Failure of Current Cefepime Breakpoints To Predict Clinical Outcomes of Bacteremia Caused by Gram-Negative Organisms

Bhat, Sunil; Peleg, Anton Y.; Lodise, Thomas P.; Shutt, Kathleen A.; Capitano, Blair; Potoski, Brian A.; Paterson, David L.

doi:10.1128/aac.01487-06

Cited by 112 publications

(91 citation statements)

References 9 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.…”

Section: Discussionmentioning

confidence: 99%

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%

Clinical Outcomes of Enterobacteriaceae Infections Stratified by Carbapenem MICs

Patel

Nagel

2015

J Clin Microbiol

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“…The CLSI recommends using the highest doses of CFP originally approved by the FDA for empirical therapy of febrile neutropenia to treat organisms with a MIC of 8 g/ml (2 g i.v. q8h) (20,21). However, PK/pharmacodynamics (PD) analysis in children was required to define the appropriate dosing regimen for GNB with a MIC of 4 or 8 g/ml, realizing that children will often have greater renal clearance of ␤-lactams than adults.…”

Section: Discussionmentioning

confidence: 99%

“…For young infants older than 30 days with greater CFP CL values, Monte Carlo simulation shows that the FDA-approved usual maximum dosage regimen of CFP, 50 mg/kg q8h infused over 30 min, did not provide a sufficient attainment rate of 60% TAM for organisms with a MIC of Ն8 g/ml. Based on several reports indicating a poor prognosis of infections caused by organisms with a higher CFP MIC (20,32), there is clearly a need to revise the treatment options for infections caused by these organisms. On the other hand, sufficiently high target attainment rates were observed for neonates with a relatively low CFP CL with infections caused by organisms with a MIC of 8 g/ml.…”

Section: Discussionmentioning

confidence: 99%

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Population Pharmacokinetic Assessment and Pharmacodynamic Implications of Pediatric Cefepime Dosing for Susceptible-Dose-Dependent Organisms

Shoji

Bradley

Reed

et al. 2016

Antimicrob Agents Chemother

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The Clinical and Laboratory Standards Institute (CLSI) revised cefepime (CFP) breakpoints for Enterobacteriaceae in 2014, and MICs of 4 and 8 g/ml were reclassified as susceptible-dose dependent (SDD). Pediatric dosing to provide therapeutic concentrations against SDD organisms has not been defined. CFP pharmacokinetics (PK) data from published pediatric studies were analyzed. Population PK parameters were determined using NONMEM, and Monte Carlo simulation was performed to determine an appropriate CFP dosage regimen for SDD organisms in children. A total of 664 CFP plasma concentrations from 91 neonates, infants, and children were included in this analysis. The median patient age was 1.0 month (interquartile range [IQR], 0.2 to 11.2 months). Serum creatinine (SCR) and postmenstrual age (PMA) were covariates in the final PK model. Simulations indicated that CFP dosing at 50 mg/kg every 8 h (q8h) (as 0.5-h intravenous [i.v.] infusions) will maintain free-CFP concentrations in serum of >4 and 8 g/ml for >60% of the dose interval in 87.1% and 68.6% of pediatric patients (age, >30 days), respectively, and extending the i.v. infusion duration to 3 h results in 92.3% of patients with free-CFP levels above 8 g/ml for >60% of the dose interval. CFP clearance (CL) is significantly correlated with PMA and SCR. A dose of 50 mg/kg of CFP every 8 to 12 h does not achieve adequate serum exposure for older children with serious infections caused by Gram-negative bacilli with a MIC of 8 g/ml. Prolonged i.v. infusions may be useful for this population. Health care-associated infections (HAI), such as ventilator-associated pneumonia, catheter-associated urinary tract infection, surgical site infection, and catheter-related bloodstream infection, may lead to morbidity and mortality in children (1-3). Infections caused by Gram-negative bacilli (GNB) are a major cause of HAI, including infections caused by Pseudomonas aeruginosa and the Enterobacteriaceae, such as Klebsiella pneumoniae and Escherichia coli (4, 5). The incidence of multidrug-resistant GNB, based on the presence of extended-spectrum ␤-lactamases (ESBLs) and AmpC ␤-lactamases, is increasing globally (6-9). Infections caused by these organisms are associated with a poor prognosis (10, 11). Further complicating this clinical challenge is that development of new antibiotics effective against these important pathogens has been slow (12). It is important to use existing antibiotics effectively whenever possible, using pharmacokinetics (PK) and pharmacodynamics (PD) analyses. Cefepime (CFP), a fourth-generation cephalosporin, is widely used to treat infections caused by GNB in both adult and pediatric patients (13,14). Several studies have shown the effectiveness and safety of CFP in treating urinary tract and lower respiratory infections in children (15,16). Further, CFP is also an important choice to treat multidrug-resistant GNB, such as AmpC ␤-lactamase-producing strains and several strains of ESBL-producing organisms with MICs that correspond to clinically achievable pl...

