No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Antibiotic-Induced Neutropenia During Treatment of Hematogenous Osteoarticular Infections in Otherwise Healthy Children
Abstract
OBJECTIVES We studied the frequency and characteristics of antibiotic-induced neutropenia in otherwise healthy children receiving antibiotic therapy for hematogenous osteoarticular infections (OAIs).
METHODS We retrospectively enrolled otherwise healthy children between 1 month and 18 years of age discharged with an OAI from our institution over an 11-year period. An absolute neutrophil count (ANC) ≤1500 cells/μL was defined as neutropenia. We recorded demographic and clinical information, as well as the value and timing of each ANC in relation to changes in antibiotic therapy. A multivariable regression model assessed the contributions of various risk factors.
RESULTS A total of 186 children were enrolled (mean age, 7.6 years; 67.2% boys). β-Lactams represented 61.2% of all prescriptions. During treatment, 61 subjects (32.8%) developed neutropenia (median time to onset, 24 days). An ANC < 500 cells/μL occurred in 7 subjects (3.8%). Neutropenic subjects (mean age, 6.0 years) were significantly younger than those without neutropenia (mean age, 8.5 years) (OR = 0.86; 95% CI: 0.79–0.93; p < 0.001) and received significantly longer courses of total (89.3 vs. 55.8 days) and parenteral (24.6 vs. 19.9 days) antibiotic therapy (OR = 1.01; 95% CI: 1.01–1.02; p = 0.004 and OR = 1.02; 95% CI: 1.01–1.04; p = 0.041, respectively). Recurrent neutropenia occurred in 23.0% of all neutropenic subjects and was significantly more common in those with a longer mean duration of parenteral therapy (OR = 1.05; 95% CI: 1.02–1.09; p = 0.004.). No complications from neutropenia occurred.
CONCLUSIONS Neutropenia was common in our cohort of children receiving prolonged antibiotic therapy for OAIs. Younger age and longer courses of therapy were associated with an increased risk of neutropenia.
... 11 One recent study showed a correlation between cefepime-induced neutropenia and intravenous push administration, and another study of hospitalized pediatric patients found younger age was associated with neutropenia development. 12,13 Incidence of BLIN varies based on the beta-lactam utilized and the total duration of therapy. Approximate incidence based on duration of therapy greater than 2 weeks is 10%. ...
... 19 This has been seen with BLIN, specifically in pediatric patients; although, as of now, no study has been identified showing older age to be associated with BLIN. 13 Still, the potential for confounding with distributions of geriatric patients differing between groups (75% vs. 20%) must be considered. ...
Background: Beta-lactam-induced neutropenia (BLIN) is a serious adverse reaction associated with extended treatment courses. For many severe infections, guideline-directed medical therapy frequently involves weeks or months of IV antibiotics. To avoid health care costs associated with hospitalization and as a method to improve hospital bed capacity, clinicians are encouraged to discharge patients to receive IV antibiotics in the ambulatory setting once clinically stable. The purpose of this study was to compare the incidence of cefazolin-induced neutropenia between intravenous push (IVP) administration and intermittent infusions among home infusion patients. This study is unique in its analysis of neutropenia monitoring and interventions in a pharmacist-led outpatient parenteral anti-infective therapy (OPAT) model. Cefazolin was examined over other beta-lactams due to high utilization in home infusion and administration methods by IVP and intermittent infusion at this institution. Methods: This was a retrospective cohort study within a single large health system that includes an associated home infusion pharmacy. Patients were included for analysis if they met the following criteria: ≥18 years of age, received cefazolin through the home infusion pharmacy between July 1, 2017, and July 1, 2022, and were discharged from an acute care site within the health system for index cefazolin episode to the home or an affiliated long-term care facility. Lab values within 2 weeks of the cefazolin treatment course were evaluated for neutropenia. The primary outcome was the incidence of neutropenia by the method of administration: IVP versus intermittent infusion. Patients who received intermittent infusions in this study utilized elastomeric devices or ambulatory infusion pumps. Duration of IVP and intermittent infusion were defined as being given over 10 minutes and 30 minutes, respectively. Results: A total of 431 patients were included in the study. Home infusion pharmacists recorded 18 BLIN events. All patients were asymptomatic. Fourteen events were classified as mild, with an absolute neutrophil count (ANC) nadir of 1.1-1.5 cells×1000/μL. Two events were considered moderate and 2 were considered severe, with ANC nadirs between 0.5 to 1.0 cells×103/μL and <0.5 cells×103/μL, respectively. Conclusions: The relationship between baseline ANC and the development of BLIN later in treatment reported a 3.4-fold increased risk of cefazolin-induced neutropenia, and individuals with neutrophil counts between 1.6×103 cells/μL and 3.9×103 cells/μL at baseline require the highest degree of care. Our data suggests that low absolute neutrophil count (ANC) at cefazolin initiation is the strongest risk factor for subsequent development of neutropenia. Keywords: beta-lactams, home infusion, neutropenia, intravenous push, infusion
... 11 One recent study showed a correlation between cefepime-induced neutropenia and intravenous push administration, and another study of hospitalized pediatric patients found younger age was associated with neutropenia development. 12,13 Incidence of BLIN varies based on the beta-lactam utilized and the total duration of therapy. Approximate incidence based on duration of therapy greater than 2 weeks is 10%. ...
... 19 This has been seen with BLIN, specifically in pediatric patients; although, as of now, no study has been identified showing older age to be associated with BLIN. 13 Still, the potential for confounding with distributions of geriatric patients differing between groups (75% vs. 20%) must be considered. ...
... Previous reports support the increased risk of neutropenia with longer treatment courses, as we saw in our cohort. 33,34 While standard intravenous and oral dosing for many common antibiotics (e.g., clindamycin) results in similar blood concentrations, prolonged oral antibiotic administration did not correlate with neutropenia in our cohort. One possible explanation is that more severe infections that tend to require a longer IV treatment duration also have a greater impact on hematopoiesis. ...
