[Show abstract][Hide abstract] ABSTRACT: Antimicrobial resistance in Gram-negative bacteria is an emerging and serious global public health threat. Carbapenems have
been used as the “last-line” treatment for infections caused by resistant enterobacteriaceae, including those producing extended
spectrum ß-lactamases. However, enterobacteriaceae that produce carbapenemases, which are enzymes that deactivate carbapenems
and most other ß-lactam antibiotics, have emerged and are increasingly being reported worldwide. Despite this increasing burden,
the most optimal treatment for carbapenem-resistant enterobacteriaceae (CRE) infections is largely unknown. For the few remaining
available treatment options, there is limited efficacy data to support their role in therapy. Nevertheless, current treatment
options include the use of older agents, such as polymyxins, fosfomycin, and aminoglycosides, which have been rarely used
due to efficacy and/or toxicity concerns. Optimization of dosing regimens and combination therapy are additional treatment
strategies being explored. CRE infections are associated with poor outcomes and high mortality. Continued research is critically
needed to determine the most appropriate treatment.
[Show abstract][Hide abstract] ABSTRACT: Alcohols, including ethanol and isopropyl alcohol, are used in clinical practice for disinfection and infection prevention. Recent studies, however, demonstrate that alcohols may enhance biofilm production in Staphylococci.
We quantified biofilm formation in the presence of ethanol and isopropyl alcohol in six different, well-characterized strains of Staphylococcus epidermidis and Staphylococcus aureus. After 24 h of biofilm development, each strain was exposed to normal saline (NS), ethanol, or isopropyl alcohol (40%, 60%, 80% and 95%) for additional 24 h incubation. Adherent biofilms were stained and optical density was determined. Viability of strains was also determined after alcohol exposure.
Ethanol increased biofilm formation in all six strains compared to normal saline (p < 0.05). There was increased biofilm formation with increasing ethanol concentration. Isopropyl alcohol also increased biofilm formation with increasing alcohol concentration in all six strains (p < 0.01 vs NS). The slime-negative, chemical mutant strain of S. epidermidis increased biofilm formation after exposure to both alcohols, likely reverting back its primary phenotype through modulation of the intercellular adhesin repressor. All strains demonstrated viability after exposure to each alcohol concentration, though viability was decreased.
Ethanol and isopropyl alcohol exposure increases biofilm formation of S. aureus and S. epidermidis at concentrations used in clinical settings. Ethanol and isopropyl alcohol did not eradicate viable Staphylococci from formed biofilm.
[Show abstract][Hide abstract] ABSTRACT: Multidrug resistant pathogens have become a major public health concern. There is a great need for the development of novel antibiotics with alternative mechanisms of action for the treatment of life-threatening bacterial infections. Antimicrobial peptides (AMPs), a major class of antibacterial agents, share amphiphilicity and cationic structural properties with cell-penetrating peptides (CPPs). Herein, several amphiphilic cyclic CPPs and their analogs were synthesized and exhibited potent antibacterial activities against multidrug resistant pathogens. Among all the peptides, cyclic peptide [R4W4] (1) showed the most potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA, exhibiting a minimum inhibitory concentration (MIC) of 2.67 µg/mL). Cyclic [R4W4] and the linear counterpart R4W4 exhibited MIC values of 42.8 and 21.7 µg/mL, respectively, against Pseudomonas aeruginosa. In eukaryotic cells, peptide 1 exhibited the cell-penetrating properties as expected, and showed more than 84% cell viability at 15 µM (20.5 µg/mL) concentration in three different human cell lines. Twenty-four hour time-kill studies evaluating [R4W4] with 2× the MIC in combination with tetracycline demonstrated bactericidal activity at 4 and 8× the MIC of tetracycline against MRSA (MIC = 0.5 µg/mL) and 2-8× the MIC against E. coli (MIC = 2 µg/mL), respectively. This study suggests that when amphiphilic cyclic CPPs are used in combination with an antibiotic such as tetracycline, they provide significant benefit against multi-drug resistant pathogens when compared with the antibiotic alone.
[Show abstract][Hide abstract] ABSTRACT: Objectives Antimicrobial lock solutions are used for prevention and management of catheter-related bloodstream infections. ML8-X10 (a
prototype oil-in-water micro-emulsion based on a novel free fatty acid), vancomycin/heparin and taurolidine/citrate/heparin
(Taurolock™-Hep500) lock solutions were tested against biofilm-forming Staphylococcus epidermidis and methicillin-susceptible Staphylococcus aureus.
