Thomas P. Lodise

Outcomes Analysis of Delayed Antibiotic Treatment for Hospital-Acquired Staphylococcus aureus Bacteremia

The objective of this study was to determine the effect of delayed therapy on morbidity and mortality associated with nosocomial Staphylococcus aureus bacteremia. The study included all episodes of S. aureus bacteremia that developed >2 days after hospital admission during 1999 to 2001. Classification and regression tree analysis (CART) was used to select the mortality breakpoint between early and delayed treatment. During the 25-month study period, 167 patients met the inclusion criteria. The breakpoint between delayed and early treatment derived using CART was 44.75 hours. On multivariate analysis, delayed treatment was found to be an independent predictor of infection-related mortality (odds ratio, 3.8; 95% confidence interval, 1.3-11.0; P=.01) and was associated with a longer hospital stay than was early treatment (20.2 days versus 14.3 days; P=.05). These findings support the notion that delay of therapy has deleterious effects on clinical outcomes, and efforts should be made to ensure that appropriate therapy is initiated promptly.

Relationship between Initial Vancomycin Concentration-Time Profile and Nephrotoxicity among Hospitalized Patients

BACKGROUNDnData suggest that higher doses of vancomycin can increase the risk of nephrotoxicity. No study has been undertaken to determine the pharmacodynamic index (ie, the area under the curve [AUC] or the trough value) that best describes the relationship between vancomycin exposure and onset of nephrotoxicity.nnnMETHODSnA retrospective study was conducted among patients who received vancomycin for a suspected or proven gram-positive infection during the period from 1 January 2005 through 31 December 2006 at Albany Medical Center Hospital. Patients were included in our study if they (1) were > or =18 years old, (2) had an absolute neutrophil count of > or =1000 cells/mm(3), (3) received vancomycin for >48 h, (4) had 1 vancomycin trough level collected within 96 h of vancomycin therapy, and (5) had a baseline serum creatinine level of <2.0 mg/dL. Patients were excluded if they (1) had a diagnosis of cystic fibrosis, (2) received intravenous contrast dye within 7 days of starting vancomycin or during therapy, or (3) required vasopressor support during therapy. Demographics, comorbid conditions, and treatment data were collected. The highest observed vancomycin trough value within 96 h of initiation of vancomycin therapy and the estimated vancomycin AUC were analyzed as measures of vancomycin exposure. The vancomycin AUC value from 0 to 24 h at steady state (in units of mg x h/L) for each patient was estimated by use of the maximum a posteriori probability Bayesian procedure in ADAPT II. Nephrotoxicity was defined as an increase in serum creatinine level of 0.5 mg/dL or 50%, whichever was greater, following initiation of vancomycin therapy. Logistic and Cox proportional hazards regression models identified the vancomycin pharmacodynamic index that best describes the relationship between vancomycin exposure and toxicity.nnnRESULTSnDuring the study period, 166 patients met the inclusion criteria. Both initial vancomycin trough values and 0-24-h at steady state AUC values were associated with nephrotoxicity in the bivariate analyses. However, the vancomycin trough value, modeled as a continuous variable, was the only vancomycin exposure variable associated with nephrotoxicity in the multivariate analyses.nnnCONCLUSIONSnThe results indicate that a vancomycin exposure-toxicity response relationship exists. The vancomycin trough value is the pharmacodynamic index that best describes this association.

Systematic Review and Meta-Analysis of Vancomycin-Induced Nephrotoxicity Associated with Dosing Schedules That Maintain Troughs between 15 and 20 Milligrams per Liter

ABSTRACT In an effort to maximize outcomes, recent expert guidelines recommend more-intensive vancomycin dosing schedules to maintain vancomycin troughs between 15 and 20 mg/liter. The widespread use of these more-intensive regimens has been associated with an increase in vancomycin-induced nephrotoxicity reports. The purpose of this systematic literature review is to determine the nephrotoxicity potential of maintaining higher troughs in clinical practice. All studies pertaining to vancomycin-induced nephrotoxicity between 1996 and April 2012 were identified from PubMed, Embase, Cochrane Controlled Trial Registry, and Medline databases and analyzed according to Cochrane guidelines. Of the initial 240 studies identified, 38 were reviewed, and 15 studies met the inclusion criteria. Overall, higher troughs (≥15 mg/liter) were associated with increased odds of nephrotoxicity (odds ratio [OR], 2.67; 95% confidence interval [CI], 1.95 to 3.65) relative to lower troughs of <15 mg/liter. The relationship between a trough of ≥15 mg/liter and nephrotoxicity persisted when the analysis was restricted to studies that examined only initial trough concentrations (OR, 3.12; 95% CI, 1.81 to 5.37). The relationship between troughs of ≥15 mg/liter and nephrotoxicity persisted after adjustment for covariates known to independently increase the risk of a nephrotoxicity event. An incremental increase in nephrotoxicity was also observed with longer durations of vancomycin administration. Vancomycin-induced nephrotoxicity was reversible in the majority of cases, with short-term dialysis required only in 3% of nephrotoxic episodes. The collective literature indicates that an exposure-nephrotoxicity relationship for vancomycin exists. The probability of a nephrotoxic event increased as a function of the trough concentration and duration of therapy.