Prolonged antibiotic exposure causes dangerous hematologic side effects, including neutropenia, in up to 34% of patients. Murine studies established a link between the intestinal microbiota and hematopoiesis. To identify factors that predispose to neutropenia in pediatric patients, we evaluated changes in microbiota‐derived metabolites and intestinal microbiota composition after prolonged courses of antibiotics. In this multi‐center study, patients with infections requiring anticipated antibiotic treatment of two or more weeks were enrolled. Stool samples were obtained at the start and completion of antibiotics or at neutropenia onset (prospective arm). Some patients were enrolled in a retrospective arm in which a stool sample was collected at the time of neutropenia during antibiotic therapy and 2–4 weeks after completion of antibiotics with recovery of blood counts. We identified 10 patients who developed neutropenia on antibiotics and 29 controls matched for age, sex, race, and ethnicity. Clinical data demonstrated no association between neutropenia and the type of infection or antibiotic used; however, patients with neutropenia were admitted to the intensive care unit more often and received longer courses of antibiotics. Reduced intestinal microbiome richness and, specifically, decreased abundance of Lachnospiraceae family members correlated with neutropenia. Untargeted stool metabolomic profiling revealed several metabolites that were depleted exclusively in patients with neutropenia, including members of the urea cycle pathway, pyrimidine metabolism, and fatty acid metabolism that are known to be produced by Lachnospiraceae. Our study shows a relationship between intestinal microbiota disruption and abnormal hematopoiesis and identifies taxa and metabolites likely to contribute to microbiota‐sustained hematopoiesis.
... We identified associations between neutropenia and the total length of antibiotic therapy, length of intravenous antibiotic therapy, length of admission to the hospital and admission to the intensive care unit ( Table 2). Previous reports concur with the increased risk of neutropenia with longer treatment courses, as we saw in our cohort 33,34 . While standard intravenous and oral dosing for many common antibiotics (e.g. ...
Hematologic side effects are associated with prolonged antibiotic exposure in up to 34% of patients. Neutropenia, reported in 10-15% of patients, increases the risk of sepsis and death. Murine studies have established a link between the intestinal microbiota and normal hematopoiesis. We sought to identify predisposing factors, presence of microbiota-derived metabolites, and changes in intestinal microbiota composition in otherwise healthy pediatric patients who developed neutropenia after prolonged courses of antibiotics. In this multi-center study, patients with infections requiring anticipated antibiotic treatment of two or more weeks were enrolled. Stool samples were obtained at the start and completion of antibiotics and at the time of neutropenia. We identified 10 patients who developed neutropenia on antibiotics and 29 controls matched for age, sex, race, and ethnicity. Clinical data demonstrated no association between neutropenia and type of infection or type of antibiotic used; however intensive care unit admission and length of therapy were associated with neutropenia. Reduced intestinal microbiome richness and decreased abundance of Lachnospiraceae family members correlated with neutropenia. Untargeted stool metabolomic profiling revealed several metabolites that were depleted exclusively in patients with neutropenia, including members of the urea cycle pathway, pyrimidine metabolism and fatty acid metabolism that are known to be produced by Lachnospiraceae . Our study confirms a relationship between intestinal microbiota disruption and abnormal hematopoiesis and identifies taxa and metabolites likely to contribute to microbiota-sustained hematopoiesis. As the microbiome is a key determinant of stem cell transplant and immunotherapy outcomes, these findings are likely to be of broad significance.
Key Points
Neutropenia occurred in 17% of patients receiving prolonged antibiotic therapy.
We found no association between neutropenia and type of infection or class of antibiotic used.
Development of neutropenia after prolonged antibiotic treatment was associated with decreased prevalence of Lachnospiraceae and Lachnospiraceae metabolites such as citrulline.
... The incidence of non-chemotherapy idiosyncratic drug-induced neutropenia is reported to range from 2.4 to 15.4 cases per million people [4]. Among the reported cases of antibiot-ic-induced neutropenia, beta-lactams and glycopeptides are the most common reported causative agents [5][6][7]. The mechanism of antibiotic-induced neutropenia remains uncertain and potentially multifactorial. ...
Background:
Cefalexin, a first-generation cephalosporin, is commonly used as oral continuation therapy for paediatric bone and joint infections (BJIs). The standard four times daily cefalexin dose makes treatment adherence challenging. A pharmacokinetic modelling study found that a cefalexin dose of 45 mg/kg (maximum 1.5 g) three times daily achieves the same pharmacodynamic target.
Objectives:
To evaluate the efficacy and tolerability of three times daily cefalexin dosing in children with BJIs.
Patients and methods:
Retrospective audit of children aged 1-18 years who received cefalexin at a dose of 40-50 mg/kg (maximum 1.5 g) three times daily as oral continuation therapy for a haematogenous BJI at a quaternary paediatric hospital in Australia over a 4 year period (January 2019 to December 2022).
Results:
Of 149 children with BJIs treated with three times daily cefalexin dosing, the majority (147/149; 99%) achieved cure, with two experiencing recurrence of their infection. Most children tolerated the higher cefalexin dose; 4 children experienced gastrointestinal symptoms and 13 developed neutropenia, which was mild in most cases with no associated complications.
Conclusions:
A reduced frequency dosing regimen using a high cefalexin dose of 45 mg/kg (maximum 1.5 g) three times daily is effective and well tolerated in most children with BJIs.
Monitoring for antibiotic-related lab abnormalities (ARLA), including hematologic, renal, and/or hepatic toxicity, in pediatric osteomyelitis is common. In 240 cases of osteomyelitis with outpatient laboratory monitoring, ARLA occurred in 13.3% with the most common finding being neutropenia. ARLA impacted antibiotic therapy in <1% of subjects, however, raising questions about the value of such monitoring being performed routinely.
Prolonged neutrophil recovery during acute lymphoblastic leukemia (ALL) treatment increases infection risk and delays chemotherapy. Emerging evidence implicates the gut microbiota in neutrophil reconstitution after chemotherapy. We explored the interplay between the gut microbiota and neutrophil dynamics, including neutrophil chemoattractants, in 51 children with newly-diagnosed ALL. Daily absolute neutrophil count (ANC), weekly plasma chemokines (CXCL1 and CXCL8), granulocyte colony-stimulating factor (G-CSF), and fecal samplings were monitored until day 29 during ALL induction treatment. Fecal sequencing by 16S rRNA revealed an overall significant reduction in bacterial diversity and Enterococcus overgrowth throughout the induction treatment. Prolonged neutropenia (ANC < 0.5x10⁹ cells/L at day 36) and elevated chemokines levels were associated with decreased abundance of genera from the Ruminococcaceae and Lachnospiraceae families, decreased Veillonella genus, and Enterococcus overgrowth from diagnosis and throughout induction treatment. G-CSF was upregulated in response to neutropenia but unrelated to microbiota changes.
Overall, this study reveals that diminished abundance of specific intestinal commensals and Enterococcus overgrowth are associated with delayed neutrophil reconstitution and increased chemokine signaling. These findings enhance our understanding of the mechanisms behind the huge variability in neutrophil reconstitution post-chemotherapy, emphasizing the need for gut microbiota-sparing strategies to minimize the impact of gut dysbiosis on immune recovery.
Aims
Acute neutropenia induced by antibiotics is a rare side effect of this frequently prescribed class of drugs. We aim to find similarities and differences between reported cases.
Methods
Through a database search (PubMed, 1968–2020), we identified published case reports and extracted, among other data, patient demographics, duration of treatment with the respective agent, and duration of recovery.
