelling. When classified against the gold-standard expert criteria, there were 437 allergies (57.6%) and 159 intolerances (21.0%). Overall, the number of incorrect EMR AR labels was 133/759 (17.5%). Both medical and surgical specialties had significant numbers of patients with TMP-SMX AR labels and incorrectly classified EMR AR labels.
Conclusion:
TMP-SMX AR labels affect inpatients admitted under multiple specialty units. The user-entered categorization as allergy or intolerance labels in EMRs are frequently used incorrectly. These incorrect labels may inappropriately contraindicate the use of TMP-SMX, and formal evaluation of TMP-SMX ARs with immunological assessment and relabelling where appropriate may increase the use of this agent.
... Since the incidence of cotrimoxazole-related adverse events was much lower than the incidence of PJP in the control group (8.6%), prophylactic cotrimoxazole may be beneficial to pemphigus patients treated with a first cycle of rituximab, especially to those receiving concomitant moderate-to high-dose corticosteroids. Moreover, we found that most of the cotrimoxazole-related adverse events were reversible [53][54][55], whereas serious PJP might have a fatal outcome [15], further emphasizing the importance of adequate prophylaxis for PJP in these high-risk patients. ...
Introduction:
Pneumocystis jirovecii pneumonia (PJP) is a severe, life-threatening complication in patients treated with rituximab. However, there is no consensus on the primary prophylaxis for it in rituximab-treated pemphigus patients. Therefore, we sought to investigate the prophylactic efficacy and safety profile of cotrimoxazole for reducing the risk of developing PJP in pemphigus patients receiving rituximab.
Methods:
This single-center retrospective study investigated 148 pemphigus patients undergoing a first cycle of rituximab between 2008 and 2021 at a tertiary referral center in northern Taiwan. Patients were divided into the prophylaxis group (N = 113) and the control group (N = 35) according to whether or not cotrimoxazole was administered. The primary outcome was the 1-year incidence of PJP in the two groups, while the secondary outcome was the incidence of cotrimoxazole-related adverse events.
Results:
Of the 148 patients enrolled in this study, three patients, all in the control group, developed PJP during the 1-year follow-up. The incidence of PJP (8.6%) in the control group was significantly higher than that in the prophylaxis group (0%) (p = 0.012). The incidence of cotrimoxazole-related adverse events was 2.7%, and none of the cases were associated with life-threatening conditions. In addition, the cumulative prednisolone dose was associated with a trend of a higher risk of PJP (p = 0.0483).
Conclusions:
Prophylactic cotrimoxazole significantly reduces the risk of PJP in a certain high-risk population and has a tolerable safety profile.
... TMP/SMX has been reported to cause neutropenia due to folate deficiency [17]; however, the mechanism has not yet been fully clarified [18]. We found a frequency of neutropenia of 29.82%, similar to that identified by Tamir et al. in 2019, who reported a frequency of leukopenia of 24.4% [14]. ...
Introduction
Trimethoprim/sulfamethoxazole (TMP/SMX) is the antimicrobial of first choice in the treatment and prophylaxis of Pneumocystis jirovecii pneumonia (PCP) in immunocompromised patients, particularly in people living with human immunodeficiency virus (HIV). TMP/SMX use entails different adverse effects, and its association with early neutropenia is minimally documented. This study aimed to identify the risk of early neutropenia associated with TMP/SMX use in adults living with HIV in Mexico.
Methods
A prospective cohort study was conducted in TMP/SMX-naïve adults living with HIV admitted to a third-level hospital between August 2019 and March 2020. Socio-demographic, clinical, and laboratory data were collected. According to patients’ diagnostic, if they required treatment or prophylaxis against PCP, medical staff decided to prescribe TMP/SMX, as it is the first-line treatment. The risk of TMP/SMX induced early neutropenia, as well as associated factors were analyzed through a bivariate model and a multivariate Poisson regression model. The strength of association was measured by incidence rate ratio (IRR) with 95% confidence interval.
Results
57 patients were enrolled in the study, of whom 40 patients were in the TMP/SMX treatment-group for treatment or prophylaxis of PCP (204.8 person-years of observation, median 26.5 days) and 17 patients were in the non-treatment group because they did not need the drug for treatment or prophylaxis of PCP (87.0 person-years of observation, median 21 days). The incidence rate of early neutropenia in the TMP/SMX-treatment group versus non-treatment group was 7.81 and 1.15 cases per 100 person-years, respectively. After adjusting for stage 3 of HIV infection and neutrophil count <1,500 cells/mm³ at hospital admission, the current use of TMP/SMX was not associated with an increase in the incidence rate ratio of early neutropenia (adjusted IRR: 3.46; 95% CI: 0.25–47.55; p = 0.352).
Conclusions
The current use of TMP/SMX in Mexican adults living with HIV was not associated with an increase in the incidence rate ratio of early neutropenia.
... Ampicillin and norfloxacin have been detected at concentrations up to 5.5 μgL −1 and 6.1 μgL −1 respectively (Danner et al., 2019). SMX is an effective and low cost antibiotic and it is commonly used, while when combined with trimethoprim is used for urinary tract inflections (Ho and Juurlink, 2011). SMX, among other functional groups, contains an aromatic ring and an amino group (Lykoudi et al., 2020). ...
... However, antipseudomonal β-lactams, to which SM are intrinsically resistant [4], are often selected as empiric therapy for high-risk patients with neutropenia caused by the malignancy itself or its treatment [5]. Sulfamethoxazoletrimethoprim (SMX-TMP) is considered the first-line treatment for SM but causes myelosuppression, hyperkalemia, and hypercreatinemia [6]. This makes clinicians hesitant to administer early SMX-TMP, but delay can lead to fatal outcomes. ...
Difficulties in immediately distinguishing Stenotrophomonas maltophilia (SM) bacteremia from Pseudomonas aeruginosa (PA) bacteremia in the clinical setting can lead to treatment delay. We aimed to develop a scoring system to immediately distinguish SM bacteremia from PA bacteremia using clinical indicators. We enrolled cases of SM and PA bacteremia in adult patients with hematological malignancies between January 2011 and June 2018. The patients were randomized into derivation and validation cohorts (2:1), and a clinical prediction tool for SM bacteremia was developed and verified. In total, 88 SM and 85 PA bacteremia cases were identified. In the derivation cohort, the following independent predictors of SM bacteremia were identified: no evidence of PA colonization, antipseudomonal β-lactam breakthrough bacteremia, and central venous catheter insertion. We scored each of the three predictors according to their regression coefficient (2, 2, and 1, respectively). Receiver operating characteristic curve analysis confirmed the score’s predictive performance, with an area under the curve of 0.805. The combined sensitivity and specificity (0.655 and 0.821) was highest with a cut-off value of 4 points. Positive and negative predictive values were 79.2% (19/24) and 69.7% (23/33), respectively. This novel predictive scoring system is potentially useful for distinguishing SM bacteremia from PA bacteremia, which would facilitate immediate administration of appropriate antimicrobial therapy.
... Pneumocystis jirovecii is one of the most important opportunistic infections and increases with the use of high doses glucocorticoids for more than 1 month and prophylaxis is recommended in these cases. TMP-SMX is the most preferred agent in prophylaxis, but as in our case, severe renal failure limits its use [5,6]. Alternative prophylactic treatment regimens (Dapsone, pentamidine) should be preferred in such cases. ...
... [6] In its use, SMZ is combined with trimethoprim (TMP), known as co-trimoxazole [7]. This antibiotic was found to cause side effects, including hyperkalemia, especially in patients with impaired kidney function, elderly patients, diabetics, or AIDS [7], [8]. Therefore, it is necessary to conduct therapeutic drug monitoring (TDM) to optimize drug therapy and ensure patient safety [9]. ...
An analytical method for analyzing SMZ in human plasma and urine using high-performance liquid chromatography (HPLC) was developed. The separation was carried out on a Shim-pack GIST® C18 column (150 × 4.6 mm, 5 ?m) with a temperature setting of 30°C. The mobile phase consisted of glacial acetic acid pH 2.5: methanol: acetonitrile (70:25:5, v/v/v) at a rate of 0.8 mL/min. Detection was done using a PDA detector in the range of ?190-800 nm, and quantification was carried out at ?265 nm. Plasma sample preparation used the protein precipitation method with acetonitrile as the precipitating solvent (1:3, v/v), while urine preparation used the liquid-liquid extraction method with 0.03 M H2SO4 and ethyl acetate. The developed method was proven selective, linear (r = 0.998) for plasma and (r = 0.996) for urine, accurate (%error ?11.76% for LLOQ and ?14.08% for concentrations above), precision (%RSD ?4.52% for LLOQ and ?4.48% for the concentrations above), sensitive with 0.7 ?g/mL (plasma) and 0.17 ?g/mL (urine). Stability tests were carried out to determine the shelf life of the samples under several conditions. The developed method is valid and suitable for pharmacokinetic studies of SMZ in human plasma and urine.
... Petersen and his colleagues found that moderate-dose trimethoprim exposure for 7 days led to a significant decrease in serum folate levels in healthy patients, which could indicate the first stage of a negative folate balance preceding the depletion of folate from tissues. It is necessary to assess patients' folate status before treatment with trimethoprim, especially for those at risk of deficiency [29], and if this is the case, supplementation with folic acid could be of use [30]. ...
In recent years, many healthcare systems, along with healthcare professionals, have provided services in a patient-centered manner, in which patients are key actors in the care process. Encouraging self-care creates responsible patients, but it must be practiced responsibly. This study aims to analyze the tendency towards self-medication for patients from a rural area in Northeastern Romania. Data were collected using a questionnaire, which consisted of 25 questions, that has been developed by the research team. Student’s T test or one-way ANOVA was used, and the reliability of the questionnaire was calculated using Cronbach’s alpha coefficient. Fifty-eight patients agreed to participate and were interviewed. The results of the study suggest that respondents practice self-medication, which they resort to when their condition cannot be treated with natural remedies or herbs and when it impairs their ability to do their daily activities. Self-medication could be explained by the lack of self-care services as well as the trust patients have in the specific treatment. Patients prefer asking the pharmacist for drugs instead of visiting a physician, which could be due to higher accessibility and time-efficiency, while also being prone to stock up on certain medications due to limited access to healthcare.
... It is a combination of 2 antibiotics that produce a bactericidal effect by blocking the biosynthesis of proteins. 4 While the exact mechanism of action is unknown, TMP-SMX is known to block aldosterone-mediated sodium reabsorption in the collecting ducts of the kidney. The trimethoprim component is structurally like potassium-sparing diuretics, which block sodium uptake at the distal nephron and, in combination with the inactivated aldosterone-mediated process, can cause hyponatremia. ...
Introduction:
Trimethoprim-sulfamethoxazole (TMP-SMX) use in immunocompromised patients can cause dose-dependent electrolyte irregularities including hyponatremia, hyperkalemia, and metabolic acidosis. We report a case of isolated hyponatremia caused by low-dose TMP-SMX use in an immunocompetent patient that mimicked the syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Case presentation:
A 72-year-old woman was admitted to the hospital for acute onset of weakness and ambulatory dysfunction after starting TMP-SMX (160 mg/800 mg). She was found hyponatremic (sodium level, 125 mmol/L, down from 141 mmol/L prior to medication initiation). After ruling out diuretics use, and adrenal and thyroid dysfunction, we started her on intravenous saline infusion to manage her TMP-SMX-induced hyponatremia, and her symptoms resolved.