[Show abstract][Hide abstract] ABSTRACT: Streptococcus pneumoniae is a major cause of morbidity and mortality. We sought to describe the epidemiology of non-invasive and invasive pneumococcal disease in a national Veterans Affairs population within the United States.
[Show abstract][Hide abstract] ABSTRACT: Enterococci are the third most frequent cause of infective endocarditis. A high-inoculum stationary phase in vitro pharmacodynamic model with simulated endocardial vegetations was used to simulate human pharmacokinetics of daptomycin 6 or 10mg/kg/day, or linezolid 600mg q12h alone and in combination with gentamicin 1.3mg/kg q12h, rifampin 300mg q8h or 900mg q24h. Biofilm-forming vancomycin-susceptible Enterococcus faecalis and vancomycin-resistant E. faecium (VRE) were tested. At 24, 48 and 72h, all daptomycin-containing regimens demonstrated significantly more activity (decline in CFU/g) than any linezolid-containing regimen against biofilm-forming E. faecalis. The addition of gentamicin to daptomycin (6 and 10mg/kg) in the first 24 hours significantly improved the bactericidal activity. In contrast, addition of rifampin delayed the bactericidal activity of daptomycin against E. faecalis; and against VRE, antagonized all regimens at 24h. Also, against VRE, addition of gentamicin to linezolid at 72h improved activity and was bactericidal. Rifampin significantly antagonized the activity of linezolid against VRE at 72h. In in vivo Galleria mellonella survival assays, linezolid and daptomycin improved survival. Daptomycin 10mg/kg improved survival significantly over linezolid against E. faecalis. Addition of gentamicin improved efficacy of daptomycin against E. faecalis and linezolid and daptomycin against VRE. We conclude that in enterococcal infection models, daptomycin has more activity than linezolid alone. Against biofilm-forming E. faecalis, the addition of gentamicin in the first 24h causes the most rapid decline in CFU/g. Of interest, addition of rifampin delayed or antagonized activity of daptomycin against biofilm-forming E. faecalis and VRE respectively in the first 24h.
[Show abstract][Hide abstract] ABSTRACT: As variability in vancomycin dosing, susceptibility, and tolerability has driven the need to compare newer agents with vancomycin in real-world clinical settings, we sought to quantify the effectiveness of linezolid compared with vancomycin on clinical outcomes for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia.
Retrospective cohort study.
Veterans Health Administration national databases.
Adults admitted to Veterans Affairs hospitals between January 2002 and September 2010 with diagnosis codes for MRSA and pneumonia, plus initiation and receipt of at least 3 days of continuous intravenous vancomycin therapy (4943 patients) or intravenous or oral linezolid therapy (328 patients) while in the hospital.
Propensity score-adjusted Cox proportional hazards regression models quantified the effect of linezolid compared with vancomycin on time to 30-day mortality (primary outcome), therapy change, hospital discharge, discharge from intensive care, intubation, 30-day readmission, and 30-day MRSA reinfection. In addition, a composite outcome of clinical success was defined as discharge from the hospital or intensive care unit by day 14 after treatment initiation, in the absence of death, therapy change, or intubation by day 14. Subgroup analyses were performed in a validated microbiology-confirmed MRSA subgroup and clinical subgroup meeting clinical criteria for infection. Although a number of baseline variables differed significantly between the vancomycin and linezolid treatment groups, balance was achieved within propensity score quintiles. A significantly lower rate of therapy change was observed in the linezolid group (adjusted hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.48-0.96). The clinical success rate was significantly higher among patients treated with linezolid (adjusted HR 1.25, 95% CI 1.07-1.47). Comparable findings were observed in the subgroup analyses.
Individual clinical outcomes were similar among patients treated for MRSA pneumonia with linezolid compared with vancomycin. A significantly higher rate of the composite outcome of clinical success was observed, however, among patients treated with linezolid compared with vancomycin.
[Show abstract][Hide abstract] ABSTRACT: A recent analysis demonstrated that infectious diseases (ID) specialty intervention was associated with decreased mortality and hospital readmission. These benefits were greatest if involvement occurred within two days of hospital admission. Antimicrobial stewardship programs should augment the services of an ID specialist team and promote formal consultation. Implementation of an antimicrobial stewardship program at the Providence Veterans Affairs Medical Center was associated with an increased number of consults (increase of 72.2%) and decreased time to consult (3.5 days sooner), which might also dramatically improve patient outcomes, including mortality and readmission rates.