Results
Overall, 83 cases were included. Neutropenia developed after a median (min–max) of 21 (17.5–28.5) days of treatment and was resolved after a median (min–max) of 6 (3.0–8.75) days. Vancomycin and ceftaroline emerged as the two most commonly described antibiotics. In 51.8% of cases, the suspected antibiotic was discontinued; in 37.4% of cases, it was substituted by another agent. Only three case reports mentioned death as a result of neutropenia. The use of granulocyte colony‐stimulating growth factors (CSFs) shortened the duration of neutropenia and improved outcome for patients' health.
Conclusion
Neutropenia induced by antibiotics remains a rare or rarely reported side effect. Long‐term and high‐dose treatment regimens expose a higher risk of development. Thus, regular full blood counts are advised during therapy.
Objective:
To study the risk factors and treatment for neutropenia of late newborns (NLN).
Methods:
Related clinical data were collected from the preterm infants and critically ill neonates who were admitted to the neonatal intensive care unit from July 2019 to January 2020. A total of 46 newborns with a blood absolute neutrophil count (ANC) of < 1.5×109/L for two consecutive times at weeks 2-4 after birth were enrolled as the NLN group. A total of 92 late newborns with a blood ANC of ≥ 1.5×109/L, matched at a ratio of 1:2, were enrolled as the control group. Possible risk factors associated with NLN and the treatment process were recorded. A logistic regression analysis was performed to identify the risk factors for NLN.
Results:
Among the 46 neonates in the NLN group, 29 had a gestational age of < 32 weeks, 14 had a gestational age of 32-37 weeks, and 3 had a gestational age of > 37 weeks. There was no significant difference between the two groups in the incidence rates of gestational hypertension, premature rupture of membranes > 18 hours and intrauterine distress, 5-minute Apgar score, the duration of positive pressure ventilation, the incidence rate of early-onset sepsis, and the type of initially used antibiotics (P > 0.05). Compared with the control group, the NLN group had a higher incidence rate of late-onset sepsis and a longer duration of antibiotic use (P < 0.05). Late-onset sepsis and prolonged duration of antibiotic use were independent risk factors for NLN (P < 0.05). With the presence of late-onset sepsis, the risk of NLN was increased by 1.537 times in neonates, and the risk of NLN was increased by 76.9% for every 3-day increase in the duration of antibiotic use. The mean age at the diagnosis of NLN was (21±6) days for the 46 neonates in the NLN group. Thirteen neonates with NLN were administered with recombinant human granulocyte colony-stimulating factor (G-CSF, 10 μg/kg) once or twice. O the 13 neonates, 6 had an ANC of < 0.5×109/L and 7 had a gestational age of < 32 weeks or severe disease conditions. After treatment the ANC returned to > 1.0×109/L in the 13 neonates. No drug-related adverse reactions were found. After the diagnosis of NLN, 2 neonates developed sepsis, and the remaining 44 neonates did not develop any common purulent infections.
Conclusions:
The risk of NLN increases with the presence of late-onset sepsis and the increase in the duration of antibiotic use. NLN is generally a benign process. G-CSF appears to be safe and effective for NLN with severe disease conditions or severe reduction in ANC.
Background
Multiple studies estimate that inappropriate antibiotic prescribing ranges from 30–50% in hospitalized patients, but few have included pediatric patients. Pediatric studies characterizing inappropriate prescribing are needed to target and improve antimicrobial stewardship program (ASP) efforts.
Methods
Cross-sectional analysis of antimicrobial prescribing at 30 U.S. children’s hospitals. Participating hospitals were academic, tertiary care hospitals in the Sharing Antimicrobial Reports for Pediatric Stewardship (SHARPS) collaborative. Subjects were children 0–17 years with an active antibiotic order at 0800 on a single day during three consecutive calendar quarters (Q3 2016 – Q1 2017). Each hospital’s ASP used a standardized survey to collect data on antibiotic orders and evaluate appropriateness. Data were pooled from the three surveys. The primary outcome was the pooled estimate for the percentage of prescriptions classified as inappropriate. Secondary outcomes were pooled estimates for indication, reason for inappropriate use, and ASP review status for each antibiotic.
Results
Of 19,598 children hospitalized on survey days, 6,922 (35%) had ≥1 active antibiotic order. Median age of children receiving antibiotics was 3.7 years (0.5, 10.9). Figures 1 and 2 show the most common antibiotics and indications. Of all antibiotic orders, 1,514 (15%) were classified as inappropriate, and 19% of patients with antibiotic orders had at least one inappropriate order. The most common reasons for inappropriate use were bug-drug mismatch (26%), surgical prophylaxis > 24 hours (18%) and unnecessary duplicate therapy (12%). ASPs would not have routinely reviewed 50% of all inappropriate orders. An additional 22% of inappropriate orders were for antibiotics typically reviewed by ASPs, but were yet to be reviewed at the time of the survey.
Conclusion
Across 30 children’s hospitals, approximately 1 in 3 hospitalized children is receiving an antibiotic at any given time. Almost 20% of these children are receiving inappropriate therapy, and a substantial portion of inappropriate use is not captured by current ASP practices.
Figures 1 and 2:
Disclosures
C. Terrill, Merck: Grant Investigator, Research grant; Allergan: Grant Investigator, Research grant; J. Newland, Merck: Grant Investigator, Research grant; Allergan: Grant Investigator, Research grant.
We carried out a case-control study in children with acute hematogenous osteomyelitis (AHO) with and without suppurative complications discharged from our institution over an 11-year period to test the hypothesis that abscess formation was associated with a delayed presentation to care. Of 102 children with AHO, 54 abscesses were documented in 46 patients (25 bone, 29 muscle). A delay in presentation was not associated with abscess formation (6.5 vs. 5.0 days, P=0.26). Overall, 78% of all bone abscesses were visible on initial MRI. Consistent use of MRI at presentation may identify children with suppurative complications of AHO.
Bone marrow suppression is an adverse effect associated with many antibiotics, especially when administered for prolonged treatment courses. Recent advances in our understanding of steady-state hematopoiesis have allowed us to explore the effects of antibiotics on hematopoietic progenitors in detail using a murine model. Antibiotic-treated mice exhibited anemia, thrombocytosis, and leukopenia, with pronounced pan-lymphopenia as demonstrated by flow cytometric analysis of peripheral blood. Bone marrow progenitor analysis revealed depletion of hematopoietic stem cells and multipotent progenitors across all subtypes. Granulocytes and B cells were also diminished in the bone marrow, whereas the number of CD8+ T cells increased. Reductions in progenitor activity were not observed when cells were directly incubated with antibiotics, suggesting that these effects are indirect. Hematopoietic changes were associated with a significant contraction of the fecal microbiome and were partially rescued by fecal microbiota transfer. Further, mice raised in germ-free conditions had hematopoietic abnormalities similar to those seen in antibiotic-treated mice, and antibiotic therapy of germ-free mice caused no additional abnormalities. The effects of antibiotics were phenocopied in Stat1-deficient mice, with no additional suppression by antibiotics in these mice. We conclude that microbiome depletion as a result of broad-spectrum antibiotic treatment disrupts basal Stat1 signaling and alters T-cell homeostasis, leading to impaired progenitor maintenance and granulocyte maturation. Methods to preserve the microbiome may reduce the incidence of antibiotic-associated bone marrow suppression.