Discussion:
Electrolyte problems in immunocompromised patients treated for opportunistic infections with high-dose TMP-SMX (≥ 8 mg/kg/d TMP) are well-documented. However, the effects in immunocompetent patients are uncommon when standard dose (< 8 mg/kg/d TMP) is used.
Conclusions:
TMP-SMX blocks the aldosterone-mediated sodium reabsorption in the collecting ducts, and the trimethoprim component itself is structurally similar to potassium-sparing diuretics, which block sodium uptake at the distal nephron-both of which can cause hyponatremia.
... Supplementation with vitamin B 6 , folic acid, and vitamin B 12 helps to decrease the levels of homocysteine (Westphal et al., 2003). Table 2 demonstrated the impact of interactions of several classes of drugs with vitamins, resulting in vitamin deficiencies generally occurring in medical practice (Bhagavan & Brin, 1983;Galdo, 2013;Hendler & Rorvik, 2008;Ho & Juurlink, 2011;Palmery et al., 2013;Prescott et al., 2018;Pronsky, 2004). Usually in healthy persons, the influence of these drugs for short-term use is almost negligible and no intervention is necessarily needed. ...
Dietary components have been investigated for the modulation of various detoxifying metabolic pathways. Vitamins are essential micronutrients present in the diet for undergoing the metabolism in the body because human body cannot make all the vitamins. A deficiency of vitamins is related to alter hepatic functions. Hepatic microsomal drug-metabolizing enzymes (DMEs) production depends greatly on various vitamins. Vitamins E and A among fat-soluble vitamins are important for metabolism and modulation of DMEs. The production of microsomal metabolic substrates directly depends on vitamin E levels in the body. Generally, nutritional deficiencies cause diminished xenobiotic metabolism rates. However, in case of deficiency of vitamin B1 and mild vitamin B2 deficiency, increased rates of xenobiotic metabolism were attained. In this chapter, we have summarized how deficiency of fat-soluble vitamins and water-soluble vitamins regulate the levels of DMEs, especially involved in xenobiotic metabolism, challenges caused by vitamin deficiencies and possible strategies to be adopted for controlling and managing the intake of vitamins through diet or supplementation.
... The current preferred drug is TMP/SMX, but its resistance rate 14 has also increased, with frequent adverse effects such as anaphylaxis, renal impairment and myelosuppression. 15 Hence, TMP/SMX should be administered with caution to pediatric cases. In the cases we reported, although the two drugs, meropenem and cefixime, were the intermediary of drug susceptibility prompts, the drug was not changed due to the small range of drug options for infants, and the clinical symptoms of the children improved when the drug susceptibility results came out. ...
Background
Stenotrophomonas maltophilia (S. maltophilia) is a pathogen causing opportunistic and nosocomial infections that are invasive and fatal, especially in hospitalized and immunocompromised patients. However, community-acquired S. maltophilia is rarely reported in children with normal immunity. S. maltophilia is a multi-drug-resistant bacterium, and the preferred drug is trimethoprim/sulfamethoxazole (TMP/SMX), which has greater side effects in children.
Case Presentation
Herein, we reported the case of a child with clinical manifestations of fever, high C-reactive protein (CRP) and white blood cells, and severe pneumonia. The blood culture yielded S. maltophilia. The initial treatment regimen was meropenem IV, which was subsequently changed to ceftazidime IV, and finally to oral cefixime, which has less side effects in children. The child recovered completely. At the 1-month follow-up, anteroposterior chest X-ray was normal, and the child was in good general health.
Conclusion
Although community-acquired S. maltophilia infection in children is rare, it can occur. The doctor encountered such a child in clinical work. This child has a normal immune system, his disease comes from a community infection and has lobar pneumonia located in the lower lung area. At the same time, the child’s white blood cells and CRP values are high, the doctor should be concerned that the child may have S. maltophilia infection. When treating patients, doctors can try to use drugs empirically, such as ceftazidime, instead of using ciprofloxacin, SMZ and other drugs that have relatively large side effects in children. It is worth mentioning that doctors also need to adjust the medication in a timely manner according to the efficacy evaluation and drug sensitivity of the children after the medication, so as to minimize the drug resistance of community-acquired infections. This will prevent the misuse of Meropenem, which has been given in a community patient and that too in a child. Its important to prevent this malpractise.
Studies of fluoroquinolone (FQ) safety across indications show increased collagen/neurological adverse event (AE) risk, yet patients still receive FQs for uncomplicated urinary tract infections (uUTIs). This retrospective, cohort study investigated the risk of collagen/neurological AEs of special interest (AESIs) with short-term FQ use versus standard-of-care antibiotics (trimethoprim–sulfamethoxazole [SXT], nitrofurantoin [NTF]) among female outpatients with uUTIs. This study was conducted between December 2009 and 2019 using Optum’s de-identified Clinformatics Data Mart Database. Adjusted absolute risks were calculated for composite/collagen/neurological AESIs (Kaplan–Meier cumulative hazards, after applying stabilized inverse probability of treatment weighting [sIPTW]). Adjusted hazard ratios were generated (sIPTW Cox proportional hazard modeling). Overall, 954,777 patients were included: FQ ( n = 386,537 [40.5%]); SXT ( n = 237,120 [24.8%]); NTF ( n = 314,585 [32.9%]). Adjusted absolute risk range for collagen/neurological AESIs was <1%–4.5%. The hazard (95% CI) of tendon rupture was 25% higher with FQ versus SXT (1.25 [1.00–1.57]; P = 0.0497). Patients receiving FQ had lower hazard of neurological (0.95 [0.93–0.97]; P < 0.0001), central nervous system (0.85 [0.80–0.89]; P < 0.0001), and peripheral nervous system (0.96 [0.93–0.98]; P = 0.0016) AESIs versus NTF. Following a short treatment duration, FQs were associated with increased risk of tendon rupture versus SXT and reduced risk (adjusted hazard ratios) of neurological AESI versus NTF. Individual patient risk and consequences for known uncommon, yet serious, AEs need to inform appropriate antibiotic choice in treating uUTIs. Patient profile, efficacy, microbiome impact, safety, and surveillance should inform antibiotic selection for uUTI management, in accordance with guidelines.
A Novel bioanalytical detector based on Poly(Diaquabis(1,10-phenanthroline copper (II) Iodide) (poly([Cu(H2O)2P2]I2)/GCE) has been fabricated by potentiodynamic polymerization of [Cu(H2O)2P2]I2. The synthesized complex and the fabricated electrodes showed a promising electrocatalytic behavior towards the electrooxidation of Trimethoprim (TPM). Based on the regression coefficient value of scan rate with peak current and square root of peak current, the oxidation of TMP at poly([Cu(H2O)2P2]I2)/GCE was dominated by diffusion. Under the optimized experimental conditions and square wave voltammetric parameters, the poly([Cu(H2O)2P2]I2)/GCE revealed very wide responses in the range of concentration of 500 nM–160 μM with a limit of detection of 3.91 nM and a Limit of quantification of 13.02 nM with the relative standard deviation below 1.75 %. The valuable applicability of the fabricated sensor for the determination of TMP in real samples, including cow's milk, blood serum, and human urine, was successfully investigated. The electroanalysis results from the spike recovery and interference study provided an excellent range of recovery with an error percent of below 3.0 % in the combination effect with the potential interferents. The sensor exhibited excellent reproducibility, sensitivity, long-term stability, high accuracy, and fast response. The developed bioanalytical sensor revealed the best application prospect for biomedicine and environmental monitoring activities.
Objectives
Risk factors for adverse drug reactions (ADRs) associated with prophylactic sulfamethoxazole-trimethoprim (SMX/TMP) in patients with rheumatic and musculoskeletal diseases undergoing immunosuppressive therapy remain unclear; we aimed to identify the risk factors associated with ADRs.
Methods
Consecutive patients with rheumatic and musculoskeletal diseases, who were admitted to Keio University Hospital and received prophylactic administration of SMX/TMP, were included. Data regarding ADRs to SMX/TMP were collected to identify the associated risk factors using multivariable analysis.
Results
Of 438 patients included in the analysis, 82 (18.7%) experienced ADRs. Patients in the ADR group were significantly older, had chronic kidney disease, and exhibited lower lymphocyte and platelet counts, lower albumin levels, lower estimated glomerular filtration rates, higher aspartate aminotransferase levels, and higher ferritin levels than those in the non-ADR group. Regarding the underlying rheumatic and musculoskeletal diseases, adult-onset Still’s disease (ASD) was associated with a significantly higher incidence of ADRs (67%) than other diseases. Multivariable analysis identified the presence of ASD and low lymphocyte counts as independent risk factors for allergic ADRs and older age and use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers for nonallergic ADRs.
Conclusions
Risk factors for ADRs associated with prophylactic SMX/TMP treatment in patients with rheumatic and musculoskeletal diseases were identified.
Objective
To assess the association of trimethoprim sulfamethoxazole (TMP-SMX) prophylaxis with serious infections in rituximab-treated patients with granulomatosis with polyangiitis (GPA).
Methods
This retrospective cohort study included adults with GPA (2011–2020) within the United States Merative™ Marketscan® Research Databases with ≥6 months’ enrolment prior to first (index) rituximab treatment. We defined TMP-SMX prophylaxis as a ≥28-day prescription dispensed after or overlapping the index date. Serious infection was a hospital primary diagnosis for infection (excluding viral or mycobacterial codes). Secondary outcomes were outpatient infection, Pneumocystis jirovecii pneumonia (PJP) and adverse events potentially attributable to TMP-SMX. Cox proportional hazards regression assessed the association of time-varying TMP-SMX with outcomes of interest, adjusting for potential confounders. Individuals were followed until the outcome of interest, end of database enrolment or 31 Decamber 2020.
Results
Among 919 rituximab-treated individuals (53% female), mean (s.d.) age was 52.1 (16) years and 281 (31%) were dispensed TMP-SMX within 30 days of index date. Over a median of 496 (interquartile range 138–979) days, 130 serious infections occurred among 104 individuals (incidence 6.1 [95% CI: 5.0, 7.4] per 100 person-years). Time-varying TMP-SMX was negatively associated with serious infection (adjusted hazard ratio [aHR] 0.5; 95% CI: 0.3, 0.9). The aHR for outpatient infections was 0.8 (95% CI: 0.6, 1.1). The estimate for PJP was imprecise (13 events, unadjusted HR 0.2; 95% CI: 0.03–1.8). TMP-SMX was potentially associated with adverse events (aHR 1.3; 95% CI: 0.9, 1.9).
Conclusions
TMP-SMX prophylaxis was associated with reduced serious infections in rituximab-treated GPA, but may increase adverse events, warranting further study of optimal prophylaxis strategies.
Background
Pneumocystis jirovecii pneumonia (PCP) has a significant mortality rate for non-HIV immunocompromised patients. Prevention is primarily based on combined trimethoprim and sulfamethoxazole (TMP-SMX) but guidelines on pneumocystosis prophylaxis are scattered and not consensual.
Objectives
This study aims to describe PCP in non-HIV patients and to review case by case the prior indication of prophylaxis according to specific guidelines.
