Michael Postelnick

In Vitro Activities of Various Antimicrobials Alone and in Combination with Tigecycline against Carbapenem-Intermediate or -Resistant Acinetobacter baumannii

ABSTRACT The activities of tigecycline alone and in combination with other antimicrobials are not well defined for carbapenem-intermediate or -resistant Acinetobacter baumannii (CIRA). Pharmacodynamic activity is even less well defined when clinically achievable serum concentrations are considered. Antimicrobial susceptibility testing of clinical CIRA isolates from 2001 to 2005 was performed by broth or agar dilution, as appropriate. Tigecycline concentrations were serially increased in time-kill studies with a representative of the most prevalent carbapenem-resistant clone (strain AA557; imipenem MIC, 64 mg/liter). The in vitro susceptibility of the strain was tested by time-kill studies in duplicate against the average free serum steady-state concentrations of tigecycline alone and in combination with various antimicrobials. Ninety-three CIRA isolates were tested and were found to have the following antimicrobial susceptibility profiles: tigecycline, MIC50 of 1 mg/liter and MIC90 of 2 mg/liter; minocycline, MIC50 of 0.5 mg/liter and MIC90 of 8 mg/liter; doxycycline, MIC50 of 2 mg/liter and MIC90 of ≥32 mg/liter; ampicillin-sulbactam, MIC50 of 48 mg/liter and MIC90 of 96 mg/liter; ciprofloxacin, MIC50 of ≥16 mg/liter and MIC90 of ≥16 mg/liter; rifampin, MIC50 of 4 mg/liter and MIC90 of 8 mg/liter; polymyxin B, MIC50 of 1 mg/liter and MIC90 of 1 mg/liter; amikacin, MIC50 of 32 mg/liter and MIC90 of ≥32 mg/liter; meropenem, MIC50 of 16 mg/liter and MIC90 of ≥128 mg/liter; and imipenem, MIC50 of 4 mg/liter and MIC90 of 64 mg/liter. Among the tetracyclines, the isolates were more susceptible to tigecycline than minocycline and doxycycline, according to FDA breakpoints (95%, 88%, and 71% of the isolates were susceptible to tigecycline, minocycline, and doxycycline, respectively). Concentration escalation studies with tigecycline revealed a maximal killing effect near the MIC, with no additional extent or rate of killing at concentrations 2× to 4× the MIC for tigecycline. Time-kill studies demonstrated indifference for tigecycline in combination with the antimicrobials tested. Polymyxin B, minocycline, and tigecycline are the most active antimicrobials in vitro against CIRA. Concentration escalation studies demonstrate that tigecycline may need to approach concentrations higher than those currently achieved in the bloodstream to adequately treat CIRA bloodstream infections. Future studies should evaluate these findings in vivo.

Potential Impact of Vancomycin Pulmonary Distribution on Treatment Outcomes in Patients with Methicillin‐Resistant Staphylococcus aureus Pneumonia

Vancomycin as the drug of choice for treatment of methicillin‐resistant Staphylococcus aureus (MRSA) pneumonia has been called into question on the basis of therapeutic failures. In patients with MRSA pneumonia, treatment failures are probably due to the complex interplay of variables affecting the host‐antimicrobial‐pathogen interrelationship. However, it has been suggested that decreased penetration of vancomycin into the lungs may contribute. This review explores physiochemical and physiologic variables that affect pulmonary penetration and describes methods used in quantifying pulmonary vancomycin concentrations. Most important, findings are evaluated in the clinical context of the chemotherapeutic options available for treatment of MRSA pneumonia. The possibility of increased serum vancomycin concentrations as a method to optimize current treatment outcomes is also explored.

Increasing Incidence of Linezolid-Intermediate or -Resistant, Vancomycin-Resistant Enterococcus faecium Strains Parallels Increasing Linezolid Consumption

ABSTRACT Clinical enterococcal resistance to linezolid is defined by the presence of the G2576T mutation. We evaluated the incidence of genetically proven linezolid resistance among vancomycin-resistant Enterococcus faecium strains and linezolid consumption for a possible association. A relationship was found (r2 = 0.73, P = 0.03) and predicts increasing resistance with current trends of linezolid use.