Blood polymorphonuclear neutrophils provide immune protection against pathogens, but may also promote tissue injury in inflammatory diseases. Although neutrophils are generally considered to be a relatively homogeneous population, evidence for heterogeneity is emerging. Under steady-state conditions, neutrophil heterogeneity may arise from ageing and replenishment by newly released neutrophils from the bone marrow. Aged neutrophils upregulate CXCR4, a receptor allowing their clearance in the bone marrow, with feedback inhibition of neutrophil production via the IL-17/G-CSF axis, and rhythmic modulation of the haematopoietic stem-cell niche. The aged subset also expresses low levels of L-selectin. Previous studies have suggested that in vitro-aged neutrophils exhibit impaired migration and reduced pro-inflammatory properties. Here, using in vivo ageing analyses in mice, we show that neutrophil pro-inflammatory activity correlates positively with their ageing whilst in circulation. Aged neutrophils represent an overly active subset exhibiting enhanced αMβ2 integrin activation and neutrophil extracellular trap formation under inflammatory conditions. Neutrophil ageing is driven by the microbiota via Toll-like receptor and myeloid differentiation factor 88-mediated signalling pathways. Depletion of the microbiota significantly reduces the number of circulating aged neutrophils and dramatically improves the pathogenesis and inflammation-related organ damage in models of sickle-cell disease or endotoxin-induced septic shock. These results identify a role for the microbiota in regulating a disease-promoting neutrophil subset.
Background:
Although long treatment courses of outpatient antimicrobials are often used in pediatric patients, few data exist regarding the frequency of adverse events (AEs) associated with these medications.
Methods:
We performed a retrospective cohort study of all patients seen in the Infectious Diseases clinic at a tertiary referral children's hospital from August 1, 2009 to August 1, 2011. We included patients who received ≥14 days of oral or intravenous antibiotic, antiviral, or antifungal medications. Patients receiving only prophylactic medications or human immunodeficiency virus treatment were excluded.
Results:
Three hundred thirty-five subjects met inclusion criteria, with a median age of 7.4 years at start of therapy. The cohort was predominantly male (60%), white (54%), and previously healthy (59%). A majority (88.4%) of subjects were treated for bacterial infections. β-Lactam agents were the most commonly used antimicrobial class (210 subjects; 62.7%), followed by clindamycin (86; 25.7%), rifampin (76; 22.7%), and vancomycin (62; 18.5%). Overall, 107 (31.9%) subjects experienced 151 distinct AEs. The most common individual AE noted was diarrhea (44; 29.1% of all AEs). Serious AEs developed in 42 (12.5%) subjects, including allergic reactions (15; 11.3% of all AEs), venous catheter-related complications (14; 13.0% of those with catheters), neutropenia (9; 3.0%), renal insufficiency (7; 2.5%), and hepatotoxicity (3; 1.1%). Rates of AEs were similar between those on oral and intravenous antimicrobials.
Conclusions:
In our study population, patients on prolonged oral or intravenous outpatient antimicrobials experienced AEs frequently. These findings support the need for close monitoring of pediatric patients on prolonged antimicrobial therapy and vigilance for unwanted effects of these medications.
Neutropenia is probably the strongest known predisposition to infection with otherwise harmless environmental or microbiota-derived species. Because initial swarming of neutrophils at the site of infection occurs within minutes, rather than the hours required to induce "emergency granulopoiesis," the relevance of having high numbers of these cells available at any one time is obvious. We observed that germ-free (GF) animals show delayed clearance of an apathogenic bacterium after systemic challenge. In this article, we show that the size of the bone marrow myeloid cell pool correlates strongly with the complexity of the intestinal microbiota. The effect of colonization can be recapitulated by transferring sterile heat-treated serum from colonized mice into GF wild-type mice. TLR signaling was essential for microbiota-driven myelopoiesis, as microbiota colonization or transferring serum from colonized animals had no effect in GF MyD88(-/-)TICAM1(-/-) mice. Amplification of myelopoiesis occurred in the absence of microbiota-specific IgG production. Thus, very low concentrations of microbial Ags and TLR ligands, well below the threshold required for induction of adaptive immunity, sets the bone marrow myeloid cell pool size. Coevolution of mammals with their microbiota has probably led to a reliance on microbiota-derived signals to provide tonic stimulation to the systemic innate immune system and to maintain vigilance to infection. This suggests that microbiota changes observed in dysbiosis, obesity, or antibiotic therapy may affect the cross talk between hematopoiesis and the microbiota, potentially exacerbating inflammatory or infectious states in the host.
Benign reductions in neutrophil counts may be more common at certain ages and in certain ethnic groups and may be affected by sex and smoking status.
To determine differences in neutrophil counts in the U.S. population according to ethnicity, age, sex, and smoking status.
Population-based, cross-sectional study.
Various locations in the United States.
25,222 participants in the 1999 to 2004 National Health and Nutrition Examination Survey who were 1 year of age or older.
Complete blood counts and comparison of means and the proportion of participants with neutropenia.
Relative to white participants, black participants had lower leukocyte counts (mean difference, 0.89 x 10(9) cells/L; P < 0.001), lower neutrophil counts (0.83 x 10(9) cells/L; P < 0.001), and similar lymphocyte counts (0.022 x 10(9) cells/L; P = 0.36), whereas Mexican-American participants had slightly higher mean leukocyte counts (0.16 x 10(9) cells/L; P = 0.014), higher neutrophil counts (0.11 x 10(9) cells/L; P = 0.026), and higher lymphocyte counts (0.095 x 10(9) cells/L; P < 0.001). The prevalence of neutropenia (neutrophil count <1.5 x 10(9) cells/L) was 4.5% among black participants, 0.79% among white participants, and 0.38% among Mexican-American participants. The prevalence of neutropenia was higher among males and children younger than 5 years of age. Neutrophil counts less than 1.0 x 10(9) cells/L were observed in fewer than 1% of the overall sample (0.57% in black participants, 0.11% in white participants, and 0.08% in Mexican-American participants). Smoking was associated with higher leukocyte and neutrophil counts but had a smaller effect among black and Mexican-American participants than among white participants.