We included patients with confirmed diagnosis of PCP admitted to one university hospital from 2007 to 2020. Prior indication for pneumocystis prophylaxis was assessed according to the specific guidelines for the underlying pathology or treatment.
Results
Of 150 patients with a medical diagnosis of PCP, 78 were included. Four groups of underlying pathologies were identified: hematological pathologies (42%), autoimmune diseases (27%), organ transplantation (17%), and other pathologies at risk of PCP (14%). A small subgroup of 14 patients (18%) had received a prior prescription of pneumocystis prophylaxis but none at the time of the episode. Transfer to intensive care was necessary for 33 (42%) patients, and the mortality rate at 3 months was 20%. According to international disease society guidelines, 52 patients (59%) should have been on prophylaxis at the time of the pneumocystis episode. Lowest compliance with guidelines was observed in the hematological disease group for 24 patients (72%) without prescription of indicated prophylaxis.
Conclusion
Infectious disease specialists should draw up specific prophylactic guidelines against pneumocystis to promote a better prevention of the disease and include additional criteria in their recommendations according to individual characteristics to prevent fatal cases.
Acne is a common skin condition that can have profound physical and psychological impacts. This article outlines its clinical presentation and recommended management in primary care and discusses when referral to secondary care is necessary.
Background: Environmental pollution exposes human to various toxics. Food is one main route of toxic exposure, encompass pesticides, per- and polyfluoroalkyl substances (PFAS), polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), metals and nanoplastics [1]. Maternal exposure is a concern due to rising childhood neurodevelopmental disorders like autism spectrum disorders (ASD) [1,2] and environmental contaminants are suspected to be a main potential cause of these disorders, with significant socioeconomic costs [2,3]. Objective: Verify the association between maternal exposure to toxics and the increase in the prevalence of ASD at pediatric ages.
Trimethoprim-sulfamethoxazole (TMP/SMX) is widely used for various infections, yet its potential to cause neurotoxicity is underreported, typically emerging from case reports and predominantly involving immunocompromised patients. Here, we document a rare instance of TMP/SMX-induced neurotoxicity in a 61-year-old male who developed encephalopathy with myoclonus, without any prior immune compromise or relevant underlying diseases. Clinical evaluation, including laboratory tests and imaging, excluded metabolic and seizure-related origins. Remarkably, the patient's neurological condition improved rapidly following the cessation of TMP/SMX and the initiation of supportive care, with symptoms resolving within a few days. Recognizing the signs of drug-induced neurotoxicity early can prevent unnecessary diagnostic procedures, reduce the risk of complications, and ensure a swift recovery, with most cases resolving within 3-11 days after discontinuation. This case highlights the critical need for awareness among clinicians regarding the potential neurotoxic effects of TMP/SMX, even in patients without typical risk factors.
Pharmaceutical waste disposal is a significant problem for the global healthcare system. It poses a threat to water safety, which is already a challenge as 1 out of 3 people still lack access to safe drinking water. We conducted a thorough literature review of relevant articles published between 2000 and 2023. Our review scrutinized 107 studies, each of which applied pre-set inclusion and exclusion criteria to ensure high-quality research. The focus of our interest was on the health risks posed by pharmaceutical compounds in waste. We also evaluated recycling methods and proposed practical measures for proper education and the implementation of strict legislation to address this issue. Pharmaceutical compounds have been found in water resources worldwide. These compounds can have negative effects on multiple organs and it’s important to remove them from water resources. However, water quality varies globally due to limitations in accessibility and budget for water purification and recycling efforts. Comprehensive studies are needed to identify drinking water’s most common pharmaceutical residues and develop effective removal strategies. Proper disposal of pharmaceuticals is crucial to protect water resources and ensure clean drinking water. This requires raising awareness, educating the public population, implementing strict regulations, and collaborating among stakeholders.
Non-tuberculous mycobacteria (NTM) can cause a variety of infections, including serious pulmonary disease. Treatment encompasses polypharmacy, with a targeted regimen of 2-5 active medications, depending on site of infection, species, and clinical characteristics. Medications may include oral, intravenous, and inhalational routes. Medication acquisition can be challenging for numerous reasons, including investigational status, limited distribution models, and insurance prior authorization. Additionally, monitoring and managing adverse reactions and drug interactions is a unique skill set. While NTM is primarily medically managed, clinicians may not be familiar with the intricacies of medication selection, procurement, and monitoring. This review offers insights into the pharmacotherapeutic considerations of this highly complex disease state, including regimen design, medication acquisition, safety monitoring, relevant drug-drug interactions, and adverse drug reactions.
Introduction
There are known disparities in the treatment of infectious diseases. However, disparities in treatment of complicated urinary tract infections (UTIs) are largely uninvestigated.
Objectives
We characterized UTI treatment among males in Veterans Affairs (VA) outpatient settings by age, race, and ethnicity and identified demographic characteristics predictive of recommended first‐choice antibiotic therapy.
Methods
We conducted a national, retrospective cohort study of male VA patients diagnosed with a UTI and dispensed an outpatient antibiotic from January 2010 through December 2020. Recommended first‐choice therapy for complicated UTI was defined as use of a recommended first‐line antibiotic drug choice regardless of area of involvement (ciprofloxacin, levofloxacin, or sulfamethoxazole/trimethoprim) and a recommended duration of 7 to 10 days of therapy. Multivariable models were used to identify demographic predictors of recommended first‐choice therapy (adjusted odds ratio [aOR] > 1).
Results
We identified a total of 157,898 males diagnosed and treated for a UTI in the outpatient setting. The average antibiotic duration was 9.4 days (±standard deviation [SD] 4.6), and 47.6% of patients were treated with ciprofloxacin, 25.1% with sulfamethoxazole/trimethoprim, 7.6% with nitrofurantoin, and 6.6% with levofloxacin. Only half of the male patients (50.6%, n = 79,928) were treated with recommended first‐choice therapy (first‐line drug choice and appropriate duration); 77.6% ( n = 122,590) were treated with a recommended antibiotic choice and 65.9% ( n = 104,070) with a recommended duration. Age 18–49 years (aOR 1.07, 95% confidence interval [CI] 1.03–1.11) versus age ≥65 years was the only demographic factor predictive of recommended first‐choice therapy.
Conclusions
Nearly half of the patients included in this study did not receive recommended first‐choice therapies; however, racial and ethnic disparities were not identified. Underutilization of recommended first‐choice antibiotic therapy in complicated UTIs continues to be an area of focus for antimicrobial stewardship programs.
Background:
Stenotrophomonas maltophilia (S. maltophilia) is a nosocomial pathogen causing life-threatening invasive infections with a high mortality rate in some patient populations, especially those who are severely ill or immunocompromised. There is a need for data on mortality in patients with S. maltophilia bacteremia.
Objective:
In this meta-analysis, we aimed to investigate risk factors for mortality in S. maltophilia bacteremia.
Methods:
Studies comparing patients who died from S. maltophilia bacteremia with patients who survived were considered for inclusion. Studies were included if they reported one or more risk factors for mortality. Mortality risk factors included clinical predisposing factors, predisposing comorbidities and appropriateness of antibiotic therapy.
Results:
Nineteen studies with 1248 patients were included in the meta-analysis. Five hundred and six (40.5%) patients died. The following risk factors for mortality were identified: ICU admission, septic shock, need for mechanical ventilation, indwelling central venous catheter, neutropenia, comorbid hematological malignancies, chronic kidney disease, inappropriate antimicrobial therapy and prior antibiotic use.
Conclusions:
Appropriate antimicrobial therapy had a protective effect against mortality in S. maltophilia bacteremia. Indwelling central venous catheter, neutropenia, hematological malignancies and chronic kidney disease were also risk factors for mortality.
PURPOSE
High-dose methotrexate (HDMTX) is an antineoplastic dosing strategy used to treat various cancers including primary central nervous system lymphoma. Trimethoprim-sulfamethoxazole (TMP/SMX) is commonly used for antibiotic prophylaxis against Pneumocystis pneumonia infections in this patient population. Significant drug-drug interactions between TMP/SMX and methotrexate (MTX) leading to adverse outcomes have been documented, primarily in adult patients taking MTX for rheumatologic conditions.
METHODS
This study is a single-center, retrospective, cohort study comparing outcomes in patients where TMP/SMX was held during HDMTX and patients who received concurrent prophylactic TMP/SMX during treatment. The primary end point was mean MTX level at 24, 48, and 72 hours. Secondary end points included rate of nonhematologic toxicity, rate of hematologic toxicity, median days to MTX clearance, and frequency of glucarpidase utilization.
RESULTS
In total, 248 cycles of HDMTX were analyzed from 221 individual patients. One hundred ninety-one cycles were administered without prophylactic TMP/SMX, and 57 were administered with TMP/SMX. The median MTX level at 24, 48, and 72 hours in those without versus with prophylactic TMP/SMX was 4.30 versus 4.30, 0.29 versus 0.30, and 0.14 versus 0.15, respectively. Similarly, rates of hematologic and nonhematologic toxicities did not differ significantly between groups with the exception of neutropenia; however, there was no corresponding increased rate of neutropenic fever. Only one patient received glucarpidase and had not received TMP/SMX.
CONCLUSION
Prophylactic TMP/SMX had minimal interaction with HDMTX and does not lead to increased time to clearance or clinically relevant toxicities. Prophylactic TMP/SMX can be safely administered with HDMTX in adult patients.
Pneumocystis jirovecii is a ubiquitous opportunistic fungus that can cause life-threatening pneumonia. People with HIV (PWH) who have low CD4 counts are one of the populations at the greatest risk of Pneumocystis jirovecii pneumonia (PCP). While guidelines have approached the diagnosis, prophylaxis, and management of PCP, the numerous studies of PCP in PWH are dominated by the 1980s and 1990s. As such, most studies have included younger male populations, despite PCP affecting both sexes and a broad age range. Many studies have been small and observational in nature, with an overall lack of randomized controlled trials. In many jurisdictions, and especially in low- and middle-income countries, the diagnosis can be challenging due to lack of access to advanced and/or invasive diagnostics. Worldwide, most patients will be treated with 21 days of high-dose trimethoprim sulfamethoxazole, although both the dose and the duration are primarily based on historical practice. Whether treatment with a lower dose is as effective and less toxic is gaining interest based on observational studies. Similarly, a 21-day tapering regimen of prednisone is used for patients with more severe disease, yet other doses, other steroids, or shorter durations of treatment with corticosteroids have not been evaluated. Now with the widespread availability of antiretroviral therapy, improved and less invasive PCP diagnostic techniques, and interest in novel treatment strategies, this review consolidates the scientific body of literature on the diagnosis and management of PCP in PWH, as well as identifies areas in need of more study and thoughtfully designed clinical trials.
Background
Staphylococcus aureus bloodstream infection (bacteraemia) is traditionally treated with at least two weeks of IV antibiotics in adults, 3-7 days in children, and often longer for those with complicated disease. The current practice of treating S. aureus bacteraemia (SAB) with prolonged IV antibiotics (rather than oral antibiotics) is based on historical observational research and expert opinion. Prolonged IV antibiotic therapy has significant disadvantages for patients and healthcare systems, and there is growing interest in whether a switch to oral antibiotics following an initial period of IV therapy is a safe alternative for clinically stable patients.