Impact of Carbapenem Resistance and Receipt of Active Antimicrobial Therapy on Clinical Outcomes of Acinetobacter baumannii Bloodstream Infections

ABSTRACT Nosocomial Acinetobacter baumannii bloodstream infections occur with significant prevalence and mortality. The relationship between carbapenem resistance in A. baumannii and patient outcomes remains unclear. A retrospective cohort study was conducted on patients with A. baumannii bacteremia. Outcomes, controlling for confounders, were compared for carbapenem-nonresistant A. baumannii (CNRAB) and carbapenem-resistant A. baumannii (CRAB). The primary outcome studied was all-cause hospital mortality, and the secondary endpoints evaluated were time to mortality, time to negative cultures, and length of stay postinfection for survivors. A total of 79 patients, 37 infected with CRAB and 42 with CNRAB, were studied. Hospital mortality was greater in the CRAB group as determined based on bivariate analysis (P < 0.01); however, this effect was nullified when controlling for relevant confounders with logistic regression and a Cox proportional-hazards model (P = 0.71 and 0.75, respectively). Values for time to mortality and time to negative cultures did not differ between the groups. The median number of days of stay postinfection for survivors was greater for the CRAB group than the CNRAB group (14 versus 6.5; P < 0.01). Patients who received active antimicrobial therapy were less likely to die (93.5% versus 74.2%; P = 0.02), regardless of carbapenem susceptibility classifications, and this result was robust in the multivariate model (P = 0.02). Trends existed for improved outcomes in patients receiving an active beta-lactam, and patients fared worse if they had received a polymyxin as an active agent. Patients with CRAB bloodstream infections were more chronically ill and had more comorbidities. Inactive therapy was more important than carbapenem susceptibility with respect to outcomes, was a strong predictor of death, and is potentially modifiable.

The utility of aminoglycosides in an era of emerging drug resistance

As the problem of global antibiotic resistance continues to worsen, aminoglycosides have assumed increasing importance in clinical practice. Their broad antimicrobial spectrum, rapid bactericidal action, and ability to act synergistically with other drugs have made them especially useful in the treatment of serious nosocomial infections. However, as with other drugs, their overuse and misuse leads to the development of resistance in important microbial pathogens. The appropriate use of the aminoglycosides is essential to assure their continued efficacy. Therefore, physicians must familiarize themselves with both the clinical indications and the limitations of these drugs if they are to remain efficacious in the years to come.

Use of Electronic Health Records and Clinical Decision Support Systems for Antimicrobial Stewardship

Electronic health records (EHRs) and clinical decision support systems (CDSSs) have the potential to enhance antimicrobial stewardship. Numerous EHRs and CDSSs are available and have the potential to enable all clinicians and antimicrobial stewardship programs (ASPs) to more efficiently review pharmacy, microbiology, and clinical data. Literature evaluating the impact of EHRs and CDSSs on patient outcomes is lacking, although EHRs with integrated CDSSs have demonstrated improvements in clinical and economic outcomes. Both technologies can be used to enhance existing ASPs and their implementation of core ASP strategies. Resolution of administrative, legal, and technical issues will enhance the acceptance and impact of these systems. EHR systems will increase in value when manufacturers include integrated ASP tools and CDSSs that do not require extensive commitment of information technology resources. Further research is needed to determine the true impact of current systems on ASP and the ultimate goal of improved patient outcomes through optimized antimicrobial use.

Cost-effectiveness analysis of an antimicrobial stewardship team on bloodstream infections: a probabilistic analysis

OBJECTIVES We sought to determine the cost-effectiveness of Antimicrobial Stewardship Teams (ASTs) on the reduction of morbidity and mortality associated with nosocomial bacteraemia. METHODS A decision analytic model compared costs and outcomes of bacteraemic patients receiving standard treatment with or without an AST consult. Patients with a bacteraemic event during their hospital admission were included in the model. Effectiveness was estimated as quality-adjusted life years (QALYs) over the lifetime of patients. Model variables and costs, along with their distributions, were obtained from the literature and expert opinion. Incremental cost-effectiveness ratios (ICERs) were calculated to estimate the cost per QALY gained from the hospital perspective. Uncertainty in ICERs was evaluated with probabilistic sensitivity analyses. The cost-effectiveness of clinical decision support systems was evaluated as a secondary analysis. RESULTS Implementing an AST for bacteraemia review cost

Impact of inactive empiric antimicrobial therapy on inpatient mortality and length of stay.

39,737 (95% CI

The Impact of Anti-infective Drug Shortages on Hospitals in the United States: Trends and Causes

27,272-53, 017) and standard treatment cost

Antimicrobial stewardship programs: methods of operation and suggested outcomes

39,563 (95% CI