Because estimates are based on single measures, fluctuations over time could not be determined.
In the United States, neutrophil counts are lower in black persons than in white persons and neutropenia is more prevalent in black persons. Neutrophil counts are slightly higher in Mexican-American persons than in white persons, and neutropenia is uncommon in both groups. The clinical implications of these findings are unclear, but they suggest that when determining the need for a diagnostic evaluation for neutropenia, clinicians should consider the patient's age, sex, ethnicity, and smoking status.
Neutropenia, usually defined as a blood neutrophil count <1·5 × 109/l, is a common medical problem for children and adults. There are many causes for neutropenia, and at each stage in life the clinical pattern of causes and consequences differs significantly. I recommend utilizing the age of the child and clinical observations for the preliminary diagnosis and primary management. In premature infants, neutropenia is quite common and contributes to the risk of sepsis with necrotizing enterocolitis. At birth and for the first few months of life, neutropenia is often attributable to isoimmune or alloimmune mechanisms and predisposes to the risk of severe bacterial infections. Thereafter when a child is discovered to have neutropenia, often associated with relatively minor symptoms, it is usually attributed to autoimmune disorder or viral infection. The congenital neutropenia syndromes are usually recognized when there are recurrent infections, the neutropenia is severe and there are congenital anomalies suggesting a genetic disorder. This review focuses on the key clinical finding and laboratory tests for diagnosis with commentaries on treatment, particularly the use of granulocyte colony-stimulating factor to treat childhood neutropenia.
Only few reports have looked into the risk of invasive bacterial infection in children with neutropenia that is not malignancy related. The objective of the current study was to determine the clinical significance of neutropenia as a predictor of serious bacterial infection (SBI) in immunocompetent children. We conducted a retrospective case-control study including children 3 months to 18 years of age with fever ≥38°C hospitalized or presenting to the emergency department. Patients who had neutropenia ≤1000 ANC/μL and had a blood culture taken were matched for age with the consecutive febrile patients for whom a blood culture was taken. The main outcome was the rate of SBI. SBIs were more prevalent among the control group than in the group of children with neutropenia, 19/71 and 6/71, respectively (P=0.0005). More children were treated with antibiotics among the control group than in the group of children with neutropenia, 39/71 and 20/71, respectively (P<0.0001). Acute-phase reactants including CRP and platelets were higher in the control group. We concluded that immunocompetent patients with fever and moderate neutropenia do not carry a higher risk for SBIs compared with patients with fever who do not have neutropenia.
Postdischarge treatment of acute osteomyelitis in children requires weeks of antibiotic therapy, which can be administered orally or intravenously via a peripherally inserted central catheter (PICC). The catheters carry a risk for serious complications, but limited evidence exists on the effectiveness of oral therapy.
To compare the effectiveness and adverse outcomes of postdischarge antibiotic therapy administered via the PICC or the oral route.
We performed a retrospective cohort study comparing PICC and oral therapy for the treatment of acute osteomyelitis. Among children hospitalized from January 1, 2009, through December 31, 2012, at 36 participating children's hospitals, we used discharge codes to identify potentially eligible participants. Results of medical record review confirmed eligibility and defined treatment group allocation and study outcomes. We used within- and across-hospital propensity score-based full matching to adjust for confounding by indication.
Postdischarge administration of antibiotics via the PICC or the oral route.
The primary outcome was treatment failure. Secondary outcomes included adverse drug reaction, PICC line complication, and a composite of all 3 end points.
Among 2060 children and adolescents (hereinafter referred to as children) with osteomyelitis, 1005 received oral antibiotics at discharge, whereas 1055 received PICC-administered antibiotics. The proportion of children treated via the PICC route varied across hospitals from 0 to 100%. In the across-hospital (risk difference, 0.3% [95% CI, -0.1% to 2.5%]) and within-hospital (risk difference, 0.6% [95% CI, -0.2% to 3.0%]) matched analyses, children treated with antibiotics via the oral route (reference group) did not experience more treatment failures than those treated with antibiotics via the PICC route. Rates of adverse drug reaction were low (<4% in both groups) but slightly greater in the PICC group in across-hospital (risk difference, 1.7% [95% CI, 0.1%-3.3%]) and within-hospital (risk difference, 2.1% [95% CI, 0.3%-3.8%]) matched analyses. Among the children in the PICC group, 158 (15.0%) had a PICC complication that required an emergency department visit (n = 96), a rehospitalization (n = 38), or both (n = 24). As a result, the PICC group had a much higher risk of requiring a return visit to the emergency department or for hospitalization for any adverse outcome in across-hospital (risk difference, 14.6% [95% CI, 11.3%-17.9%]) and within-hospital (risk difference, 14.0% [95% CI, 10.5%-17.6%]) matched analyses.
Given the magnitude and seriousness of PICC complications, clinicians should reconsider the practice of treating otherwise healthy children with acute osteomyelitis with prolonged intravenous antibiotics after hospital discharge when an equally effective oral alternative exists.
Unless acute osteomyelitis in children is diagnosed promptly and treated appropriately, it can be a devastating or even fatal disease. This review summarizes the current approach to the treatment of acute osteomyelitis in children. Bacteria may reach bone through direct inoculation from traumatic wounds, by spreading from adjacent tissue affected by cellulitis or septic arthritis, or through hematogenous seeding. In children, an acute bone infection is most often hematogenous in origin.(1) In high-income countries, acute osteomyelitis occurs in about 8 of 100,000 children per year,(2) but it is considerably more common in low-income countries. Boys are affected twice as often as girls.(2),(3) Unless acute osteomyelitis is diagnosed promptly and treated appropriately,(4) it can be a devastating or even fatal disease with a high rate of sequelae, especially in resource-poor countries where patients present ...
Neutropenia, defined as an absolute neutrophil count (ANC) <1.5 × 10(9)/L, encompasses a wide range of diagnoses, from normal variants to life-threatening acquired and congenital disorders. This review addresses the diagnosis and management of isolated neutropenia, not multiple cytopenias due to splenomegaly, bone marrow replacement, or myelosuppression by chemotherapy or radiation. Laboratory evaluation generally includes repeat complete blood cell counts (CBCs) with differentials and bone marrow examination with cytogenetics. Neutrophil antibody testing may be useful but only in the context of clinical and bone marrow findings. The discovery of genes responsible for congenital neutropenias now permits genetic diagnosis in many cases. Management of severe chronic neutropenia includes commonsense precautions to avoid infection, aggressive treatment of bacterial or fungal infections, and administration of granulocyte colony-stimulating factor (G-CSF). Patients with severe chronic neutropenia, particularly those who respond poorly to G-CSF, have a risk of eventually developing myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) and require monitoring for this complication, which also can occur without G-CSF therapy. Patients with cyclic, idiopathic, and autoimmune neutropenia have virtually no risk of evolving to MDS or AML. Hematopoietic stem cell transplantation is a curative therapy for congenital neutropenia with MDS/AML or with cytogenetic abnormalities indicating impending conversion.