Protocol
The early oral switch (EOS) domain of the S. aureus Network Adaptive Platform (SNAP) trial will assess early switch to oral antibiotics compared with continued IV treatment in clinically stable patients with SAB. The primary endpoint is 90-day all-cause mortality. Hospitalised SAB patients are assessed at platform day 7 +/- 2 (uncomplicated SAB) and day 14 +/-2 (complicated SAB) to determine their eligibility for randomisation to EOS (intervention) or continued IV treatment (current standard of care).
Discussion
Recruitment is occurring to the EOS domain of the SNAP trial. As of August 2023, 21% of all SNAP participants had been randomised to the EOS domain, a total of 264 participants across 77 centres, with an aim to recruit at least 1000 participants. We describe challenges and facilitators to enrolment in this domain to aid those planning similar trials.
Background:
Co-trimoxazole has been reported as a common culprit drug for various cutaneous adverse drug reactions (CADRs). However, information on genotypic and phenotypic characteristics is still limited. We aimed to study clinical characteristics, genetic suitability, laboratory findings, and treatment outcome in patients with co-trimoxazole-induced CADR and determine variables associated with severe cutaneous adverse reactions (SCARs).
Methods:
The medical records of all patients diagnosed with co-trimoxazole-induced CADR during October 2015 and October 2021 were reviewed. Clinical characteristics and laboratory investigation with an emphasis on HLA class I and HLA-DRB1 results linked to subtypes of cutaneous adverse reactions were evaluated.
Results:
Seventy-two patients diagnosed with co-trimoxazole-induced CADR were included in the study. Mean age at diagnosis was 38.0±14.6 years old, and 72% were female. Subtypes of reactions included maculopapular eruption (MPE; 56.9%), drug reaction with eosinophilia and systemic symptoms (DRESS; 23.6%), Stevens-Johnson syndrome (SJS; 12.5%), fixed drug eruption (4.2%), and urticaria (2.8%). Characteristics that were significantly associated with SCARs included male gender (OR=3.01, 95%CI 1.04-8.75), HIV infection (OR=3.48, 95%CI 1.13-10.75), prophylactic use of co-trimoxazole (OR=4.89, 95%CI 1.54-15.57), and co-trimoxazole administration longer than 10 days (OR=7.65, 95%CI 2.57-22.78). HLA-B*38:02 was associated with co-trimoxazole-induced SJS, while HLA-A*11:01, HLA-B*13:01, and HLA-DRB1*12:01 were associated with co-trimoxazole-induced DRESS. HLA-B*52:01 was associated with co-trimoxazole-induced MPE.
Conclusions:
Co-trimoxazole could induce various phenotypes of CADRs. Genotypic and phenotypic factors that may potentially predict co-trimoxazole-induced SCARs include male gender, HIV infection, prophylactic and prolonged drug use, as well as the presence of HLA-A*11:01, HLA-B*13:01, HLA-B*38:02, or HLA-DRB1*12:01 alleles.
Abstract IntroductionPresent day medical treatment often involves a polytherapeutic approach whereby patients receive several medications from multiple physicians, thereby risking adverse drug interactions. Checking for possible drug interactions in a busy clinical setting poses a challenge due to the time pressures of modern medical practice. Otolaryngologists and rhinology sub-specialists receive very little education in drug interactions, and easy to use reference materials are not readily available in most ENT offices. In this manuscript, we review potential drug interactions for one of the most commonly prescribed classes of medication that ENT specialists prescribe, antibiotics. We provide a practical reference for general otolaryngologists and rhinologists to utilize in their busy modern day clinical practices. Methods/ResultsDrug interactions for commonly prescribed antibiotics in ENT/rhinology practice were identified using PubMed and Cochrane Library database to search for articles published from inception until December 31, 2022. Full-text articles were reviewed to identify drug combinations that present risk and to identify specific management recommendations to reduce potential harm. DiscussionNumerous drug-drug interactions exist between antibiotics and other commonly prescribed medications. These interactions can potentially lead to the development of toxic levels of a drug and harm. We provide an easily accessible summary of these interactions and management considerations that would allow ENTs/rhinologists to screen for these potential sources of harm in their busy clinical practices.
Abstract IntroductionPresent day medical treatment often involves a polytherapeutic approach whereby patients receive several medications from multiple physicians, thereby risking adverse drug interactions. Checking for possible drug interactions in a busy clinical setting poses a challenge due to the time pressures of modern medical practice. Otolaryngologists and rhinology sub-specialists receive very little education in drug interactions, and easy to use reference materials are not readily available in most ENT offices. In this manuscript, we review potential drug interactions for one of the most commonly prescribed classes of medication that ENT specialists prescribe, antibiotics. We provide a practical reference for general otolaryngologists and rhinologists to utilize in their busy modern day clinical practices. Methods/ResultsDrug interactions for commonly prescribed antibiotics in ENT/rhinology practice were identified using PubMed and Cochrane Library database to search for articles published from inception until December 31, 2022. Full-text articles were reviewed to identify drug combinations that present risk and to identify specific management recommendations to reduce potential harm. DiscussionNumerous drug-drug interactions exist between antibiotics and other commonly prescribed medications. These interactions can potentially lead to the development of toxic levels of a drug and harm. We provide an easily accessible summary of these interactions and management considerations that would allow ENTs/rhinologists to screen for these potential sources of harm in their busy clinical practices.
Antibiotic chemotherapy is widely regarded as one of the most significant medical advancements in history. However, the continued misuse of antibiotics has contributed to the rapid rise of antimicrobial resistance (AMR) globally. Staphylococcus aureus, a major human pathogen, has become synonymous with multidrug resistance and is a leading antimicrobial-resistant pathogen causing significant morbidity and mortality worldwide. This review focuses on (1) the targets of current anti-staphylococcal antibiotics and the specific mechanisms that confirm resistance; (2) an in-depth analysis of recently licensed antibiotics approved for the treatment of S. aureus infections; and (3) an examination of the pre-clinical pipeline of anti-staphylococcal compounds. In addition, we examine the molecular mechanism of action of novel antimicrobials and derivatives of existing classes of antibiotics, collate data on the emergence of resistance to new compounds and provide an overview of key data from clinical trials evaluating anti-staphylococcal compounds. We present several successful cases in the development of alternative forms of existing antibiotics that have activity against multidrug-resistant S. aureus. Pre-clinical antimicrobials show promise, but more focus and funding are required to develop novel classes of compounds that can curtail the spread of and sustainably control antimicrobial-resistant S. aureus infections.
Prodrug strategy is critical for innovative drug development. Structural modification is the most straightforward and effective method to develop prodrugs. Improving drug defects and optimizing the physical and chemical properties of a drug, such as lipophilicity and water solubility, changing the way of administration can be achieved through specific structural modification. Designing prodrugs by linking microenvironment-responsive groups to the prototype drugs is of great help in enhancing drug targeting. In the meantime, making connections between prodrugs and suitable drug delivery systems could realize drug loading increases, greater stability, bioavailability and drug release control. In this paper, lipidic, water-soluble, pH-responsive, redox-sensitive and enzyme-activatable prodrugs are reviewed on the basis of structural modification.
Stenotrophomonas maltophilia is a Gram-negative opportunistic pathogen that can cause serious infection. We aimed to analyze the prevalence and susceptibility rates to trimethoprim/sulfamethoxazole of S. maltophilia. We conducted a retrospective study of S. maltophilia isolates from a university hospital from 2001 to 2020. Clinical information, the numbers of isolates and susceptibility rates were analyzed by year. Susceptibility rates and changes in respiratory and non-respiratory samples were compared. 1805 S. maltophilia isolates were identified, of which 81.4% (1469/1805) were from respiratory samples. There was a male predominance and 52% of the isolates were from general wards. The average susceptibility rate was 87.7% and there was no significant annual trend (P = .519). The susceptibility rate was 88.7% in respiratory samples and 84.1% in non-respiratory samples (P = .018). Susceptibility analyses using clinical data over long periods can guide the choice of antimicrobials especially for pathogen whose treatment options are limited.
Objectives
This study evaluated the clinical outcomes associated with use of highly bioavailable oral antibiotics (fluoroquinolones and trimethoprim-sulfamethoxazole) compared to less bioavailable oral antibiotics (beta-lactams) in Gram negative bloodstream infections (BSIs).
Methods
Among hospitalized older adult patients in Ontario, Canada, discharged home on oral treatment for Gram negative BSI between January 1, 2017, and December 31, 2019, we utilized a matched cohort design to compare outcomes among those receiving highly versus less bioavailable agents; hard-matching 1:1 on sex, BSI pathogen (Escherichia coli vs non-E. coli), and infection source (urinary vs. non-urinary/unknown source) along with a propensity score, incorporating specific pathogen, patient, and infection characteristics. The primary outcome was the composite of 90-day all-cause mortality, recurrent BSI with the same pathogen (genus and species), and re-admission to any Ontario hospital.
Results
A total of 2,012 patients were included in the study (1006 in each bioavailability category). Those who at discharge, received highly (compared to less) bioavailable antibiotics had lower rates of the composite outcome (171/1006 (17.0%) vs 216/1006 (21.5%), adjusted odds ratio (aOR) 0.74 (95% CI, 0.60 – 0.92). Recurrent BSI at 90 days was the main driver for the composite outcome occurring in 64 (5.4%) and 107 (9.4%) of the highly and less bioavailable group, respectively (p <0.001) (aOR 0.56 (95% CI, 0.40 – 0.78).
Conclusions
Use of highly (compared to less) bioavailable antibiotics at discharge was associated with significantly better clinical outcomes among patients with Gram negative BSIs.
The objective of this study was to evaluate whether orally administered anti-infectives increase the risk of severe hypoglycemia in users of glipizide or glyburide. We performed two case-control studies and two case-crossover studies using US Medicaid data. All the anti-infectives examined were associated with an elevated risk of severe hypoglycemia. Using cephalexin as the reference category, in glipizide users, statistically significant associations were found with co-trimoxazole (odds ratio (OR) = 3.14; 95% confidence interval (CI): 1.83-5.37); clarithromycin (OR = 2.90; 95% CI: 1.69-4.98); fluconazole (OR = 2.53; 95% CI: 1.23-5.23); and levofloxacin (OR = 2.09; 95% CI: 1.35-3.25). In glyburide users, with cephalexin as the reference, statistically significant associations were found with clarithromycin (OR = 5.02; 95% CI: 3.35-7.54); levofloxacin (OR = 2.83; 95% CI: 1.73-4.62); co-trimoxazole (OR = 2.68; 95% CI: 1.59-4.52); fluconazole (OR = 2.20; 95% CI: 1.04-4.68); and ciprofloxacin (OR = 2.08; 95% CI: 1.23-3.52). In conclusion, exposure to all studied anti-infective agents were associated with subsequent severe hypoglycemia. Using cephalexin as the reference, drug-drug interactions were evident with ciprofloxacin (in glyburide users only), clarithromycin, co-trimoxazole, fluconazole, and levofloxacin.
To develop recommendations for the use of methotrexate (MTX) in patients with rheumatoid arthritis.
Canadian rheumatologists who participated in the international 3e Initiative in Rheumatology (evidence, expertise, exchange) in 2007-2008 formulated 5 unique Canadian questions. A bibliographic team systematically reviewed the relevant literature on these 5 topics. An expert committee consisting of 26 rheumatologists from across Canada was convened, and a set of recommendations was proposed based on the results of systematic reviews combined with expert opinions using a nominal group consensus process.
