Dana R. Bowers

Outcomes of Appropriate Empiric Combination versus Monotherapy for Pseudomonas aeruginosa Bacteremia

ABSTRACT Pseudomonas aeruginosa bacteremia is associated with high hospital mortality. Empirical combination therapy is commonly used to increase the likelihood of appropriate therapy, but the benefits of employing >1 active agent have yet to be established. The purpose of this study was to compare outcomes of patients receiving appropriate empirical combination versus monotherapy for P. aeruginosa bacteremia. This was a retrospective, multicenter, cohort study of hospitalized adult patients with P. aeruginosa bacteremia from 2002 to 2011. The primary endpoint (30-day mortality) was assessed using multivariate logistic regression, adjusting for underlying confounding variables. Secondary endpoints of hospital mortality and time to mortality were assessed by Fishers exact test and the Cox proportional hazards model, respectively. A total of 384 patients were analyzed. Thirty-day mortality was higher for patients receiving inappropriate therapy than for those receiving appropriate empirical therapy (43.8% versus 21.5%; P = 0.03). However, there were no statistical differences in 30-day mortality following appropriate empirical combination versus monotherapy after adjusting for baseline APACHE II scores and lengths of hospital stay prior to the onset of bacteremia (P = 0.55). Observed hospital mortality was 36.6% for patients administered combination therapy, compared with 28.7% for monotherapy patients (P = 0.17). After adjusting for baseline APACHE II scores, the relationship between time to mortality and combination therapy was not statistically significant (P = 0.59). Overall, no significant differences were observed for 30-day mortality, hospital mortality, and time to mortality between combination and monotherapy for P. aeruginosa bacteremia. Empirical combination therapy did not appear to offer an additional benefit, as long as the isolate was susceptible to at least one antimicrobial agent.

Assessment of Minocycline and Polymyxin B Combination against Acinetobacter baumannii

ABSTRACT Antimicrobial resistance among Acinetobacter baumannii is increasing worldwide, often necessitating combination therapy. The clinical utility of using minocycline with polymyxin B is not well established. In this study, we investigated the activity of minocycline and polymyxin B against 1 laboratory isolate and 3 clinical isolates of A. baumannii. Minocycline susceptibility testing was performed with and without an efflux pump inhibitor, phenylalanine-arginine β-naphthylamide (PAβN). The intracellular minocycline concentration was determined with and without polymyxin B (0.5 μg/ml). Time-kill studies were performed over 24 h using approximately 106 CFU/ml of each strain with clinically relevant minocycline concentrations (2 μg/ml and 8 μg/ml), with and without polymyxin B (0.5 μg/ml). The in vivo efficacy of the combination was assessed in a neutropenic murine pneumonia model. Infected animals were administered minocycline (50 mg/kg), polymyxin B (10 mg/kg), or both to achieve clinically equivalent exposures in humans. A reduction in the minocycline MIC (≥4×) was observed in the presence of PAβN. The intracellular concentration and in vitro bactericidal effect of minocycline were both enhanced by polymyxin B. With 2 minocycline-susceptible strains, the bacterial burden in lung tissue at 24 h was considerably reduced by the combination compared to monotherapy with minocycline or polymyxin B. In addition, the combination prolonged survival of animals infected with a minocycline-susceptible strain. Polymyxin B increased the intracellular concentration of minocycline in bacterial cells and enhanced the bactericidal activity of minocycline, presumably due to efflux pump disruption. The clinical utility of this combination should be further investigated.

Emerging Issues and Treatment Strategies in Carbapenem-Resistant Enterobacteriaceae (CRE).

Carbapenems are the broadest spectrum antimicrobials utilized in the treatment of serious infections since the 1980s. Soon after their introduction, the discovery of carbapenem-resistant Enterobacteriaceae (CRE) was reported in the 1990s. Invasive CRE infections are associated with high mortality and limited treatment options making care for patients with these infections challenging for clinicians. Current practice has reverted back to the use of “older” antimicrobials, such as the polymyxins, tigecycline, and fosfomycin, to combat invasive CRE infections. However, recent approval of ceftazidime-avibactam has added another treatment option to the current antimicrobial armamentarium. Resistance among the “older” agents is still rare but has been reported. Currently, there are numerous agents that are under investigation as well as combination therapy that looks promising in the treatment of CRE infections.

Kidney Injury Associated with Telavancin Dosing Regimen in an Animal Model

ABSTRACT The elevation of serum creatinine levels is a concern with telavancin therapy. We examined the onset of kidney injury associated with telavancin in an animal model. Urine samples were collected at baseline and daily to determine the concentrations of kidney injury molecule 1 (KIM-1), a marker for early kidney injury. When a clinically relevant exposure of telavancin was given daily to rats, some differences in kidney injury were attributed to the dosing regimen. Further investigations of alternative telavancin dosing regimens are warranted.