Healthy children presenting with neutropenia are often hospitalized and treated empirically with antibiotics without an evidence of infection. The objective of this study was to investigate the infectious causes of isolated transient neutropenia in otherwise previously healthy children.
A 2-year prospective study was conducted at a tertiary hospital in Kuwait. All previously healthy children (aged 1 month to 12 years) hospitalized with isolated neutropenia defined as absolute neutrophil count (ANC) ≤ 1.5 × 10/L were enrolled in the study. Investigations to identify the infectious causes included blood and urine culture for bacteria whereas for viruses, serology for Epstein-Barr virus, cytomegalovirus, adenovirus, parvovirus and polymerase chain reaction for human herpes virus 6 and enterovirus were performed.
Fifty-five children were enrolled during the study. Children less than 2 years of age constituted 73% of the sample. There were 2 peaks of presentation: March-May (33%) and September-November (38%). Associated features were congested throat (56%), runny nose (53%) and cervical lymphadenopathy (20%). The median ANC on admission was 0.6 × 10/L. Associated infections were documented in 55% of enrolled children and were as follows: human herpesvirus 6, 30%; enterovirus, 23%; influenza A H1N1, 13%; parvovirus, 10%; Epstein-Barr virus, 10%; urinary tract infection, (Eshcherichia coli) 7%; and adenovirus, 7%. No serious bacterial infection was identified, and the mean time for recovery of the ANC was 16.7 ± 15 days.
Neutropenia in previously healthy children in Kuwait is caused by demonstrable infections in 55% of cases. Majority of children will recover their ANC completely within 1 month without significant infectious complications.
We examined 785 placentas, including 51 from documented cases of congenital toxoplasmosis. Toxoplasma was detected in 16 placentas,including 1 in which congenital toxoplasmosis was ruled out. Placental screening had poor sensitivity (25%) but good specificity (99%), positive predictive value (93%), and negative predictive value (95%).
Two major unresolved problems in drug-related immune agranulocytosis are understanding the mechanism by which sensitization takes place in vivo, and verification of the diagnosis. Using a sensitive, competitive enzyme-linked immunoassay (ELISA) we were able to characterize the causative antibodies in 13 patients with drug-related agranulocytosis [metamizole (n= 5), penicillin (n= 5), dimethylaminophenazone (n=1), propyphenazone (n=1) and diclofenac (n= 1)]. Irrespective of the causative drug, the majority of patients appear to have developed autoantibodies (aab) in addition to drug-dependent antibodies (ddab) of the IgG and/or IgM classes. In all cases related to metamizole, and in the single case related to diclofenac, the ddab appeared to recognize only metabolites of the drug since they were reactive in the presence of ex vivo antigens (urine from individuals receiving therapeutic levels of the drugs), but not the native drugs. Only a few ddab were reactive with granulocytes pretreated with the drug (cell-drug complexes); the majority of ddab could not be detected unless the drug or ex vivo antigen was added to the incubation mixture as well as the solution used for subsequent washes.
Our results indicate that drugs and/or their metabolites interact with target cells and thereby directly function as immunogenic haptens, even when the drugs do not bind tightly to the cells.
Neutropenia is an occasional complication of treatment with cephalosporin antibiotics. This report describes two patients who had neutropenia while receiving high doses of cephalosporins. The neutrophil counts returned to normal after stopping the drug, and cephalosporin-dependent neutrophil antibodies were demonstrated in both cases, using the granulocyte immunofluorescence test. In one patient, the immune neutropenia appeared to be due to a drug adsorption mechanism similar to penicillin-induced haemolytic anaemia, while an immune complex mechanism may have been involved in the second patient.
β-Lactam antibiotics can induce severe neutropenia by a hitherto unknown mechanism. Fifty cases of β-lactam antibiotic-induced
neutropenia (<1,000 neutrophils/mm3) from 17 hospitals were analyzed and compared with 140 literature cases. The incidence of neutropenia was 5%–>15% in patients
treated for ⩾10 days with large doses of any β-lactam antibiotic but <0.1% with shorter duration of therapy. In >95% of cases
recovery occurred between one to seven days after withdrawal of β-lactam antibiotics. Bone marrow aspirates were characterized
by a lack of well-differentiated myeloid elements in the presence of numerous immature granulocyte precursors. Nine penicillins
and eight cephalosporins inhibited in vitro granulopoiesis in a dose-dependent manner. There was a good correlation between
the inhibitory capacity of β-lactam antibiotics in vitro and the doses inducing neutropenia in vivo. These observations may
be relevant for therapy in the granulocytopenic patient.
Two patients who developed neutropenia while receiving beta-lactam antibiotics are presented, and the literature on beta-lactam-induced neutropenia is reviewed. A 55-year-old white woman was admitted to the hospital with a white blood cell (WBC) count of 8700/cu mm (68% neutrophils, 12% neutrophil bands, 0% eosinophils, 14% lymphocytes, 5% monocytes). Moxalactam 2 g i.v. (as the disodium salt) every eight hours was started on hospital day 15 after a postoperative fever failed to respond to a regimen of intravenous tobramycin and clindamycin. The patient again had surgery on hospital day 27, and the moxalactam regimen was continued postoperatively. Approximately one week later the patient's WBC count had dropped to 1900/cu mm (8% neutrophils, 14% neutrophil bands, 6% eosinophils, 54% lymphocytes, 16% monocytes); moxalactam was discontinued, and the WBC count gradually increased after substitution of tobramycin and clindamycin for moxalactam. The second patient was a 75-year-old white man who was being treated with intravenous tobramycin and cefoxitin for a hospital-acquired pneumonia. Ticarcillin 3 g i.v. (as the disodium salt) every four hours was added to this regimen on hospital day 23 after sputum cultures revealed Pseudomonas aeruginosa; four days previously, the WBC count had been 25,100/cu mm (64% neutrophils, 31% neutrophil bands, 1% eosinophils, 3% lymphocytes, 0% monocytes). The WBC count on hospital day 36 was 11,900/cu mm (39% neutrophils, 33% neutrophil bands, 11% eosinophils, 10% lymphocytes, 6% monocytes). Two days later it had dropped to 3700/cu mm (2% neutrophils, 0% neutrophil bands, 53% eosinophils, 24% lymphocytes, 16% monocytes), and ticarcillin was discontinued. The WBC count gradually increased and returned to normal within three days after discontinuing ticarcillin. Neutropenia associated with the administration of beta-lactam antibiotics appears to result from an immunologic reaction characterized by rapid destruction of peripheral neutrophils. Among penicillin analogs, penicillinase-resistant penicillins are involved most frequently, especially in pediatric patients receiving dosages of 150 mg/kg/day or greater. Two case reports have implicated ticarcillin as a cause of neutropenia; moxalactam has not been associated with this adverse effect in previous literature reports. Discontinuation of the suspected agent and initiation of an alternative antibiotic regimen is recommended as initial treatment of this condition since recovery usually occurs within days after discontinuing the offending drug.