The 5 questions addressed drug interactions, predictors of response, strategies to reduce non-serious side effects, variables to assess clinical response, and incorporating patient preference into decision-making. The systematic review retrieved 93 pertinent articles; this evidence was presented to the expert committee during the interactive workshop. After extensive discussion and voting, a total of 9 recommendations were formulated: 2 on drug interactions, 1 on predictors of response, 2 on strategies to reduce non-serious side effects, 3 on variables to assess clinical response, and 1 on incorporating patient preferences into decision-making. The level of evidence and the strength of recommendations are reported. Agreement among panelists ranged from 85% to 100%.
Nine recommendations pertaining to the use of MTX in daily practice were developed using an evidence-based approach followed by expert/physician consensus with high level of agreement.
To report a case of clinically significant hypoglycemia attributed to the concomitant use of trimethoprim/sulfamethoxazole (TMP/SMX) and repaglinide by a diabetic patient.
A 76-year-old diabetic patient with impaired renal function and no history of hypoglycemia was receiving treatment with repaglinide 1 mg 3 times daily. Five days after TMP/SMX therapy was started for a urinary tract infection, the man developed symptomatic hypoglycemia. Repaglinide and TMP/SMX were stopped and intravenous D-glucose was administered to normalize glucose levels. Repaglinide, but not TMP/SMX, was reintroduced 5 days later and no other hypoglycemic episode occurred. Objective causality assessments revealed that the interaction was probable (World Health Organization-Uppsala Monitoring Centre) or possible (Horn Drug Interaction Probability Scale).
This interaction between TMP/SMX and repaglinide was predictable according to available pharmacokinetic data in healthy subjects. Trimethoprim induced CYP2C8 inhibition, thus increasing the plasma concentration of repaglinide. This interaction is mentioned in the repaglinide product information. To our knowledge, however, no case of symptomatic hypoglycemia associated with a combination of repaglinide and trimethoprim has been described before. This discrepancy may be explained by the subtherapeutic dosage used in the pharmacokinetic study. Moreover, our patient had impaired renal function, which may have led to trimethoprim accumulation and potentiated its interaction with repaglinide. A direct lowering of blood glucose levels due to sulfamethoxazole, also potentiated by renal failure, could also be involved in triggering hypoglycemia.
This interaction between TMP/SMX and repaglinide may have involved inhibition of CYP2C8 by trimethoprim. Clinicians should be aware that this association may lead to symptomatic hypoglycemia, particularly in patients with renal dysfunction.
There are few Canadian studies that have assessed prescribing patterns and antibiotic preferences of physicians for acute uncomplicated cystitis. A cross-Canada study of adult women with symptoms of acute cystitis seen by primary care physicians was conducted to determine current management practices and first-line antibiotic choices.
A random sample of 2000 members of The College of Family Physicians of Canada were contacted in April 2002, and were asked to assess two women presenting with new urinary tract symptoms. Physicians completed a standardized checklist of symptoms and signs, indicated their diagnosis and antibiotics prescribed. A urine sample for culture was obtained.
Of the 418 responding physicians, 246 (58.6%) completed the study and assessed 446 women between April 2002 and March 2003. Most women (412 of 420, for whom clinical information about antibiotic prescriptions was available) reported either frequency, urgency or painful urination. Physicians would have usually ordered a urine culture for 77.0% of the women (95% CI 72.7 to 80.8) and prescribed an antibiotic for 86.9% of the women (95% CI 83.3 to 90.0). The urine culture was negative for 32.8% of these prescriptions. The most commonly prescribed antibiotic was trimethoprim/sulfamethoxazole (40.8%; 95% CI 35.7 to 46.1), followed by fluoroquinolones (27.4%; 95% CI 22.9 to 32.3) and nitrofurantoin (26.6%; 95% CI 22.1 to 31.4).
Empirical antibiotic prescribing is standard practice in the community, but is associated with high levels of unnecessary antibiotic use. While trimethoprim/sulfamethoxazole is the first-line empirical antibiotic choice, fluoroquinolone antibiotics have become the second most commonly prescribed empirical antibiotic for acute cystitis. The effect of current prescribing patterns on community levels of quinolone-resistant Escherichia coli may need to be monitored.
The aim of this study was to determine whether a potential pharmacokinetic interaction between warfarin and orally administered anti-infectives increases the risk of hospitalization for gastrointestinal (GI) bleeding in warfarin users. We conducted a nested case-control and case-crossover study using US Medicaid data. Logistic regression was used to determine the association between GI bleeding and prior use of ciprofloxacin, levofloxacin, gatifloxacin, co-trimoxazole, or fluconazole vs. no exposure and also vs. use of cephalexin, which would not be expected to interact with warfarin. All of the anti-infectives examined were associated with elevated odds ratios (ORs) when compared to no exposure to these drugs. With cephalexin data as the reference, the ORs for co-trimoxazole (OR: 1.68 (95% confidence interval (CI): 1.21-2.33) in the prior 6-10 days) and fluconazole (OR: 2.09 (95% CI: 1.34-3.26) in the prior 11-15 days) were significantly elevated. Warfarin users who had received an anti-infective agent showed a substantially increased risk of GI bleeding. However, a drug-drug interaction with warfarin was evident only for co-trimoxazole and fluconazole.
The optieal enantiomorphs of warfarin were studied in 10 normal sub;ects. Eaeh sub;ect was given in separate experiments a single oral dose of R(+) warfarin, S(-) warfarin, and the racemate, R,S(±) warfarin, in the amount of 1.5 mg of drug per kilogram of body weight. The biologie half-life for (+) warfarin, (-) warfarin, and raeemie warfarin was 58 ± 5, 33 ± 4, and 42 ± 2 hours, respeetively, a highly significant differenee (p < 0.01) between the enantiomorphs. The blood level of drug for (+) warfarin was 94% greater than that tor (-) warfarin. The area under the pro thrombin time curve plotted logarithmically showed a 76% greater effect for (-) warfarin than for (+) warfarin. Thus, the intrinsic activity of (-) warfarin was 3.4 times as great as thot of (+) warfarin in the induction of hypoprothrombinemia. A high degree of direct correlation was found between the area for the blood level of drug and the hypoprothrombinemic effect for both the (+) and (-) warfarin enantiomorphs. It is concluded that the greater intrinsic activity of (-) warfarin than (+) warfarin does not result primarily from the blood level of the enantiomorphs but may result from a difference in permeability or affinity for the receptor site.
LactMed, released in the spring of 2006, is a new peer-reviewed database from the Specialized Information Services division of the National Library of Medicine that is accessible free of charge through the TOXNET suite of databases. As its name indicates, Lact-Med provides information on medicines used during lactation along with data on the levels of these drugs in breast milk and infant blood, the potential effects on the breastfed infants, and possible alternatives to these drugs.
The following is a summary of selected sections (focusing on updates) of the OI Prevention and Treatment Guidelines. The clinician is encouraged to download the full set of PCP Prophylaxis and Pregnancy: Chemoprophylaxis for PCP should be administered to pregnant women as is done for other adults and adolescents. TMP-SMX is the recommended prophylactic agent; dapsone is an alternative. Because of theoretical concerns regarding possible teratogenicity associated with drug exposures during the first trimester, aerosolized pentamidine can be considered because of its lack of systemic absorption and the resultant lack of exposure of the developing embryo to the drug. Toxoplasma gondii Encephalitis (TE): Prevention of Exposure: HIV-infected persons should be tested for IgG antibody to Toxoplasma soon after the diagnosis of HIV infection to detect latent infection with T. gondii.
Objective:
To study human teratogenic potential of two trimethoprim-sulfonamide combinations: trimethoprim-sulfamethoxazole (cotrimoxazole) and trimethoprim-sulfamethazine during pregnancy. These agents have antifolate effects and other antifolate agents can induce multiple congenital abnormalities, neural-tube defects, cardiovascular, and other malformations in animal experiments and in humans.
Design:
Pair analysis of cases with congenital abnormalities and matched healthy controls in the large population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities between 1980 and 1996.
Participants:
38,151 pregnant women who had newborn infants without any congenital abnormalities (control group) and 22,865 case pregnant women who had newborns or fetuses with congenital abnormalities.
Main outcome:
Prevalence of drug use in matched case-control pairs to study the possible association with congenital abnormalities.
Results:
In the case group 351 (1.5%) and in the control group 443 (1.2%) pregnant women were treated with cotrimoxazole (crude OR 1.3 with 95% CI 1.1-1.5). In addition 45 (0.2%) case and 39 (0.1%) control pregnant women had trimethoprim-sulfamethazine treatment (crude OR 1.9 with 95% CI 1.3-3.0). A higher rate of multiple congenital abnormalities (including mainly urinary tract and cardiovascular abnormalities) was found in case infants born to mothers with cotrimoxazole treatment during the second-third months of pregnancy. In addition, a higher rate of cardiovascular malformations occurred in cases born to mothers with cotrimoxazole treatment and trimethoprim-sulfamethazine treatment during the second-third months of pregnancy, respectively.
Conclusion:
Treatment with cotrimoxazole during pregnancy may increase the risk of cardiovascular malformations, and particularly multiple congenital abnormalities including defects of the urinary tract and cardiovascular system. A higher rate of cardiovascular malformations was also found after treatment with trimethoprim-sulfamethazine in the second-third months of pregnancy.
To determine the association between anti-infective exposure during the last two trimesters of pregnancy and the risk of small-for-gestational-age (SGA) newborns.
Case-control study within the Québec Pregnancy Registry.
Province of Québec, Canada.
Analyses were performed on prospectively collected data of 63,338 pregnant women that met eligibility criteria for the study (8192 cases and 55,146 controls).
Unconditional logistic regression models were used to quantify the association between exposure to anti-infective drugs and the risk of SGA.
A case of SGA was defined as a pregnancy resulting in a baby that weighs below the tenth percentile, adjusted for gestational age and gender, according to the Canadian gender-specific reference curves. A control was defined as a pregnancy resulting in a baby that weighs greater or equal to the tenth percentile, adjusted for gestational age and gender.
Exposure to all combined anti-infective drugs was not associated with the risk of SGA (OR 0.97; 95% CI 0.91-1.04). The use of sulfamethoxazole/trimethoprim was associated with SGA (OR 1.61; 95% CI 1.16-2.23), whereas the use of urinary anti-infective drugs decreased the risk (OR 0.80; 95% CI 0.65-0.97).
Exposure to sulfamethoxazole/trimethoprim during the last two trimesters of pregnancy was associated with SGA. Further research is needed to address the use of other therapeutic alternatives in the management of infections that predispose infants being born SGA in pregnant women with other risk factors for this condition.
Pharmacokinetic studies suggest that trimethoprim (TMP) can inhibit the hepatic metabolism of phenytoin, but the clinical relevance of this is uncertain. We studied the risk of phenytoin toxicity following the prescription of trimethoprim/sulfamethoxazole (TMP/SMX), a commonly used antibiotic, among elderly patients receiving phenytoin.