Early Administration of Adjuvant β-Lactam Therapy in Combination with Vancomycin among Patients with Methicillin-Resistant Staphylococcus aureus Bloodstream Infection: A Retrospective, Multicenter Analysis

To determine whether early administration of adjuvant β‐lactam in combination with vancomycin (COMBO) affects clinical outcomes compared to standard vancomycin therapy alone (STAN) among patients with methicillin‐resistant Staphylococcus aureus (MRSA) bloodstream infection.

Polymyxin B in Combination with Rifampin and Meropenem against Polymyxin B-Resistant KPC-Producing Klebsiella pneumoniae

ABSTRACT Safe and effective therapies are urgently needed to treat polymyxin-resistant KPC-producing Klebsiella pneumoniae infections and suppress the emergence of resistance. We investigated the pharmacodynamics of polymyxin B, rifampin, and meropenem alone and as polymyxin B-based double and triple combinations against KPC-producing K. pneumoniae isolates. The rates and extents of killing with polymyxin B (1 to 128 mg/liter), rifampin (2 to 16 mg/liter), and meropenem (10 to 120 mg/liter) were evaluated against polymyxin B-susceptible (PBs) and polymyxin B-resistant (PBr) clinical isolates using 48-h static time-kill studies. Additionally, humanized triple-drug regimens of polymyxin B (concentration at steady state [Css] values of 0.5, 1, and 2 mg/liter), 600 mg rifampin every 12 or 8 h, and 1 or 2 g meropenem every 8 h dosed as an extended 3-h infusion were simulated over 48 h by using a one-compartment in vitro dynamic infection model. Serial bacterial counts were performed to quantify the pharmacodynamic effect. Population analysis profiles (PAPs) were used to assess the emergence of polymyxin B resistance. Monotherapy was ineffective against both isolates. Polymyxin B with rifampin demonstrated early bactericidal activity against the PBs isolate, followed by regrowth by 48 h. Bactericidal activity was sustained at all polymyxin B concentrations of ≥2 mg/liter in combination with meropenem. No two-drug combinations were effective against the PBr isolate, but all simulated triple-drug regimens showed early bactericidal activity against both strains by 8 h that was sustained over 48 h. PAPs did not reveal the emergence of resistant subpopulations. The triple-drug combination of polymyxin B, rifampin, and meropenem may be a viable consideration for the treatment of PBr KPC-producing K. pneumoniae infections. Further investigation is warranted to optimize triple-combination therapy.

Pseudomonas aeruginosa treatment and transmission reduction

Infections caused by Pseudomonas aeruginosa can be difficult to treat and require a coordinated approach for their management. This involves quickly controlling the source of infection, establishing a correct etiologic diagnosis and administering appropriate empiric antimicrobial therapy. Once antimicrobial therapy has been initiated and susceptibilities are available, therapy should be tailored with optimized antibiotic doses for an appropriate duration in order to sufficiently treat the infection and minimize resistance emergence.

Overtreatment of Asymptomatic Candiduria among Hospitalized Patients: A Multi-institutional Study

ABSTRACT Candiduria is common in hospitalized patients, and asymptomatic candiduria contributes to antifungal overuse. The guidelines for management of asymptomatic candiduria do not recommend antifungal use, but rather the elimination of predisposing factors. It is unknown whether these recommendations are being followed. The primary objective of this study was to characterize candiduria management among hospitalized patients. This was a retrospective cohort study of a random sample of 305 hospitalized patients with candiduria at four U.S. medical centers from January 2010 to December 2013. Patients were classified as asymptomatic or symptomatic based on established criteria, and data were collected by chart review. Infectious Diseases Society of America (IDSA) treatment guideline adherence and its association with clinical outcomes, including candiduria recurrence (short- and long-term) and 30-day readmission, were assessed. Eighty percent of patients were classified as having asymptomatic candiduria. Overall, 143 (47%) patients were not managed according to recommended guidelines, including 105/243 (43%) in the asymptomatic candiduria group and 38/62 (61%) in the symptomatic group (P = 0.01). Discordance among asymptomatic patients was driven by overtreatment with an antifungal (98/105 [93%]). Thirty-three percent of patients with asymptomatic candiduria not managed according to the guidelines were treated for over 7 days, and 5% received over 14 days of therapy. Fluconazole was the most commonly used empirical antifungal among asymptomatic candiduria patients (96%), followed by micafungin (4%). Asymptomatic candiduria patients not managed according to the guidelines had a trend toward higher 30-day readmission (35% versus 26%, P = 0.27). Inappropriate management of candiduria among hospitalized patients was high, leading to overtreatment with antifungal therapy.