[Show abstract][Hide abstract] ABSTRACT: Background
The treatment of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia is exceedingly complicated, which is concerning because of the high mortality rate associated with the infection. Identification of independent predictors of clinical success can optimize patient care by assisting clinicians in treatment decisions.
Our goal was to identify independent predictors of clinical success in a national Veterans Affairs (VA) cohort of patients with MRSA pneumonia.
A nested case-control study was conducted among a cohort of VA patients with MRSA pneumonia receiving linezolid or vancomycin between January 2002 and September 2010. Cases included those demonstrating clinical success, defined as discharge from the hospital or intensive care unit by day 14 after treatment initiation, in the absence of death, therapy change, or intubation by day 14. Control subjects represented nonsuccess, defined as therapy change, intubation, intensive care unit admission, readmission, or death between treatment initiation and day 14. The potential predictors assessed included treatment, patient demographic and admission characteristics, previous health care and medication exposures, comorbidities, and medical history. Odds ratios (ORs) and 95% CIs were calculated from logistic regression.
Our study included 2442 cases of clinical success and 1290 control subjects. Demographic characteristics varied between the clinical success and nonsuccess groups, including age, race, and region of facility. A current diagnosis of chronic respiratory disease (46% vs 42%) and diagnosis of pneumonia in the year before the MRSA pneumonia admission (37% vs 32%) were both more common in the clinical success group. Despite these significant differences, only 2 predictors of clinical success were identified in our study: previous complication of an implant or graft, including mechanical complications and infections, in the year before the MRSA pneumonia admission (adjusted OR, 1.55 [95% CI, 1.17–2.06]) and treatment with linezolid (adjusted OR, 1.53 [95% CI, 1.12–2.10]). Predictors of nonsuccess (adjusted OR [95% CI) included diagnosis of concomitant urinary tract infection (0.82 [0.70–0.96]), intravenous line (0.76 [0.66–0.89]), previous coagulopathy (0.74 [0.56–0.96]), previous amputation procedure (0.72 [0.53–0.98]), current coagulopathy diagnosis (0.71 [0.53–0.96]), dialysis (0.54 [0.38–0.76]), multiple inpatient procedures (0.53 [0.45–0.62]), inpatient surgery (0.48 [0.41–0.57]), and previous endocarditis (0.24 [0.07–0.81]).
MRSA pneumonia tends to affect patients with complex care, and identification of the predictors of clinical success is useful when considering different therapeutic approaches. In this national cohort of VA patients with MRSA pneumonia, treatment was the only modifiable variable predicting clinical success.
[Show abstract][Hide abstract] ABSTRACT: Results of a pharmacoepidemiologic evaluation of fluoroquinolone-associated hepatotoxicity using national hospital admissions data on Veterans Affairs (VA) patients are reported.
In a retrospective case-control study, all adults with a primary diagnosis of hepatotoxicity on admission to a VA facility during a 6.5-year period (January 2002-June 2008) were identified. After the exclusion of patients whose records indicated known causes of hepatotoxicity or a history of liver disease, a subgroup of 7,862 patients with exposure to fluoroquinolone antibiotics in the six months prior to hospital admission were matched with nonexposed controls (n = 45,512). Conditional logistic regression was used to assess the overall and drug-specific risks of hepatotoxicity in the case group, controlling for comorbidities, concomitant use of known hepatotoxic medications, and other variables.
After adjusting for confounders, logistic regression analysis indicated a significantly higher overall risk of hepatotoxicity development among fluoroquinolone users relative to controls (odds ratio [OR], 1.20; 95% confidence interval [CI], 1.04-1.38). Drug-specific risk analyses focused on three fluoroquinolone agents (ciprofloxacin, levofloxacin, and moxifloxacin) indicated a significant association between ciprofloxacin use and an increased risk of hepatotoxicity (OR, 1.29; 95% CI, 1.05-1.58); when considered as independent variables, levofloxacin use and moxifloxacin use were not significantly associated with hepatotoxicity risk.
The findings of a national VA safety study suggested an increased hepatotoxicity risk asssociated with fluoroquinolone exposure in the study population.