We conducted a population-based, nested case-control study of a cohort of Ontario residents aged 66 years of age or older treated with phenytoin over a 17-year period (April 1 1992 to March 31 2009). Within this group, case patients were those hospitalized with phenytoin toxicity. For each case, we identified up to four control patients from the same cohort, matched for age and sex, and determined the odds ratio (OR) for the association between phenytoin toxicity and receipt of TMP/SMX in the preceding 30 days.
Among 58 429 elderly patients receiving phenytoin during the study period, we identified 796 case patients hospitalized for phenytoin toxicity and 3148 matched controls. Following multivariable adjustment for potential confounders, we observed a more than doubling of the risk of phenytoin toxicity following the receipt of TMP/SMX [adjusted OR 2.11, 95% confidence interval (CI) 1.24, 3.60]. In contrast, we observed no such risk with amoxicillin, an antibiotic with similar indications but not expected to interact with phenytoin (adjusted OR 1.12, 95% CI 0.64, 1.98).
Among older patients receiving phenytoin, treatment with TMP/SMX is associated with a more than twofold increase in the risk of phenytoin toxicity. When clinically appropriate, alternate antibiotics should be considered for these patients.
Trimethoprim therapy can cause hyperkalemia and is often coprescribed with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). The objective of this study was to characterize the risk of hyperkalemia-associated hospitalization in elderly patients who were being treated with trimethoprim-sulfamethoxazole along with either an ACEI or an ARB.
We conducted a population-based, nested case-control study of a cohort of elderly patients 66 years or older who were residents of Ontario, Canada, and who were receiving continuous therapy with either an ACEI or an ARB. Case patients were those with a hyperkalemia-associated hospitalization within 14 days of receiving a prescription for trimethoprim-sulfamethoxazole, amoxicillin, ciprofloxacin, norfloxacin, or nitrofurantoin. For each case, we identified up to 4 control patients from the same cohort matched for age, sex, and presence or absence of chronic renal disease and diabetes. Odds ratios were determined for the association between hyperkalemia-associated hospitalization and previous antibiotic use.
During the 14-year study period, we identified 4148 admissions involving hyperkalemia, 371 of which occurred within 14 days of antibiotic exposure. Compared with amoxicillin, the use of trimethoprim-sulfamethoxazole was associated with a nearly 7-fold increased risk of hyperkalemia-associated hospitalization (adjusted odds ratio, 6.7; 95% confidence interval, 4.5-10.0). No such risk was found with the use of comparator antibiotics.
Among older patients treated with ACEIs or ARBs, the use of trimethoprim-sulfamethoxazole is associated with a major increase in the risk of hyperkalemia-associated hospitalization relative to other antibiotics. Alternate antibiotic therapy should be considered in these patients when clinically appropriate.
Patients with rheumatoid arthritis (RA) often have comorbidities that require multiple medications. Several of these medications may alter the efficacy or increase the toxicity of methotrexate (MTX). The purpose of our study was to determine which drugs used in combination with MTX (excluding disease modifying antirheumatic drugs, folic and folinic acid, corticosteroids, and biologic agents) enhance side effects or toxicity of MTX or lower its efficacy.
A systematic literature search was performed with Medline, Embase, Cochrane Register and Database, and abstracts from the 2006/2007 annual congresses of the American College of Rheumatology and the European League Against Rheumatism. A manual search of the citation lists of retrieved publications was performed.
Of the 1172 articles identified, 67 were included: 21 pharmacokinetics studies, 5 observational studies, and 78 case reports. Most medications do not significantly affect the pharmacokinetics profile of MTX. Among the clinical studies, cytopenia and elevation of liver enzymes were the main reported toxicities. The use of trimethoprim-sulfamethoxazole (TMP-SMX) was mentioned as a risk factor for developing cytopenia in one observational study and in 17 case reports. Thirty case reports of cytopenia were attributed to the use of concomitant nonsteroidal antiinflammatory drugs, including acetylsalicylic acid. Two studies described mild abnormalities of liver enzymes with the use of isoniazid, and one study with the use of high-dose ASA.
Based on the published literature, MTX has limited drug interactions, with the exception of TMP-SMX and high-dose ASA, which can exacerbate toxicity of MTX. The clinical significance of these interactions has not been substantiated by extensive clinical observations.
Some antibiotic agents, including cotrimoxazole, inhibit the metabolism of warfarin sodium and possibly increase the risk of hemorrhage. We examined the risk of upper gastrointestinal (UGI) tract hemorrhage in older patients receiving warfarin in combination with antibiotics commonly used to treat urinary tract infection, with a focus on cotrimoxazole.
This population-based, nested case-control study using health care databases in Ontario, Canada, between April 1, 1997, and March 31, 2007, identified residents 66 years or older who were continuously treated with warfarin. Cases were hospitalized with UGI tract hemorrhage. For each case, we selected up to 10 age- and sex-matched control subjects. We calculated adjusted odds ratios (aORs) for exposure to cotrimoxazole, amoxicillin trihydrate, ampicillin trihydrate, ciprofloxacin hydrochloride, nitrofurantoin, and norfloxacin within 14 days before the UGI tract hemorrhage.
We identified 134 637 patients receiving warfarin, of whom 2151 cases were hospitalized for UGI tract hemorrhage. Cases were almost 4 times more likely than controls to have recently received cotrimoxazole (aOR, 3.84; 95% confidence interval [CI], 2.33-6.33). Treatment with ciprofloxacin was also associated with increased risk (aOR, 1.94; 95% CI, 1.28-2.95), but no significant association was observed with amoxicillin or ampicillin (1.37; 0.92-2.05), nitrofurantoin (1.40; 0.71-2.75), or norfloxacin (0.38; 0.12-1.26). Compared with amoxicillin or ampicillin, cotrimoxazole prescription was associated with an almost 3-fold risk (ratio of ORs, 2.80; 95% CI, 1.48-5.32).
Among older patients receiving warfarin, cotrimoxazole is associated with a significantly higher risk of UGI tract hemorrhage than other commonly used antibiotics. Whenever possible, clinicians should prescribe alternative antibiotics in patients receiving warfarin.
This report updates and combines earlier versions of guidelines for the prevention and treatment of opportunistic infections (OIs) in HIV-infected adults (i.e., persons aged >/=18 years) and adolescents (i.e., persons aged 13--17 years), last published in 2002 and 2004, respectively. It has been prepared by the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), and the HIV Medicine Association (HIVMA) of the Infectious Diseases Society of America (IDSA). The guidelines are intended for use by clinicians and other health-care providers, HIV-infected patients, and policy makers in the United States. These guidelines address several OIs that occur in the United States and five OIs that might be acquired during international travel. Topic areas covered for each OI include epidemiology, clinical manifestations, diagnosis, prevention of exposure; prevention of disease by chemoprophylaxis and vaccination; discontinuation of primary prophylaxis after immune reconstitution; treatment of disease; monitoring for adverse effects during treatment; management of treatment failure; prevention of disease recurrence; discontinuation of secondary prophylaxis after immune reconstitution; and special considerations during pregnancy. These guidelines were developed by a panel of specialists from the United States government and academic institutions. For each OI, a small group of specialists with content-matter expertise reviewed the literature for new information since the guidelines were last published; they then proposed revised recommendations at a meeting held at NIH in June 2007. After these presentations and discussion, the revised guidelines were further reviewed by the co-editors; by the Office of AIDS Research, NIH; by specialists at CDC; and by HIVMA of IDSA before final approval and publication. The recommendations are rated by a letter that indicates the strength of the recommendation and a Roman numeral that indicates the quality of evidence supporting the recommendation, so that readers can ascertain how best to apply the recommendations in their practice environments. Major changes in the guidelines include 1) greater emphasis on the importance of antiretroviral therapy for the prevention and treatment of OIs, especially those OIs for which no specific therapy exists; 2) information regarding the diagnosis and management of immune reconstitution inflammatory syndromes; 3) information regarding the use of interferon-gamma release assays for the diagnosis of latent Mycobacterium tuberculosis (TB) infection; 4) updated information concerning drug interactions that affect the use of rifamycin drugs for prevention and treatment of TB; 5) the addition of a section on hepatitis B virus infection; and 6) the addition of malaria to the list of OIs that might be acquired during international travel. This report includes eleven tables pertinent to the prevention and treatment of OIs, a figure that pertains to the diagnois of tuberculosis, a figure that describes immunization recommendations, and an appendix that summarizes recommendations for prevention of exposure to opportunistic pathogens.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and severe cutaneous adverse reactions to medications and infections.
We sought to determine whether a seasonal variation to SJS and TEN exists and to define the characteristics in our tertiary referral hospital.
A retrospective chart review of 50 patients from 1995 through 2007 was performed and statistically analyzed.
The most common medication implicated as a cause of SJS/TEN was trimethoprim-sulfamethoxazole (TMX) (26%). A seasonal trend, favoring springtime, was observed for the total number of cases of SJS and TEN (P = .34). There was a significant increase in cases due to TMX (53%) occurring in spring compared to other seasons (P = .002). These patients were significantly younger (37.8 +/- 13.7) than other patients with SJS and TEN (53.7 +/- 16.4) (P = .003). Their overall mortality (1 death) and average SCORTEN value (1.62 +/- 1.6) was also significantly lower (P = .04 and 0.03, respectively). Based on outpatient pharmacy records, there was no increase in TMX prescriptions filled during the spring.
The study was limited by reliance on chart data, the use of inpatient records, and number of patients.
A seasonal variation in SJS and TEN caused by TMX affecting younger patients may exist.
To report a case of probable trimethoprim/sulfamethoxazole (TMP/SMX)-induced higher-level gait disorder (HLGD) and nocturnal delirium in an elderly patient on high-dose oral therapy.
An 82-year-old man with a recent history of depression became comatose following an overdose of escitalopram and oxazepam. He was admitted, ventilated for 7 days in the intensive care unit, and treated with piperacillin/tazobactam and cefepime for aspiration pneumonia. Following discharge to a medical ward, respiratory symptoms persisted and imaging confirmed pulmonary abscesses. Stenotrophomonas maltophilia was isolated from sputum and, on day 15, TMP/SMX 800 mg/160 mg 1 tablet every 12 hours was initiated. On day 35, the dose was increased to 800 mg/160 mg 2 tablets every 12 hours. By day 37, the patient was unsteady when attempting to stand. From day 40, he was noted to have features of HLGD with gait ignition failure, poor balance, and frequent falls. His other medications at this time were thiamine 100 mg daily, multivitamin 1 tablet daily, omeprazole 20 mg every 12 hours, and modified-release venlafaxine 150 mg daily. Investigation did not reveal any cause for his acute gait disturbance. TMP/SMX was stopped on day 48 and, by day 51, the patient's gait had returned to normal.
Neuropsychiatric adverse reactions with TMP/SMX have been infrequently reported. The Naranjo probability scale indicated that TMP/SMX was the probable cause of HLGD in this patient.
At time of writing, this was the first reported case of HLGD associated with TMP/SMX. Clinicians should consider this adverse reaction as a potential cause of HLGD, especially in the elderly and those with malnutrition and hepatic or renal dysfunction.
Diminished survival of transfused platelets occurred in two patients given co-trimoxazole, and a third patient taking this drug developed thrombocytopenia. By means of an indirect immunofluorescence assay antibodies against donor platelets coated with co-trimoxazole were found in the sera in all cases. These antibodies were directed against the trimethoprim component of co-trimoxazole and not against sulphamethoxazole. Co-trimoxazole is a potent antimicrobial agent and is advocated for treatment and prophylaxis in leukaemia. Hence its adverse effect on platelets is of great importance.
