Dual beta-lactam therapy for serious Gram-negative infections: is it time to revisit?

We are rapidly approaching a crisis in antibiotic resistance, particularly among Gram-negative pathogens. This, coupled with the slow development of novel antimicrobial agents, underscores the exigency of redeploying existing antimicrobial agents in innovative ways. One therapeutic approach that was heavily studied in the 1980s but abandoned over time is dual beta-lactam therapy. This article reviews the evidence for combination beta-lactam therapy. Overall, in vitro, animal and clinical data are positive and suggest that beta-lactam combinations produce a synergistic effect against Gram-negative pathogens that rivals that of beta-lactam-aminoglycoside or beta-lactam-fluoroquinolone combination therapy. Although the precise mechanism of improved activity is not completely understood, it is likely attributable to an enhanced affinity to the diverse penicillin-binding proteins found among Gram negatives. The collective data indicate that dual beta-lactam therapy should be revisited for serious Gram-negative infections, especially in light of the near availability of potent beta-lactamase inhibitors, which neutralize the effect of problematic beta-lactamases.

Relationship between time to clinical response and outcomes among Pneumonia Outcomes Research Team (PORT) risk class III and IV hospitalized patients with community-acquired pneumonia who received ceftriaxone and azithromycin.

Recent Food and Drug Administration (FDA) guidance endorses the use of an early clinical response endpoint as the primary outcome for community-acquired bacterial pneumonia (CABP) trials. While antibiotics will now be approved for CABP, in practice they will primarily be used to treat patients with community-acquired pneumonia (CAP). More importantly, it is unclear how achievement of the new FDA CABP early response endpoint translates into clinically applicable real-world outcomes for patients with CAP. To address this, a retrospective cohort study was conducted among adult patients who received ceftriaxone and azithromycin for CAP of Pneumonia Outcomes Research Team (PORT) risk class III and IV at an academic medical center. The clinical response was defined as clinical stability for 24 h with improvement in at least one pneumonia symptom and with no symptom worsening. A classification and regression tree (CART) was used to determine the delay in response time, measured in days, associated with the greatest risk of a prolonged hospital length of stay (LOS) and adverse outcomes (in-hospital mortality or 30-day CAP-related readmission). A total of 250 patients were included. On average, patients were discharged 2 days following the achievement of a clinical response. In the CART analysis, adverse clinical outcomes were higher among day 5 nonresponders than those who responded by day 5 (22.4% versus 6.9%, P = 0.001). The findings from this study indicate that time to clinical response, as defined by the recent FDA guidance, is a reasonable prognostic indicator of real-world effectiveness outcomes among hospitalized PORT risk class III and IV patients with CAP who received ceftriaxone and azithromycin.

Pharmacokinetics and pharmacodynamics of extended-infusion piperacillin/tazobactam in adult patients with cystic fibrosis-related acute pulmonary exacerbations.

OBJECTIVES: Given the high frequency of acute pulmonary exacerbations due to Pseudomonas aeruginosa in patients with cystic fibrosis (CF), piperacillin/tazobactam is commonly used in empirical regimens. While extended-infusion piperacillin/tazobactam has been employed as one strategy to optimize this agent's pharmacodynamics, this approach has not been well characterized in patients with CF. The objectives of this study were to characterize the pharmacokinetics and pharmacodynamics of extended-infusion piperacillin/tazobactam in adult patients with CF and derive optimized piperacillin/tazobactam dosing recommendations. METHODS: Six serum samples were collected from nine adult patients with CF hospitalized for acute pulmonary exacerbations who received 3/0.375 g of piperacillin/tazobactam intravenously for 4 h every 8 h. Population pharmacokinetic models were fitted to the data utilizing first-order, Michaelis-Menten (MM) and parallel first-order/MM clearance. Monte Carlo simulations were performed to determine the probability of target attainment (PTA) for regimens where free piperacillin concentrations were above the MIC for at least 50% of the dosing interval. RESULTS: The model incorporating MM clearance best described the data. Results of our simulation revealed that piperacillin/tazobactam dosed at 3-4 g for 30 min every 6-8 h led to <90% PTA against MIC values >4 mg/L. More intensive prolonged infusion regimens than are commonly used in practice, such as continuous infusions or 3 h infusions every 6 h, were needed to maximize the PTA for MICs ≥ 8 mg/L. CONCLUSIONS: Intensive prolonged infusion regimens are the best option to ensure optimal exposures against most susceptible isolates in adult patients with CF.

Pharmacokinetics and pharmacodynamics of once-daily administration of intravenous tobramycin in adult patients with cystic fibrosis hospitalized for an acute pulmonary exacerbation.