American journal of health-system pharmacy: AJHP: official journal of the American Society of Health-System Pharmacists 01/2014; 71(1):37-43. DOI:10.2146/ajhp130165 · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Indwelling medical devices have become a major source of nosocomial infections; especially Pseudomonas aeruginosa (P. aeruginosa) infection, which remain the most common cause of ventilator associated pneumonia (VAP) in neonates and children. Using medical grade polyvinyl chloride endotracheal tubes (ETTs), the activity of tobramycin and polymyxin-E was quantified in a simulated prevention and treatment static time kill model using biofilm forming P. aeruginosa. The model simulated three clinical conditions: 1) planktonic bacteria in the presence of antibiotics, tobramycin and polymyxin-E, without ETTs, 2) planktonic bacteria grown in the presence of P. aeruginosa, antibiotic and ETTs (simulating prevention) and 3) a 24h formed P. aeruginosa biofilm on ETTs prior to antibiotic exposure (simulating treatment). In the model simulating "prevention" (conditions 1 and 2 above), tobramycin alone or in combination with polymyxin-E was more bactericidal than polymyxin-E alone at 24 hours using a concentration greater than 2 times the minimum inhibitory concentration (MIC). However, after a 24h old biofilm was allowed to form on the ETTs, neither monotherapy nor combination therapy over 24 hours exhibited bactericidal or bacteriostatic effects. Against the same pathogens, tobramycin and polymyxin-E, both alone or in combination exhibited bactericidal activity prior to biofilm attachment to the ETTs, however no activity was observed once biofilm formed on ETTs. These findings support surveillance culturing to identify pathogens for a rapid and targeted approach to therapy, especially when P. aeruginosa is a potential pathogen.
[Show abstract][Hide abstract] ABSTRACT: The prevalence of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) infections varies in the literature, complicated by the lack of routine screening procedures; however, limited data suggest hVISA has been associated with persistent bloodstream infections (BSI) and vancomycin failure yet these studies have been confounded by design. We conducted this study to characterize patients with BSI caused by hVISA compared to vancomycin-susceptible Staphylococcus aureus (VSSA) treated with vancomycin. This retrospective, multi-center matched (1:1) cohort study compared the clinical characteristics and outcomes of hVISA and VSSA. Patients with hVISA methicillin-resistant Staphylococcus aureus (MRSA) BSI from 2004-2012 were matched to VSSA-MRSA BSI. The primary outcome was vancomycin failure, defined as a composite of: persistent bacteremia (≥ 7 days), persistent signs and symptoms, change of MRSA antibiotic, recurrent BSI, or MRSA-related mortality. We identified 122 matched cases. Overall vancomycin failure was 57%; 82% hVISA vs. 33% VSSA, (p < 0.001). Individual components of failure in hVISA vs. VSSA: persistent bacteremia: 59% vs. 21%, (p < 0.001); MRSA therapy changed: 54% vs. 25%, (p = 0.001); MRSA-related mortality: 21% vs. 10%, (p = 0.081), recurrence of BSI: 26% vs. 2%, (p < 0.001). Using logistic regression analysis and adjusting for covariates, hVISA (aOR, 11.1; 95% CI 4.3-28.7) and ICU admission (aOR, 4.5; 95% CI 1.8-11.6) were still independently associated with vancomycin failure. Relative to VSSA BSI, patients with hVISA were more likely to experience failure to vancomycin, including persistent bacteremia and recurrence. Our results indicate that hVISA was responsible for considerable morbidity.
Antimicrobial Agents and Chemotherapy 06/2013; DOI:10.1128/AAC.00380-13 · 4.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The compatibility and stability of telavancin and vancomycin in heparin or sodium citrate lock solutions were evaluated.
Telavancin and vancomycin hydrochloride injection powder lyophilized for solution were reconstituted with 0.9% sodium chloride injection at room temperature according to the manufacturer's instructions and then further diluted with (1) commercially available heparin sodium to reach a final heparin concentration of 2500 units/mL or (2) sodium citrate solution 2.2% or 4% to achieve final telavancin and vancomycin concentrations of 2 and 5 mg/mL. Physical stability, chemical compatibility, and biological anticoagulant stability were analyzed for each antibiotic-anticoagulant combination immediately after preparation and at 24, 48, and 72 hours. Changes in coagulation were measured at each time point and compared using two-way analysis of variance.
Both telavancin and vancomycin retained at least 90% of the initial concentration after incubation at 37 °C over 72 hours. The biological stability of vancomycin 2 mg/mL and telavancin 2 mg/mL did not significantly alter prothrombin time when compared with that of 0.9% sodium chloride injection. However, telavancin 5 mg/mL and vancomycin 5 mg/mL significantly increased the activated partial thromboplastin time at 72 hours compared with the control solution. Visual precipitation only occurred with vancomycin-containing solutions; however, this dissipated after 10 minutes.