The efficacy and possible adverse reactions of co-trimoxazole in the treatment of typhoid fever with G-6-PD deficiency were investigated in 68 typhoid children aged 2 to 14 years old. Salmonella typhi was isolated from 45 patients but all had a significant rise of Widal agglutinin titres during the course of the disease. Decrease in G-6-PD activity of the red blood cells was found in 37 out of 51 patients tested. A daily dose of 6--10 mg of trimethoprim plus 30--50 mg of sulfamethoxazole per kg body weight was given for 14 days. Patients with G-6-PD deficiency were closely observed for evidence of intravascular hemolysis. All patients responded well and the mean period of defervescence after starting therapy was approximately 8 days. One patient with G-6-PD deficiency developed acute hemolysis on the second day of medication. The hemolytic symptoms subsided within 14 days with the continuation of co-trimoxazole therapy. No other major side-effect of the drug was observed. It is concluded that co-trimoxazole can be used successfully in the treatment of typhoid fever in G-6-PD deficient children with little risk of serious adverse reaction.
Because trimethoprim-sulfamethoxazole (TMP-SMX) causes neutropenia in children with leukemia, we investigated the possibility that pharmacokinetic interaction between methotrexate (MTX) and TMP-SMX causes accumulation of the antileukemia agent. We studied the pharmacokinetics of MTX given intravenously or orally to nine children with acute lymphoblastic leukemia, once with and once without TMP-SMX. There was an increase in free MTX fraction during TMP-SMX therapy in all patients, from (mean +/- SD) 37.4 +/- 11% without TMP-SMX to 52.2 +/- 6.4% with TMP-SMX (p less than 0.01). Plasma clearance of total MTX did not change significantly, whereas clearance of free MTX decreased significantly (from 12.5 +/- 4 to 7.6 +/- 1.5 ml/kg/min; p less than 0.05). There was a consistent decrease in the renal clearance of free MTX (from 12.1 +/- 6.8 to 5.6 +/- 2.4 ml/kg/min; p less than 0.05). Elimination half-life of MTX was not affected significantly by TMP-SMX. There was a significant correlation between serum concentrations of TMP-SMX and the percentage of decrease in the renal clearance of free MTX (r = 0.91; p less than 0.05). These changes in protein binding and tubular clearance of MTX, caused by competition with TMP-SMX, result in a mean 66% increase in systemic exposure to MTX and may explain the myelotoxicity often observed with the coadministration of the two drugs.
During the 10-year period 1976-1985, a total of 154 cases of blood dyscrasia were reported in Sweden which were evaluated as having a probable or possible causal relationship with trimethoprim-sulphamethoxazole (T-SM). There were 61 cases of leucopenia (of which 16 had agranulocytosis), 28 cases of thrombocytopenia, and two of non-haemolytic anaemia. There were also 32 cases of bicytopenia and 31 cases of tricytopenia. The median age varied from 38 years in the leucopenia group to 81 years in those with tricytopenia. The overall fatality rate was 17%, ranging from 2% in the group with mild leucopenia to 52% in the group with tricytopenia. In relation to sales and prescription data, the overall incidence of reported T-SM blood dyscrasias was 5.3 per million defined daily doses, and among out-patients the incidence was one case per 18,000 prescriptions. Thus the overall incidence of any blood reaction to T-SM appears to be low. In relation to prescription data, elderly people were overrepresented among the serious reactions.
Sulfonamides have been reported to augment the hypoglycemic effects of chlorpropamide, glyburide, and tolbutamide. This case report is the first to describe a possible interaction with glipizide. An 83-year-old man receiving glipizide 10 mg bid developed symptomatic hypoglycemia within three days of adding trimethoprim/sulfamethoxazole (TMP/SMX) to his regimen. All other factors, including laboratory data, dietary intake, activity level, and concurrent use of other medications, were stable and noncontributory. This patient may have been at increased risk for this interaction secondary to his age and history of alcohol abuse. The mechanism of the interaction is probably inhibition of glipizide metabolism rather than protein-binding displacement. This case suggests that, when TMP/SMX is combined with glipizide, patients should be closely monitored, especially those at high risk for hypoglycemia.
Antimicrobial drugs that can be taken orally are needed for the treatment of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome (AIDS). Preliminary data indicate that dapsone with trimethoprim may be an effective alternative to trimethoprim-sulfamethoxazole, which is frequently toxic.
In a double-blind trial, 60 patients with AIDS and mild-to-moderately-severe first episodes of P. carinii pneumonia (partial pressure of oxygen in arterial blood, greater than 60 mm Hg while breathing room air) were randomly assigned to 21 days of treatment with either trimethoprim-sulfamethoxazole (20 and 100 mg per kilogram of body weight per day, respectively) or trimethoprim-dapsone (20 mg per kilogram per day and 100 mg per day).
The orally administered treatment failed because of progressive pneumonitis in 3 of the 30 patients assigned to trimethoprim-sulfamethoxazole and in 2 of the 30 assigned to trimethoprim-dapsone (P greater than 0.3). Major toxic effects required a switch to intravenous pentamidine for 17 patients (57 percent) in the trimethoprim-sulfamethoxazole group, as compared with 9 (30 percent) in the trimethoprim-dapsone group (P less than 0.025). With trimethoprim-sulfamethoxazole, there were more instances of severe chemical hepatitis (six, as compared with one in the trimethoprim-dapsone group) and marked neutropenia (five vs. one). Intolerable rash (three in each treatment group) and severe nausea and vomiting (two in each group) occurred with equal frequency with both drug combinations. Methemoglobinemia occurred in most of the patients treated with trimethoprim-dapsone, but it was asymptomatic and the level exceeded 20 percent in only one patient. Mild hyperkalemia (serum potassium level, 5.1 to 6.1 mmol per liter) also occurred in 53 percent of the patients treated with trimethoprim-dapsone.
In patients with AIDS, oral therapy with trimethoprim-sulfamethoxazole and with trimethoprim-dapsone are equally effective for mild-to-moderate first episodes of P. carinii pneumonia, but with trimethoprim-dapsone there are fewer serious adverse reactions than with trimethoprim-sulfamethoxazole.
The steady-state pharmacokinetics and pharmacodynamics of procainamide and its active N-acetyl metabolite (NAPA) were assessed alone and in combination with trimethoprim. Eight healthy men received oral sustained-release procainamide, 500 mg every 6 hours for 3 days, alone and with oral trimethoprim, 200 mg daily for 4 days. Concomitant trimethoprim significantly increased the plasma AUC(0-12) of both procainamide and NAPA (63% and 52%, respectively), with concurrent decreases in their renal clearances (47% and 13%, respectively) and a 39% increase in the mean urinary recovery of NAPA (as percentage of procainamide and NAPA recovery). After trimethoprim coadministration, there was also a trend toward a decrease in the apparent acetylation clearance of procainamide (19%, p = 0.057). The change in procainamide and NAPA renal clearances after trimethoprim coadministration strongly correlated with their baseline renal clearances (r = 0.84 and r = 0.74, respectively, p less than 0.0001). There was small but significant increase in the corrected QT interval with procainamide administration, which increased further with trimethoprim coadministration. We conclude that trimethoprim increases the plasma concentrations of procainamide and NAPA by decreasing their renal clearances and allowing more conversion of procainamide to NAPA.
A 27-year-old white woman developed Heinz-body hemolytic anemia following multiple courses of oral phenazopyridine and trimethoprim-sulfamethoxazole. Her diagnosis was supported by the finding of bite cells on peripheral blood smear. The patient's rapid recovery and reversal of abnormal laboratory parameters were consistent with an acquired hemolytic disorder. This case should sensitize the clinician to the development of drug-induced oxidative hemolysis, its clinical features, and its reversibility. It is also important that the clinician recognize those drugs capable of causing this disorder and appreciate the methods available to establish the diagnosis.
Two cases of trimethoprim-sulfamethoxazole (TMP-SMX)-induced immune thrombocytopenia are reported in which unusual drug-dependent platelet antibodies were demonstrated by immunofluorescence and enzyme-linked immunosorbent assay. Whereas two distinct sulfamethoxazole-dependent antibodies of the IgG and IgM class were detectable in the serum of one patient, the serum of the other patient contained a platelet antibody exclusively reactive with N-4-acetyl-sulfamethoxazole, a metabolite of sulfamethoxazole. Urine from a healthy volunteer collected after administration of therapeutic doses of TMP-SMX proved to be an appropriate source of ex vivo metabolites for antibody testing. The results of this study stress the role of metabolite-specific antibodies in drug-dependent immune thrombocytopenia and underscore the necessity of including metabolite preparations of drugs in serologic analyses.
Decrease of blood cells may be induced by either components of co-trimoxazole. Side effects of the trimethoprim component are much more frequent, particularly in risk groups. They are dose dependent, usually not severe, only rarely of clinical significance and easily treated or prevented by folate supplementation. In contrast, side effects of the sulfamethoxazole component seem to be extremely rare. They are similar to the hematological side effects of other sulfonamide drugs. They are idiosyncratic, nonpredictable and mostly mediated by the immune-system. They may be of life-threatening severity and no therapy is known except termination of exposure and supportive measures such as substitution of blood cells and antiinfectious therapy by non-related antibiotics.
Trimethoprim-sulfamethoxazole (TMP-SMZ) has been associated with hemolytic anemia in patients deficient in glucose-6-phosphate
dehydrogenase (G-6-PD). The effect of a daily dose of SMZ of 50 mg/kg was evaluated in a double-blinded study that compared
vancomycinwith TMP-SMZ givenintravenously for treatment of serious Staphylococcus aureus infections. Levels of G-6-PD were determined when patients entered the trial. Most patients were black Americans. G-6-PD-deficient
patients were followed serially, with determinations of hemoglobin, haptoglobin, and bilirubin levels, reticulocyte count,
and urinalysis. Pretherapy hemoglobin levelswerecompared with levelsduring and after therapy. One hundred patients were divided
into four groups: group A comprised G-6-PD-deficient patients receiving TMP-SMZ (n = 20); group B, G-6-PD-deficient patients receiving vancomycin (n = 25); and groups C and D, patients with normal G-6-PD levels receiving TMP-SMZ (n = 24) and vancomycin (n = 31), respectively. Groups were comparable in terms of age of patients and duration of therapy. Hemolysis did not occur
in any patient receiving TMP-SMZ and occurred in only one patient receiving vancomycin. Both this study and published reports
indicate that TMP-SMZ rarely causes hemolysis in a G-6-PD-deficient population.
Trimethoprim-sulfamethoxazole (co-trimoxazole) is used extensively for treatment of pulmonary and urinary tract infections. Side effects may affect skin, blood, bone marrow, kidney and the liver. Although a number of sulfonamides have been reported to have produced hepatic lesions, hepatitis following therapy with trimethoprim-sulfamethoxazole is a rather rare event. While trimethoprim has not yet been reported as a cause of hepatic disorders, sulfamethoxazole has occasionally been described as inducing hepatic injury. In some cases, these reactions are accompanied by symptoms indicative for allergic reactions such as fever, rash and eosinophilia. Seven well documented cases are analyzed and discussed with respect to the nature of side effects caused by co-trimoxazole.