The serum pharmacokinetic profile of intravenous (i.v.) tobramycin administration was characterized for a sample of nine adult patients with cystic fibrosis (CF) who were hospitalized for an acute pulmonary exacerbation. Current recommended i.v. tobramycin dosing protocols are predicted through modeling and simulation to be suboptimal. Empirical tobramycin regimens of ≥15 mg/kg of body weight administered i.v. once daily should be evaluated for adult patients with CF to optimize outcomes.

Daptomycin pharmacokinetics and pharmacodynamics in a pooled sample of patients receiving thrice-weekly hemodialysis.

While the pharmacokinetic (PK) properties of daptomycin in hemodialysis (HD) patients have been evaluated previously by three groups, resultant dosing recommendations have varied. To address this clinical conundrum, this study combined concentration-time data from these PK evaluations and derived uniform dosing recommendations among patients on HD receiving daptomycin. A two-compartment model with separate HD and non-HD clearance terms was fit to the PK data from these studies by using BigNPAG. Embedded with PK parameters from the population PK analysis, 5,000-subject Monte Carlo simulations (MCS) were performed to identify HD dosing schemes that provided efficacy (cumulative and daily area under the concentration-time curve [AUC] values) and toxicity (trough concentrations of ≥ 24.3 mg/liter) profiles comparable to those from simulations employing the daptomycin PK model derived from the Staphylococcus aureus bacteremia-infective endocarditis (SAB-IE) study. Separate HD dosing schemes were sought for the two weekly interdialytic periods (48 and 72 h). For the 48-h interdialytic period, intra- and post-HD dosing provided the most isometric cumulative and daily AUCs. For the 72-h interdialytic period, all HD dosing schemes provided noncumulative AUC values from 48 to 72 h (AUC(48-72)) that were <50% of the SAB-IE AUC(48-72) values. Increasing the parent dose by 50% intra- or post-HD provided comparable AUC(48-72) values, while maintaining acceptable trough concentration (C(min)) values. When efficacy and toxicity profiles were evaluated for each individual study, higher probabilities for C(min) reaching ≥ 24.3 mg/liter were observed in one of the three studies. Given the high probability of C(min) being ≥ 24.3 mg/liter in one of the three studies, more intensive creatine phosphokinase (CPK) monitoring may be warranted in HD patients receiving daptomycin.

Comparison of serotonin toxicity with concomitant use of either linezolid or comparators and serotonergic agents: an analysis of Phase III and IV randomized clinical trial data.

OBJECTIVES AND METHODS: The present study's objective was to evaluate serotonin toxicity with concomitant use of linezolid or comparators and serotonergic agents from 20 Phase III and IV comparator-controlled clinical studies on treatment of various Gram-positive infections. All reported adverse events were evaluated for serotonin toxicity using exact and surrogate terms consistent with Sternbach Criteria and Hunter Serotonin Toxicity Criteria. RESULTS: Baseline demographics and co-morbidities were similar between linezolid and comparator groups. No patients in either group were reported to have adverse events identified as serotonin toxicity. Among the patients receiving at least one serotonergic agent, 9 of the 2208 (0.41%) linezolid patients and 3 of the 2057 (0.15%) comparator patients met the Sternbach Criteria [risk ratio (RR) 2.79; 95% confidence interval (95% CI) 0.76-10.31]; 3 (0.14%) of the linezolid patients and 1 (0.05%) of the comparator patients met the Hunter Serotonin Toxicity Criteria (RR 2.79; 95% CI 0.29-26.85). No patients met both criteria. Most patients meeting criteria for serotonin toxicity had past or present co-morbidities that may have contributed to or overlapped with reported adverse events. CONCLUSIONS: While the potential exists for serotonin toxicity to occur with concomitant use of linezolid and serotonergic agents, the risk appears to be low. Based on the large database of Phase III and IV studies included in our analysis, we did not find enough evidence to conclude that linezolid-induced serotonin toxicity was different from that of comparators.

Penetration of vancomycin into epithelial lining fluid in healthy volunteers.