S ummary
Severe neutropenia may be a more common complication of high‐dose penicillin therapy than previously recognized. This report describes five such patients, one of whom also had thrombocytopenia. The neutrophil and platelet counts rapidly increased on stopping penicillin, and the bone‐marrow, which was hypocellular in some cases, became normal. Further studies on one of these patients, using a fluorescent antiglobulin technique with paraformaldehyde‐fixed cells, demonstrated a complement‐fixing IgG penicillin antibody reacting with the patient's granulocytes and platelets in the presence of the drug. This suggested an immune mechanism similar to the well‐recognized penicillin‐induced immune haemolytic anaemia. The associated bone‐marrow hypoplasia may also be due to antibody‐mediated suppression of penicillin‐coated precursor cells.
Long-term parenteral beta-lactam treatment is often complicated by adverse reactions that necessitate drug withdrawal.
To evaluate the incidence and mechanism of beta-lactam adverse reactions during an 8-year period in all episodes of suspected infective endocarditis in patients treated at a university-affiliated institution.
Patients with 215 consecutive episodes of beta-lactam treatment for 10 days or more were prospectively enrolled during 2 periods, January 1984 through December 1988 and January 1993 through December 1995, and compared with 51 episodes of vancomycin hydrochloride treatment for 10 days or more. Incidents of adverse reactions, such as fever, rash, or neutropenia, were registered. Neutrophil counts, eosinophil counts, and penicillin antibodies were studied. Patients with delayed adverse reactions to penicillin G sodium were rechallenged with penicillin v potassium.
Incidence of delayed adverse reactions during treatment was 33% with beta-lactams compared with 4% with vancomycin. Rates of adverse event for beta-lactams increased continuously from treatment day 15 to day 30. A 6-fold difference in capacity to induce adverse events was found with different beta-lactams. Penicillin G induced neutropenia in 14% and any adverse event in 51% of treated episodes. Mean daily doses significantly influenced the frequency of adverse events. Occurrence of hemagglutinating penicillin antibodies was significantly related to patients whose penicillin-treated episodes were complicated with adverse events. Patients with delayed adverse reactions to penicillin G were safely rechallenged with penicillin.
Incidence of delayed adverse reactions to beta-lactams increases sharply when parenteral treatment is extended beyond 2 weeks. Penicillin G is the most frequent inducer of adverse reactions among beta-lactams studied. An immunological reaction mediated by antibodies to the penicilloyl determinant may be involved in the pathogenesis, possibly enhanced by a dose-related toxic trigger mechanism. Beta-Lactam-induced neutropenia followed a uniform pattern, occurring after, on average, 21 days of treatment, and might be due to both immunologic and toxic effects of treatment. Patients with a late adverse reaction to penicillin can safely be re-treated with penicillin, although they should remain under close surveillance if treatment extends beyond 2 weeks.
Complications in children receiving outpatient parenteral antibiotic therapy were reviewed. Catheter-associated complications and/or adverse drug reactions occurred in 50% of courses. Most complications were minor, and almost all infections were successfully treated. Even with early discontinuation of parenteral antibiotics because of adverse drug reactions in 24% of the courses, the outcome was excellent.
There are few data on the use of outpatient parenteral antimicrobial therapy (OPAT) in the management of osteoarticular infections (OAIs) in childhood. The objective of this study was to determine if OPAT is safe and effective in the management of OAIs. Using their OPAT database, the authors evaluated the use of OPAT in children younger than 18 years old treated for OAIs between January 1, 1995, and December 31, 1999. One hundred eighty-four OAIs were treated in 179 patients over 5 years. OPAT involved central venous lines (CVLs) in 110 (59.8%), peripherally inserted central catheters (PICCs) in 71 (38.6%), and peripheral cannulas in 3 (1.6%). One hundred eighteen (64%) OPAT courses were completed without interruption. Rehospitalization occurred in 48 (26.1%) courses and occurred earlier with PICC. OPAT complications were catheter-related in 58 (30%) courses, not catheter-related in 60 (32%), and unknown in 10 (5.3%). The mechanical complication rate was 6.3 per 1,000 catheter-days (CVL 4.2, PICC 10.6), and the rate of infectious complications was 2.7 per 1,000 catheter-days (CVL 2.8, PICC 2.4). One hundred sixty-eight (98%) of 172 evaluable OAIs were cured. Four (2.2%) patients failed treatment: one had recurrence and three had persistent infection. The authors conclude that OPAT can be safely used to manage OAIs in children without compromising outcome. Mechanical complications are more common with PICCs.
Drug therapy plays a significant role in causing neutropenia. The neutropenia may be immune mediated or due to direct inhibition of the bone marrow precursors. Recently, due to wide use of chemotherapy, febrile neutropenia has become a common and devastating problem. Neutropenia predisposes to many bacterial and fungal infections with organisms including gram negative bacilli such as E. coli, Klebsiella, and Pseudomonas; gram positive organisms such as Staphylococcus, Streptococcus viridans, and Enterococcus species; and fungi, like Candida and Aspergillus. In addition to the customary supportive care for neutropenic patients, therapy with recombinant human granulocyte colony-stimulating factor (rG-CSF) (filgrastim) has been shown to be beneficial. Filgrastim was a significant advance in the management of drug induced neutropenia in the past decade, but therapy with pegfilgrastim (a pegylated, long-acting form of filgrastim) ushers in the current decade. Pegfilgrastim (Neulasta) is administered as a single s.c. injection once per chemotherapy cycle. This results in fewer injections, fewer patient visits to the physician's office, and better patient compliance with therapy.
Nonchemotherapy drug-induced agranulocytosis is a rare adverse reaction that is characterized by a decrease in peripheral neutrophil count to less than 0.5 x 10(9) cells/L due to immunologic or cytotoxic mechanisms.
To systematically review case reports of drugs that are definitely or probably related to agranulocytosis.
English-language and German-language reports in MEDLINE (1966 to 2006) or EMBASE (1989 to 2006) and in bibliographies of retrieved articles.
Published case reports of patients with nonchemotherapy drug-induced agranulocytosis.