Telavancin 2 and 5 mg/mL was physically compatible in combination with heparin 2500 units/mL and with sodium citrate 2.2% and 4% over 72 hours. Vancomycin 2 and 5 mg/mL initially precipitated in the sodium citrate 2.2% formulation, but no precipitation was noted after 10 minutes of incubation at 37 °C. Telavancin and vancomycin 2 and 5 mg/mL retained over 90% of the initial concentration after incubation at 37 °C over 72 hours.
American journal of health-system pharmacy: AJHP: official journal of the American Society of Health-System Pharmacists 08/2012; 69(16):1405-9. DOI:10.2146/ajhp110256 · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Biofilm embedded bacterial pathogens such as Staphylococcus spp., Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii are difficult to eradicate and are major sources of bacterial infections. New drugs are needed to combat these pathogens. Hypericum is a plant genus that contains species known to have antimicrobial properties. However, the specific constituents responsible for the antimicrobial properties are not entirely known, nor have most compounds been tested as inhibitors of biofilm development. The investigation presented here tested seven secondary metabolites isolated from the species Hypericum densiflorum, Hypericum ellipticum, Hypericum prolificum, and Hypericum punctatum as inhibitors of bacterial growth and biofilm production. Assays were conducted against Staphylococcus epidermidis, Staphylococcus aureus, clinical methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, Escherichia coli, and Acinetobacter baumannii. Five of the seven compounds demonstrated growth inhibition against the Gram-positive bacteria with minimum inhibitory concentrations (MIC) ranging from 1.95 µg/mL to 7.81 µg/mL. Four of the secondary metabolites inhibited biofilm production by certain Gram-positive strains at sub-MIC concentrations.
Phytotherapy Research 07/2012; 26(7):1012-6. DOI:10.1002/ptr.3675 · 2.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In vitro coagulation effects of bevacizumab, a drug with potential risks for severe hemorrhagic and arterial thromboembolic events (ATEs), are unknown. The aim of this study was to evaluate the effects of bevacizumab, including the common ophthalmic dose of 1.25 mg, on the coagulation cascade.
Bevacizumab doses of 0.25, 0.5, 1.0, 1.25, 2.0, 2.5, and 4.0 mg were incubated at 37 °C in the presence of pooled normal plasma (PNP) to determine its biological activity via activated partial thromboplastin time (aPTT) and prothrombin time (PT) at 30 min, 1 h, and 2 h. The control consisted of 40% normal saline and 60% PNP. All evaluations were conducted in triplet. Coagulation at each time point was compared with the control group by analysis of variance with Tukey's post hoc test. A P value of ≤ 0.05 was considered significant.
Mean bevacizumab aPTT ranged from 38.4 to 43.9 s, 37.4 to 43.1 s, and 39.0 to 43.2 s at 30 min, 1 h, and 2 h, respectively. Mean bevacizumab PT ranged from 15.7 to 16.8 s at 30 min, 14.6 to 16.2 s at 1 h, and 14.0 to 15.8 s at 2 h. For the control, aPTT was similar over time (40.1, 40.0, and 40.5 s), while PT decreased from 16.5 at 30 min to 15.4 s at 2 h. Bevacizumab decreased PT significantly at 2 h, compared with the PNP control, for the following doses: 0.25 mg [difference between means 1.04 s, 95% confidence interval (CI) 0.12-1.96], 1.25 mg (1.16 s, 95% CI 0.16-2.15), 2.5 mg (0.94 s, 95% CI 0.02-1.86), and 4 mg (1.41 s, 95% CI 0.41-2.40). Significant differences were not observed in PT at 30 min and 1 h as compared with controls. For all doses of bevacizumab, aPTT did not vary from controls at the 3 measured times.
A common ophthalmic dose of bevacizumab 1.25 mg significantly increased in vitro coagulation. Further examination of the impact of ophthalmic bevacizumab on coagulation is warranted to provide insight into any putative link between ophthalmic bevacizumab and the risk for severe ATEs.
Journal of ocular pharmacology and therapeutics: the official journal of the Association for Ocular Pharmacology and Therapeutics 02/2012; 28(3):219-21. DOI:10.1089/jop.2011.0148 · 1.42 Impact Factor