Although vancomycin is often regarded as an agent that concentrates poorly in the lower respiratory tract, as determined from concentrations in epithelial lining fluid (ELF), few data are available. This study sought to determine the profile of vancomycin exposure in the ELF relative to plasma. Population modeling and Monte Carlo simulation were employed to estimate the penetration of vancomycin into ELF. Plasma and ELF pharmacokinetic (PK) data were obtained from 10 healthy volunteers. Concentration-time profiles in plasma and ELF were simultaneously modeled using a three-compartment model with zero-order infusion and first-order elimination and transfer using the big nonparametric adaptive grid (BigNPAG) program. Monte Carlo simulation with 9,999 subjects was performed to calculate the ELF/plasma penetration ratios by estimating the area under the concentration-time curve (AUC) in ELF (AUC(ELF)) and plasma (AUC(plasma)) after a single simulated 1,000-mg dose. The mean (standard deviation) AUC(ELF)/AUC(plasma) penetration ratio was 0.675 (0.677), and the 25th, 50th, and 75th percentile penetration ratios were 0.265, 0.474, and 0.842, respectively. Our results indicate that vancomycin penetrates ELF at approximately 50% of plasma levels. To properly judge the adequacy of current doses and schedules employed in practice, future studies are needed to delineate the PK/PD (pharmacodynamics) target for vancomycin in ELF. If the PK/PD target in ELF is found to be consistent with the currently proposed target of an AUC/MIC of ≥400, suboptimal probability of target attainment would be expected when vancomycin is utilized for pneumonias due to MRSA (methicillin-resistant Staphylococcus aureus) with MICs in excess of 1 mg/liter.

Predictors of agr dysfunction in methicillin-resistant Staphylococcus aureus (MRSA) isolates among patients with MRSA bloodstream infections.

Despite emerging evidence that dysfunction in the accessory gene regulator (agr) locus is associated with deleterious outcomes among patients treated with vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) infections, factors predictive of agr dysfunction have not been evaluated. This study describes the epidemiology of agr dysfunction, identifies predictors of agr dysfunction in MRSA isolates among those with MRSA bloodstream infections, and describes the relationship between agr dysfunction and other microbiologic phenotypes. A cross-sectional study of patients with MRSA bloodstream infections at two institutions in upstate New York was performed. Clinical data on demographics, comorbidities, disease severity, hospitalization history, and antibiotic history were collected. Microbiologic phenotypes, including agr dysfunction, MIC values by broth microdilution (BMD) and Etest, and vancomycin heteroresistance (hVISA) were tested. Multivariable analyses were performed to identify factors predictive of agr dysfunction. Among 200 patients with an MRSA bloodstream infection, the proportion of strains with agr dysfunction was 31.5%. The distribution of MICs determined by both BMD and Etest were equivalent across agr groups, and there was no association between agr dysfunction and the presence of hVISA. Severity of illness, comorbidities, and hospitalization history were comparable between agr groups. In the multivariate analysis, prior antibiotic exposure was the only factor of variables studied found to be predictive of agr dysfunction. This relationship was predominantly driven by prior beta-lactam and fluoroquinolone administration in the bivariate analysis. Identifying these institution-specific risk factors can be used to develop a process to assess the risk of agr dysfunction and guide empirical antibiotic therapy decisions.

Refining vancomycin protein binding estimates: identification of clinical factors that influence protein binding.

While current data indicate only free (unbound) drug is pharmacologically active and is most predictive of response, pharmacodynamic studies of vancomycin have been limited to measurement of total concentrations. The protein binding of vancomycin is thought to be approximately 50%, but considerable variability surrounds this estimate. The present study sought to determine the extent of vancomycin protein binding, to identify factors that modulate its binding, and to create and validate a prediction tool to estimate the extent of protein binding based on individual clinical factors. This single-site prospective cohort study included hospitalized adult patients treated with vancomycin and with a vancomycin serum concentration determination available. Linear regression was used to predict the free vancomycin concentration (f[vanco]) and to determine the clinical factors modulating vancomycin protein binding. Among the 50 patients in the study, the mean protein binding was 41.5%. The strongest predictor of f[vanco] was the total vancomycin concentration (total [vanco]), and this was modified by dialysis and total protein of ≥6.7 g/dl as covariates. The algebraic expression from the final prediction model was f[vanco] = 0.643 + 0.560 × total [vanco] - {0.067 × total [vanco] × D} - {0.071 × total [vanco] × TP} where D = 1 if dialysis dependent or 0 if not dialysis dependent, and TP = 1 if total protein is ≥6.7 g/dl or 0 if total protein is <6.7 g/dl. The R(2) of the final prediction model was 0.959 (P < 0.001). Validation of our model was performed in 13 patients, and the predictive performance was highly favorable (R(2) was 0.9, and bias and precision were 0.18 and 0.18, respectively). Prediction models such as ours can be utilized in future pharmacokinetics and pharmacodynamics studies evaluating the exposure-response profile and to determine the pharmacodynamic target of interest as it relates to the free concentration.