One reviewer abstracted details about cases and assessed causality between drug intake and agranulocytosis by using World Health Organization assessment criteria.
Causality assessments of 980 reported cases of agranulocytosis were definite in 56 (6%), probable in 436 (44%), possible in 481 (49%), and unlikely in 7 (1%). A total of 125 drugs were definitely or probably related to agranulocytosis. Drugs for which more than 10 reports were available (carbimazole, clozapine, dapsone, dipyrone, methimazole, penicillin G, procainamide, propylthiouracil, rituximab, sulfasalazine, and ticlopidine) accounted for more than 50% of definite or probable reports. Proportions of fatal cases decreased between 1966 and 2006. More patients with a neutrophil count nadir less than 0.1 x 10(9) cells/L had fatal complications than did those with a neutrophil count nadir of 0.1 x 10(9) cells/L or greater (10% vs. 3%; P < 0.001). Patients treated with hematopoietic growth factors had a shorter median duration of neutropenia (8 days vs. 9 days; P = 0.015) and, among asymptomatic patients at diagnosis, had a lower proportion of infectious or fatal complications (14% vs. 29%; P = 0.030) than patients without such treatment.
Case reports cannot provide rates of drug-induced complications, sometimes incompletely assess or describe important details, and sometimes emphasize atypical features and outcomes.
Many drugs can cause nonchemotherapy drug-induced agranulocytosis. Case fatality may be decreasing over time with the availability of better treatment.
Idiosyncratic drug-induced agranulocytosis or acute neutropenia is an adverse event resulting in a neutrophil count of under 0.5 x 10/l. Patients with such severe neutropenia are likely to experience life-threatening and sometimes fatal infections.
Over the last 20 years, the incidence of idiosyncratic drug-induced agranulocytosis or acute neutropenia has remained stable at 2.4-15.4 cases per million, despite the emergence of new causative drugs: antibiotics (beta-lactam and cotrimoxazole), antiplatelet agents (ticlopidine), antithyroid drugs, sulfasalazine, neuroleptics (clozapine), antiepileptic agents (carbamazepine), nonsteroidal anti-inflammatory agents and dipyrone. Drug-induced agranulocytosis remains a serious adverse event due to the occurrence of severe sepsis with severe deep infections (such as pneumonia), septicemia and septic shock in around two thirds of patients. In this setting, old age (>65 years), septicemia or shock, metabolic disorders such as renal failure, and a neutrophil count under 0.1 x 10/l are poor prognostic factors. Nevertheless with appropriate management using preestablished procedures, with intravenous broad-spectrum antibiotic therapy and hematopoietic growth factors, the mortality rate is currently around 5%.
Given the increased life expectancy and subsequent longer exposure to drugs, as well as the development of new agents, healthcare professionals should be aware of this adverse event and its management.
Neutropenia unrelated to chemotherapy toxicity occurs in a number of clinical settings. The most common conditions associated with neutropenia are those that are acquired, including viral infection, neutropenia associated with various medications, and immune neutropenia. Inherited neutropenias are rarer and often more profound. These disorders include the dominant or sporadic types of severe congenital neutropenia (often with mutations in the ELA2 gene), the recessive type or Kostmann syndrome, and the marrow failure syndromes such as Fanconi anemia. Cyclic neutropenia may be severe at the nadir of the cycle. Of particular concern is the occurrence of fever in conjunction with neutropenia. This combination creates a medical emergency that must be addressed with appropriate evaluation and prompt administration of antibiotics. The actual risk of severe infection and the likelihood of recovery depend not only on the level of the ANC, but on the duration of the neutropenia. If recovery from the neutropenia is not expected, as in severe congenital types, G-CSF administration may be indicated.
Review: drug-induced neutropenia—pathophysiology, clinical features, and management
- Bhatt
Bhatt V, Saleem A. Review: drug-induced neutropeniapathophysiology, clinical features, and management. Ann
Clin Lab Sci. 2004;34(2):131-138.
Suppurative complications of acute hematogenous osteomyelitis in children
- J J Johnson
- C Murray-Krezan
- W Dehority
Johnson JJ, Murray-Krezan C, Dehority W. Suppurative
complications of acute hematogenous osteomyelitis in
children. J Pediatr Orthop B. 2017;26(6):491-496.
OH: Wolters Kluwer Clinical Drug Information
- Vancomycin
- Lexicomp
- Hudson
Amoxicillin-clavulonate. Lexicomp. Hudson, OH: Wolters
Kluwer Clinical Drug Information. Updated May 21, 2019.
https://online.lexi.com/lco/action/home. Accessed January 11, 2019.
Infectious etiologies of transient neutropenia in previously healthy children
- E H Hussain
- A Mullah-Ali
- S Al-Sharidah
Hussain EH, Mullah-Ali A, Al-Sharidah S, et al. Infectious
etiologies of transient neutropenia in previously healthy
children. Pediatr Infect Dis J. 2012;31(6):575-577.
OH: Wolters Kluwer Clinical Drug Information
- Amoxicillin
- Lexicomp
- Hudson
OH: Wolters Kluwer Clinical Drug Information
- Cefotaxime
- Lexicomp
- Hudson
OH: Wolters Kluwer Clinical Drug Information
- Ceftriaxone
- Lexicomp
- Hudson
OH: Wolters Kluwer Clinical Drug Information
- Cefepime
- Lexicomp
- Hudson
OH: Wolters Kluwer Clinical Drug Information
- Ciprofloxacin
- Lexicomp
- Hudson
OH: Wolters Kluwer Clinical Drug Information
- Cefazolin
- Lexicomp
- Hudson
OH: Wolters Kluwer Clinical Drug Information
- Cephalexin
- Lexicomp
- Hudson
OH: Wolters Kluwer Clinical Drug Information
- Trimethoprim-Sulfamethoxazole
- Lexicomp
- Hudson
OH: Wolters Kluwer Clinical Drug Information
- Nafcillin
- Lexicomp
- Hudson
OH: Wolters Kluwer Clinical Drug Information
- Gentamicin
- Lexicomp
- Hudson
OH: Wolters Kluwer Clinical Drug Information
- Clindamycin
- Lexicomp
- Hudson
OH: Wolters Kluwer Clinical Drug Information
- Linezolid
- Lexicomp
- Hudson
OH: Wolters Kluwer Clinical Drug Information
- Piperacillin-Tazobactam
- Lexicomp
- Hudson
OH: Wolters Kluwer Clinical Drug Information
- Rifampin
- Lexicomp
- Hudson
OH: Wolters Kluwer Clinical Drug Information
- Meropenem
- Lexicomp
- Hudson
OH: Wolters Kluwer Clinical Drug Information
- Doxycycline
- Lexicomp
- Hudson