Outcomes of Bacteremia due to Pseudomonas aeruginosa with Reduced Susceptibility to Piperacillin-Tazobactam: Implications on the Appropriateness of the Resistance Breakpoint

Tam, Vincent H.; Gamez, Eric A.; Weston, Jaye; Gerard, Laura N.; LaRocco, Mark; Caeiro, Juan Pablo; Gentry, Layne O.; Garey, Kevin W.

doi:10.1086/528712

Cited by 106 publications

(69 citation statements)

References 13 publications

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“…A classification and regression tree (CART) analysis conducted in their study revealed that a cefepime MIC of Ն8 mg/liter was associated with increased mortality (58.4% compared to 21.4%, P ϭ 0.001), despite the fact that an MIC of 8 mg/liter was considered susceptible at the time of the study (13). Tam and colleagues (14) evaluated outcomes in patients with Pseudomonas aeruginosa bacteremia with reduced susceptibility (defined as an MIC of 32 to 64 mg/liter) to piperacillin-tazobactam, and the susceptibility breakpoint was Յ64 mg/liter at the time of the study. Among patients with a Pseudomonas bloodstream infection, a higher mortality rate was seen in those treated with piperacillin-tazobactam (MIC, 32 mg/liter or 64 mg/liter) than in those treated with other antipseudomonal agents (85.7% compared to 22.2%; P ϭ 0.004).…”

Section: Discussionmentioning

confidence: 99%

“…Among patients with a Pseudomonas bloodstream infection, a higher mortality rate was seen in those treated with piperacillin-tazobactam (MIC, 32 mg/liter or 64 mg/liter) than in those treated with other antipseudomonal agents (85.7% compared to 22.2%; P ϭ 0.004). (14). Similarly, in patients with Gram-negative bacteremia treated with levofloxacin, DeFife et al reported longer time to clearance of infection (2.1 days compared to 1.0 day, P Ͻ 0.001) and longer length of stay (16.4 days compared to 7.3 days, P ϭ 0.02) for patients in the high-MIC group (defined as 1 mg/liter or 2 mg/liter) than for those with lower MICs, and the susceptibility breakpoint was 2 mg/liter at the time of the study (15).…”

Section: Discussionmentioning

confidence: 99%

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Clinical Outcomes of Enterobacteriaceae Infections Stratified by Carbapenem MICs

Patel

Nagel

2015

J Clin Microbiol

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The Clinical and Laboratory Standards Institute (CLSI) lowered the MIC breakpoints for meropenem and imipenem from 4 mg/ liter to 1 mg/liter for Enterobacteriaceae in 2010. The breakpoint change improves the probability of pharmacodynamic target attainment and eliminates the need for microbiology labs to perform confirmatory testing for Klebsiella pneumoniae carbapenemase (KPC) production or other beta-lactamases that hydrolyze carbapenems. However, there are limited data evaluating clinical outcomes of the affected breakpoints, and it is unknown if patients infected with Enterobacteriaceae with reduced susceptibility are more likely to have poor outcomes when treated with a carbapenem. We conducted a single-center retrospective matched-cohort analysis in adult patients with Enterobacteriaceae infections treated with meropenem, imipenem, or doripenem. Patients with Enterobacteriaceae infection with a carbapenem MIC of 2 to 8 mg/liter were matched based on pathogen, source of infection, comorbidities, and disease severity (1:1 ratio) to those with a carbapenem MIC of <1 mg/liter. A total of 36 patients were included in the study. The group with carbapenem MICs of 2 to 8 mg/liter had a significantly higher 30-day mortality than the group with carbapenem MICs of <1 mg/liter (38.9% compared to 5.6%, P ‫؍‬ 0.04). Total hospital length of stay (LOS) and intensive care unit (ICU) LOS were longer in the group with MICs of 2 to 8 mg/liter than in the group with MICs of <1 mg/liter (57.6 days compared to 34.4 days [P ‫؍‬ 0.06] and 56.6 days compared to 21.7 days [P < 0.01], respectively). Patients infected with Enterobacteriaceae with a carbapenem MIC of 2, 4, or 8 mg/liter had higher mortality rates and longer ICU LOS than matched cohorts with carbapenem MICs of <1 mg/liter, which supports CLSI's recommendation to lower susceptibility breakpoints for carbapenems.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical Outcomes of Enterobacteriaceae Infections Stratified by Carbapenem MICs

Patel

Nagel

2015

J Clin Microbiol

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“…24,25 To increase fT >MIC by 1 . 26 Control patients received alternative empiric therapy (in doses appropriate for renal function as recommended by the manufacturer) within 24 hours of the first positive blood culture result to which the isolate was found to be susceptible using current CLSI susceptibility breakpoints. Original magnification: 132 Â 93 mm (300 Â 300 DPI).…”

Section: Dosing Strategies To Improve the Probability Of Target Attaimentioning

confidence: 99%

Use of pharmacodynamic principles to inform β‐lactam dosing: “S” does not always mean success