The effect of separate pretreatments with cotrimoxazole, sulphamethoxazole and trimethoprim on the disposition of tolbutamide was studied in seven healthy males. Tolbutamide 500 mg intravenously was administered on four separate occasions--as a control without pretreatment and on the seventh day of separate twice daily administration of cotrimoxazole (sulphamethoxazole 800 mg plus trimethoprim 160 mg) (ST phase), sulphamethoxazole 1 g (S phase) and trimethoprim 150 mg (T phase). Tolbutamide total and unbound plasma clearance (CL) were reduced following each of the individual pretreatments compared to the control phase (P less than 0.001). For unbound CL the reductions were 14% in the S and T phases and 25% in ST phase. Tolbutamide elimination half-life was prolonged following each pretreatment (P less than 0.001) by 20% in the S phase, 19% in the T phase and 30% in the ST phase. Tolbutamide total steady-state volume of distribution (VSS) was increased by 10% in the S and ST phases (P less than 0.01), the increase being accounted for by an increase in tolbutamide unbound fraction. There was no change in tolbutamide unbound VSS following any of the pretreatments. These results are consistent with inhibition of tolbutamide oxidation by cotrimoxazole, an additive effect of the two components sulphamethoxazole and trimethoprim. Sulphamethoxazole also reduces tolbutamide plasma protein binding.
The activities of NADH- and NADPH-dependent methemoglobin reductases were investigated in 22 fetuses between the 12th and 24th week of pregnancy and in eight age groups including premature and newborn babies and adults. Each blood sample was assayed simultaneously for both activities. NADH-methemoglobin reductase (MR) appears to be diminished in erythrocytes of premature and newborn babies. Infants below the 6th week of life also show significantly lower values than those observed in adults. Between 7 weeks and 6 months of life NADH-MR activity reaches values comparable to those of the adults. — NADPH activity in the erythrocytes of premature babies, newborns and infants is significantly higher than in older children and adults. Prior to the 18th week of gestation fetuses show NADH-MR levels lower than the older ones. NADH-MR values in fetuses between the 18th and 24th week of gestation are not different from those measured in premature babies. The NADPH-MR activity also appears to be significantly lower in fetuses of less than 19 weeks of intrauterine life in comparison with the older ones. Moreover, NADPH-MR activity in fetuses between the 19th and 24th week is lower than in prematures and newborns.
The possibility that low NADH-MR values in fetuses (30% as compared to adults) in the first 5 months of pregnancy could predispose to intrauterine methemoglobinemia has to be carefully evaluated when toxic drugs are prescribed to the mother.—Moreover, the still lower NADH-MR levels that might be expected in fetuses homozygous or heterozygous for NADH-MR deficiency may be a cause for the frequent occurrence of mental retardation in families with hereditary methemoglobinemia.
The optical enantiomorphs of warfarin were studied in 10 normal subjects. Each subject was given in separate experiments a single oral dose of R(+) warfarin, S(-) warfarin, and the racemate, R,S(±) warfarin, in the amount of 1.5 mg of drug per kg of body weight. The biologic halflife for (+) warfarin, (-) warfarin, and racemic warfarin was 58 ± 5, 33 ± 4, and 42 ± 2 hr, respectively, a highly significant difference (p < 0.01) between the enantiomorphs. The blood level of drug for (+) warfarin was 94% greater than that for (-) warfarin. The area under the prothrombin time curve plotted logarithmically showed a 76% greater effect for (-) warfarin than for (+) warfarin. Thus, the intrinsic activity of (-) warfarin was 3.4 times as great as that of (+) warfarin in the induction of hypoprothrombinemia. A high degree of direct correlation was found between the area for the blood level of drug and the hypoprothrombinemic effect for both the (+) and (-) warfarin enantiomorphs. It is concluded that the greater intrinsic activity of (-) warfarin than (+) warfarin does not result primarily from the blood level of the enantiomorphs but may result from a difference in permeability or affinity for the receptor site.
The rate of elimination, apparent volume of distribution, plasma clearance, and relative anticoagulant potency of the enantiomers of warfarin have been determined in man. In 9 subjects the plasma half life (T1/2) of R warfarin after a single oral dose of 0.5 mg/kg ranged from 19.9 to 69.8 hr, and was significantly longer than that of S warfarin, which ranged from 18.0 to 34.1 hr. There was no significant difference in the apparent volume of distribution of the enantiomers, and thus the plasma clearance of R warfarin was significantly less than that of S warfarin. After multiple dosing to steady state, the plasma T1/2 of R warfarin in 8 subjects ranged from 37.4 to 88.6 hr and was significantly longer than that of S warfarin, which ranged from 21.2 to 42.6 hr. The apparent volume of distribution of the enantiomers was the same, and thus the plasma clearance of R was again significantly less than that of S warfarin. The plasma T1/2 of R but not of S was significantly longer after multiple dosing than after a single dose. The ratio of the steady state plasma concentration of R to S warfarin was 3.80 : 1 in 4 patients with the same degree of anticoagulant control. The relative dose requirements of R to S warfarin were 1.59 : 1 in these subjects. S warfarin is a more potent anticoagulant than R warfarin in man.
The haematological effects of long-term treatment for three months with a combination of trimethoprim and sulphamethoxazole were studied in 10 cases of chronic bronchitis. Trimethoprim selectively inhibits dihydrofolate reductase in bacteria but not in man. Only minor effects on folate metabolism were observed in nine cases, causing no clinical concern. Some degree of thrombocytopenia occurred in the tenth case which improved when folinic acid was given.
The renal clearance of the folic acid antagonist, methotrexate, was compared with that of inulin and para-aminohippurate in 15 patients with disseminated malignancy. The clearance of methotrexate exceeded that of inulin clearance in all cases, indicating methotrexate is not only filtered but is also actively secreted by the renal tubules. The simultaneous intravenous administration of weak organic acids resulted, generally, in suppressive effects on the clearance of methotrexate. Salicylate and high concentrations of para-aminohippurate reduced methotrexate clearance well below the glomerular filtration rate; whereas, sulfisoxazole had only a minimal effect on total methotrexate clearance. The variations of plasma protein binding of methotrexate induced by these same drugs did not correlate with the direction or degree of methotrexate clearance. It is concluded from these studies that methotrexate is excreted by a combination of glomerular filtration and active tubular transport and that methotrexate clearance is not directly related to the level of free methotrexate presented to the kidneys. It is furthermore suggested that the alterations in plasma protein binding and renal clearance of methotrexate provoked by the simultaneous administration of other organic acids may be clinically exploitable in cancer chemotherapy.
Trimethoprim-sulfamethoxazole is known to produce hepatitis. We report a case involving the inadvertent rechallenge with trimethoprim-sulfamethoxazole (Bactrim) in a patient with a previous episode of drug-induced hepatitis. A liver biopsy specimen showed both cholestatic and cytotoxic changes consistent with drug-induced damage. Comparison with existing cases is presented and an immunologic cause is considered.
The pharmacokinetics of trimethoprim (TMP) and sulfamethoxazole (SMX) in cerebrospinal fluid (CSF) and serum after a single intravenous infusion of 5 mg of TMP and 25 mg of SMX per kg of body weight over approximately 120 min were studied i nine patients who had uninflamed meninges and were undergoing elective myelography. Peak concentrations of TMP and SMX in CSF were 1 microgram/ml and 13.8 micrograms/ml, respectively. The peak TMP concentration in CSF occurred significantly earlier than the peak SMX concentration (60 versus 480 min postinfusion). At 15 h, there was no detectable TMP in the CSF, and there was 4.7 micrograms of SMX per ml of CSF. In the postdistribution phase (in CSF), simultaneous CSF-to-serum concentration ratios ranged from 0.23 to 0.53 for TMP and from 0.20 to 0.36 for SMX. CSF penetration (measured by comparison of the area under the curve of the composite CSF and serum concentration-time curves) was 18% for TMP and 12% for SMX. A loading dose of TMP-SMX (bases on TMP) of 10 to 12 mg/kg and a maintenance dose of 6 mg/kg every 8 h or 8 mg/kg every 12 h (with a 2-h infusion) should yield steady-state peak concentrations of at least 5 micrograms of TMP per ml of serum and 160 micrograms of SMX per ml of serum. Further studies of TMP-SMX administered in these doses in the treatment of serious bacterial infection, including meningitis, are warranted.
Nine episodes of drug associated acute interstitial nephritis, in seven patients, were treated between 1972 and 1980. The drugs implicated were cotrimoxazole (three times), ampicillin, Magnapen (amplcillin and flucloxacillin), penicillin, gentamicin, paracetamol and ben-drofluazide. The time from exposure to the onset of symptoms ranged from one to 30 days. Presentation was with acute renal failure, which was non-oliguric in five cases, accompanied by rash (four), fever (four), and loin pain (two).
Renal biopsy was carried out in all cases, and showed a characteristic interstitial infiltrate comprising substantial numbers of lymphocytes and plasma cells, with a variable number of neutrophils, eosinophils and histiocytes. Immunofluorescence was negative in all four cases studied in the acute phase, and showed scattered deposits of IgG, IgM, IgA and C3 on the tubular basement membrane in one patient during recovery. Significant proteinuria and an abnormal urine deposit were present in all cases, and seven of nine had radiological evidence of enlarged kidneys.
Seven episodes were treated with high doses of methyl prednisolone and in all there was a response with a diuresis or spontaneous fall in serum creatinine within 72 hrs, and recovery of virtually normal renal function. Of two cases who did not initially receive steroids, one improved more slowly and one developed chronic renal impairment.
Of 1,121 hospitalized recipients of trimethoprim-sulfamethoxazole, 91 (8%) experienced reactions that were attributed to this
drug. The most common adverse effects were gastrointestinal upset (3.9%) and skin reactions (3.3%). Serious toxicity attributable
to the drug was rare.
This article has no abstract; the first 100 words appear below.
IN a previous study of the interaction between racemic warfarin (a mixture of the levorotatory and dextrorotatory enantiomorphs) and trimethoprim–sulfamethoxazole (TMP-SMZ) in man, marked augmentation of hypoprothrombinemia with little change in the plasma concentrations of warfarin was found.¹ On the basis of those data, it was concluded that the interaction did not have a pharmacokinetic basis. However, other drugs, such as phenylbutazone, have a diametrically opposite pharmacokinetic effect on each enantiomorph of warfarin.² To determine whether the interaction between racemic warfarin and TMP-SMZ is stereoselective and could have a concealed pharmacokinetic basis, the experiments were repeated with the separated enantiomorphs . . .
Supported in parts by grants (HL 8058–15 and GMS 22860–04) from the U.S. Public Health Service.
I am indebted to Dr. Collin Schroeder for supplying the enantiomorphs of warfarin and to Dr. William Trager for measuring their optical rotation, and to Mrs. Catherine Motley, Ms. Susan Nutter, and Mrs. Marjorie Kline, for their assistance.
Source Information
From the departments of Medicine, Santa Clara Valley Medical Center, San Jose, and the University of California, San Francisco, and the Institute for Medical Research, San Jose (address reprint requests to Dr. O'Reilly at the Department of Medicine, Santa Clara Valley Medical Center, 751 S. Buscom Ave., San Jose, CA 95128).