Vancomycin: We Can't Get There From Here

BACKGROUNDnWe sought to characterize the pharmacodynamic profile of the more intensive vancomycin dosing regimens currently used in response to the recent vancomycin guidelines.nnnMETHODSnA series of Monte Carlo simulations was performed for vancomycin regimens ranging from .5 g intravenous (IV) Q12H to 2 g IV Q12H. The probability of achieving an AUC/MIC ratio ≥ 400 for each dosing regimen was calculated for minimum inhibitory concentrations (MICs) from .5 to 2 mg/L. The risk of nephrotoxicity for each regimen was derived from a previously published vancomycin trough-nephrotoxicity logistic regression function. Restricted analyses were performed that only included subjects with troughs between 15 and 20 mg/L.nnnRESULTSnAt a MIC of 2 mg/L, even the most aggressive dosing regimen considered (2 g every 12 h) only yielded a probability of target attainment (PTA) of 57% while generating a nephrotoxicity probability upward of 35%(.) At a MIC of 1 mg/L, ≥3 g per day provided PTA in excess of 80% but were associated with unacceptable risks of nephrotoxicity. In the restricted analyses of subjects with troughs between 15 and 20 mg/L, all regimens produced a PTA of 100% at MICs ≤1 mg/L. The PTA was variable among the regimens at a MIC of 2 mg/L and was highly dependent on the total daily dose administered.nnnCONCLUSIONSnThis study indicates that vancomycin may not be useful for treating serious methicillin-resistant Staphylococcus aureus (MRSA) infections with MIC values > 1 mg/L where PTA is questionable. Since an AUC/MIC ratio ≥ 400 is target associated with efficacy, one should consider incorporating computation of AUC when monitoring vancomycin.

Outcomes of extended infusion piperacillin/tazobactam for documented Gram-negative infections

This comparison of intermittent versus extended-infusion piperacillin-tazobactam among patients with Gram-negative infections revealed similar mortality and length of stay. Outcomes remained similar when stratified by MIC value.

Identification of optimal renal dosage adjustments for traditional and extended-infusion piperacillin-tazobactam dosing regimens in hospitalized patients.

ABSTRACT This study examined the effect of various levels of renal impairment on the probability of achieving free drug concentrations that exceed the MIC for 50% of the dosing interval (50% fT > MIC) for traditional and extended-infusion piperacillin-tazobactam (TZP) dosing strategies. It also identified optimal renal dosage adjustments for traditional and extended-infusion dosing schemes that yielded probability of target attainment (PTA) and exposure profiles that were isometric to those of the parent regimens. Data from 105 patients were analyzed using the population pharmacokinetic modeling program BigNPAG. To assess the effect of creatinine clearance (CLCR) on overall clearance, TZP clearance was made proportional to the estimated CLCR. A Monte Carlo simulation (9,999 subjects) was performed for the traditional dosing scheme (4.5 g infused during 30 min every 6 h) and the extended-infusion TZP dosing scheme (3.375 g infused during 4 h every 8 h). The fraction of simulated subjects who achieved 50% fT > MIC was calculated for the range of piperacillin MICs from 0.25 to 32 mg/liter and stratified by CLCR. The traditional TZP regimen displayed the greatest variability in PTA across MIC values, especially for MIC values exceeding 4 mg/liter, when stratified by CLCR. In contrast, the PTA for the extended-infusion TZP regimen exceeded ≥80% for MIC values of ≤8 mg/liter across all CLCR strata. All regimens were associated with suboptimal PTA for MIC values of ≥32 mg/liter irrespective of the CLCR. The CLCR adjustments for traditional and extended-infusion TZP dosing regimens should be considered at a CLCR of ≤20 ml/min.

Association between vancomycin day 1 exposure profile and outcomes among patients with methicillin-resistant Staphylococcus aureus infective endocarditis.