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“…Inappropriate empirical antimicrobial-based therapy and delays to initiate appropriate antimicrobial-based therapy are both detrimental to patient outcome. 34 Authors have described failure of cefepime-susceptibility breakpoints to predict clinical outcomes 35 as well as the requirement of achieving adequate drug exposure to be successful in treating patients with P. aeruginosa infections. 36 Additionally, a multivariate logistic regression analysis demonstrated P. aeruginosa infection to be independently associated with treatment failure in cefepime-patients.…”

Section: Discussionmentioning

confidence: 99%

Outbreaks, persistence, and high mortality rates of multiresistant Pseudomonas aeruginosa infections in a hospital with AIDS-predominant admissions

Gomes¹,

Machado²,

Conceição³

et al. 2011

Braz J Infect Dis

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Introduction: Authors have reported increased incidence of multiresistant Pseudomonas aeruginosa (MR-PA) infections worldwide over the last decade. Researchers have proposed multifaceted approaches to control MR-PA infections, but none have been reported in the acquired immunodeficiency syndrome (AIDS) setting. Objective and Methods: Herein we report the impact of a multifaceted intervention for controlling MR-PA over five years in a hospital with AIDS-predominant admissions and describe the clinical characteristics of MR-PA infection in our patient population. The clinical outcomes of infected patients and molecular characteristics of the isolated strains were used as tools for controlling MR-PA infection rates. Results: Significant temporary decrease of new infections was achieved after intervention, although a high level of diagnostic suspicion of nosocomial infection was maintained. We obtained 35 P. aeruginosa isolates with multiresistant profiles from 13 infected and 3 colonized patients and 2 environmental samples. Most of the patients (94%) were immunocompromised with AIDS (n = 10) or HTLV-1 infections (n = 5). Of the followed patients, 67% had persistent and/or recurrent infections, and 92% died. We observed differences in the antibiotic-resistance pattern of MR-PA infection/colonization during two outbreaks, although the genetic profiles of the tested strains were identical. Conclusions: Therefore, we concluded that early multidisciplinary interventions are essential for reducing the burden caused by this microorganism in patients with AIDS. Prolonged or suppressive antibiotic-based therapy should be considered for MR-PA infections in patients with AIDS because of the persistence characteristic of MR-PA in these patients.

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Failure of Current Cefepime Breakpoints To Predict Clinical Outcomes of Bacteremia Caused by Gram-Negative Organisms

Cited by 112 publications

References 9 publications

Clinical Outcomes of Enterobacteriaceae Infections Stratified by Carbapenem MICs

Clinical Outcomes of Enterobacteriaceae Infections Stratified by Carbapenem MICs

Population Pharmacokinetic Assessment and Pharmacodynamic Implications of Pediatric Cefepime Dosing for Susceptible-Dose-Dependent Organisms

Outbreaks, persistence, and high mortality rates of multiresistant Pseudomonas aeruginosa infections in a hospital with AIDS-predominant admissions

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