Lodise¹,

Butterfield²

2011

Journal of Hospital Medicine

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Dose optimization is one of the key strategies for enhancing antimicrobial stewardship. There have been tremendous strides in our understanding of antibiotic exposure-response relationships over the past 25 years. For many antibiotics, the ''pharmacodynamic'' or the exposure variable associated with outcome has been identified. With advances in mathematical modeling, it is possible to apply our understanding of antimicrobial pharmacodynamics (PD) into clinical practice and design empirical regimens that have a high probability of achieving the PD target linked to effect. By optimizing antibiotic doses to achieve PD targets predictive of efficacy, clinicians can improve care and minimize drug toxicity. For b-lactams, the PD parameter most predictive of maximal bactericidal activity is the duration of time free drug concentrations remain above the minimum inhibitory concentration (MIC) during the dosing interval (fT > MIC). Unfortunately, the conventional intermittent b-lactam dosing schemes often used in practice have suboptimal PD profiles. Prolonging the infusion time of b-lactams is one method to maximize the probability of achieving concentrations in excess of the MIC for the majority of the dosing interval, especially against pathogens with elevated MIC values. Prolonged infusions of intravenous b-lactams are not only associated with improved probability of target attainment (PTA) profiles but offer possible cost savings and greater potential for reducing emergence of resistance relative to intermittent infusions. Journal of Hospital Medicine 2011;6:S16-S23. V C

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“…The breakpoints are often used, in conjunction with susceptibility results, to predict clinical outcome. However, emerging data highlight the lack of association between in vitro susceptibility breakpoints and outcomes (3,30).Fluoroquinolones are considered to be concentration dependent, with both the area under the concentration-time curve from 0 to 24 h (AUC 0-24 ) divided by the MIC (the AUC 0-24 /MIC ratio) and the maximum serum drug concentration (C max ) divided by the MIC (the C max /MIC ratio) as predictors of clinical outcome (13,24). Numerous studies have attempted to discern the parameter best associated with clinical outcome.…”

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confidence: 99%

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confidence: 99%

Effect of Differences in MIC Values on Clinical Outcomes in Patients with Bloodstream Infections Caused by Gram-Negative Organisms Treated with Levofloxacin

DeFife

Scheetz

Feinglass

et al. 2009

Antimicrob Agents Chemother

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The pharmacokinetic (PK) and pharmacodynamic (PD) profiles of fluoroquinolones have been well-described, and susceptibility classifications are the main determinant of their use in clinical practice. Expert guidelines contain susceptibility breakpoints to aid clinicians with the interpretation of in vitro data. These breakpoints are based on the MIC distribution for a large number of microorganisms, the observed clinical response in patients treated with usual doses, and the PK-PD properties of the drug (8, 16, 16a, 22, 24, 25). The breakpoints are often used, in conjunction with susceptibility results, to predict clinical outcome. However, emerging data highlight the lack of association between in vitro susceptibility breakpoints and outcomes (3,30).Fluoroquinolones are considered to be concentration dependent, with both the area under the concentration-time curve from 0 to 24 h (AUC 0-24 ) divided by the MIC (the AUC 0-24 /MIC ratio) and the maximum serum drug concentration (C max ) divided by the MIC (the C max /MIC ratio) as predictors of clinical outcome (13,24). Numerous studies have attempted to discern the parameter best associated with clinical outcome. Studies favoring the C max /MIC ratio have shown that maximum serum fluoroquinolone concentrations reaching 8 to 12 times the MIC are associated with favorable outcomes (4, 13, 26). However, evidence for the AUC 0-24 /MIC ratio is convincing if the colinearity of the C max /MIC and AUC 0-24 / MIC ratios is removed (27). Evaluations have shown previously that AUC 0-24 /MIC ratios greater than 125 are associated with optimal outcomes for infections with gram-negative organisms (13,17,23).The aforementioned studies were completed largely in vivo and did not account for protein binding (with the exception of one trial [4]). One can anticipate that slightly lower concentrations are needed when free drug is considered. As predicted, lower AUC 0-24 /MIC ratios are required when only free-drug values are used in calculations, and extrapolating free-drug concentrations from the data in the aforementioned clinical studies results in an optimal free-drug AUC 0-24 /MIC ratio between 61 and 105 (2,5,14).As currently defined by the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing, the MIC breakpoint of levofloxacin for aerobic and facultative gram-negative organisms is 2 mg/liter (8, 16a; Levaquin package insert [http://www.levaquin.com]). The

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Outcomes of Bacteremia due to Pseudomonas aeruginosa with Reduced Susceptibility to Piperacillin-Tazobactam: Implications on the Appropriateness of the Resistance Breakpoint

Cited by 106 publications

References 13 publications

Clinical Outcomes of Enterobacteriaceae Infections Stratified by Carbapenem MICs

Clinical Outcomes of Enterobacteriaceae Infections Stratified by Carbapenem MICs

Use of pharmacodynamic principles to inform β‐lactam dosing: “S” does not always mean success

Effect of Differences in MIC Values on Clinical Outcomes in Patients with Bloodstream Infections Caused by Gram-Negative Organisms Treated with Levofloxacin

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