ABSTRACT Given the critical importance of early appropriate therapy, a retrospective cohort (2002 to 2013) was performed at the Detroit Medical Center to evaluate the association between the day 1 vancomycin exposure profile and outcomes among patients with MRSA infective endocarditis (IE). The day 1 vancomycin area under the concentration-time curve (AUC0–24) and the minimum concentration at 24 h (Cmin 24) was estimated for each patient using the Bayesian procedure in ADAPT 5, an approach shown to accurately predict the vancomycin exposure with low bias and high precision with limited pharmacokinetic sampling. Initial MRSA isolates were collected and vancomycin MIC was determined by broth microdilution (BMD) and Etest. The primary outcome was failure, defined as persistent bacteremia (≥7 days) or 30-day attributable mortality. Classification and regression tree analysis (CART) was used to determine the vancomycin exposure variables associated with an increased probability of failure. In total, 139 patients met study criteria; 76.3% had right-sided IE, 16.5% had left-sided IE, and 7.2% had both left and right-sided IE. A total of 89/139 (64%) experienced failure by composite definition. In the CART analysis, failure was more pronounced in patients with an AUC0–24/MIC as determined by BMD of ≤600 relative to those with AUC0–24/MIC as determined by BMD of >600 (69.8% versus 54.7%, respectively, P = 0.073). In the logistic regression analysis, an AUC/MIC as determined by BMD of ≤600 (adjusted odds ratio, 2.3; 95% confidence interval, 1.01 to 5.37; P = 0.047) was independently associated with failure. Given the retrospective nature of the present study, further prospective studies are required but these data suggest that patients with an AUC0–24/MIC as determined by BMD of ≤600 present an increased risk of failure.

Daptomycin Pharmacokinetics and Pharmacodynamics in a Pooled Sample of Patients Receiving Thrice-Weekly Hemodialysis

ABSTRACT 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 (AUC48–72) that were <50% of the SAB-IE AUC48–72 values. Increasing the parent dose by 50% intra- or post-HD provided comparable AUC48–72 values, while maintaining acceptable trough concentration (Cmin) values. When efficacy and toxicity profiles were evaluated for each individual study, higher probabilities for Cmin reaching ≥24.3 mg/liter were observed in one of the three studies. Given the high probability of Cmin 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.

Relationship between Various Definitions of Prior Antibiotic Exposure and Piperacillin-Tazobactam Resistance among Patients with Respiratory Tract Infections Caused by Pseudomonas aeruginosa

ABSTRACT Contemporary literature lacks a definition of prior antibiotic exposure which captures all patients at risk of developing piperacillin-tazobactam-resistant Pseudomonas aeruginosa (PTR-PA). The results indicated that individual antibiotics that are associated with PTR-PA differ depending on the definition of prior antibiotic exposure utilized. When the specific antibiotic used was replaced by the number of prior exposures, the number of exposures was the only variable associated with an increased risk of antibiotic resistance at each time threshold.

Quantifying the matrix of relationships between reduced vancomycin susceptibility phenotypes and outcomes among patients with MRSA bloodstream infections treated with vancomycin

OBJECTIVESnSeveral phenotypic characteristics of Staphylococcus aureus have been identified as aetiological factors responsible for adverse outcomes among patients receiving vancomycin. However, characterization of the outcomes associated with these reduced vancomycin susceptibility phenotypes (rVSPs) remains largely incomplete and it is unknown if these features contribute to deleterious treatment outcomes alone or in concert. This study described the interrelationship between rVSPs and assessed their individual and combined effects on outcomes among patients who received vancomycin for a methicillin-resistant S. aureus (MRSA) bloodstream infection.nnnMETHODSnAn observational study of adult, hospitalized patients with MRSA bloodstream infections who were treated with vancomycin between January 2005 and June 2009 was performed. The rVSPs evaluated included the following: (i) Etest MIC; (ii) broth microdilution MIC; (iii) MBCu200a:u200aMIC ratio; and (iv) heteroresistance to vancomycin by the Etest macromethod. Failure was defined as any of the following: (i) 30 day mortality; (ii) bacteraemia ≥ 7 days on therapy; or (iii) recurrence of MRSA bacteraemia within 60 days of therapy discontinuation.nnnRESULTSnDuring the study period, 184 cases met the study criteria and 41.3% met the failure criteria. There was a clear linear exposure-response relationship between the number of these phenotypic markers and outcomes. As the number of phenotypes escalated, the incidence of overall failure increased incrementally by 10%-18%.nnnCONCLUSIONSnThe data suggest that rVSPs contribute to deleterious treatment outcomes in concert.