Does prolonged β-lactam infusions improve clinical outcomes compared to intermittent infusions? A meta-analysis and systematic review of randomized, controlled trials

Tamma, Pranita D.; Putcha, Nirupama; Suh, Yong; Arendonk, Kyle J. Van; Rinke, Michael L.

doi:10.1186/1471-2334-11-181

Cited by 84 publications

(82 citation statements)

References 33 publications

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“…Rather than simply adding a second agent, optimization of antimicrobial therapy includes selection of appropriate antibiotic agent(s), dose, frequency, route, and duration. It also may include prolonged antibiotic infusion strategies to exploit the time above the MIC mechanism of ␤-lactams when combating organisms with elevated MICs (239,242).…”

Section: Resultsmentioning

confidence: 99%

Combination Therapy for Treatment of Infections with Gram-Negative Bacteria

2012

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SUMMARY Combination antibiotic therapy for invasive infections with Gram-negative bacteria is employed in many health care facilities, especially for certain subgroups of patients, including those with neutropenia, those with infections caused by Pseudomonas aeruginosa , those with ventilator-associated pneumonia, and the severely ill. An argument can be made for empiric combination therapy, as we are witnessing a rise in infections caused by multidrug-resistant Gram-negative organisms. The wisdom of continued combination therapy after an organism is isolated and antimicrobial susceptibility data are known, however, is more controversial. The available evidence suggests that the greatest benefit of combination antibiotic therapy stems from the increased likelihood of choosing an effective agent during empiric therapy, rather than exploitation of in vitro synergy or the prevention of resistance during definitive treatment. In this review, we summarize the available data comparing monotherapy versus combination antimicrobial therapy for the treatment of infections with Gram-negative bacteria.

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Section: Resultsmentioning

confidence: 99%

Combination Therapy for Treatment of Infections with Gram-Negative Bacteria

2012

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“…Recent metaanalyses that focused on beta-lactams (Table 3) have mostly concluded that existing data were favorable for the use of specific or all beta-lactam agents by prolonged or continuous infusion in terms of clinical outcomes. Although 2 of these studies did not observe a clinical advantage for using continuous or extended schedules (93,97), the investigators acknowledged the many limitations of the studies included and the need for the larger, multicenter randomized control trials.…”

Section: Contemporary Studiesmentioning

confidence: 99%

“…Although quite a few of these have been conducted over time, they differ markedly in their inclusion/exclusion criteria, thus not necessarily allowing elucidation of the true effectiveness of nontraditional beta-lactam dosing regimens (4,18,(88)(89)(90)(91)(92)(93)(94)(95)(96)(97)(98)(99)(100)(101)(102). Recent metaanalyses that focused on beta-lactams (Table 3) have mostly concluded that existing data were favorable for the use of specific or all beta-lactam agents by prolonged or continuous infusion in terms of clinical outcomes.…”

Section: Contemporary Studiesmentioning

confidence: 99%

Continuous and Prolonged Intravenous β-Lactam Dosing: Implications for the Clinical Laboratory

2016

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SUMMARYBeta-lactam antibiotics serve as a cornerstone in the management of bacterial infections because of their wide spectrum of activity and low toxicity. Since resistance rates among bacteria are continuously on the rise and the pipeline for new antibiotics does not meet this trend, an optimization of current beta-lactam treatment is needed. This review provides an overview of optimization through use of prolonged- and continuous-infusion dosing strategies compared with more traditional intermittent infusions. Included is an overview of the scientific basis for using these nontraditional prolonged- and continuous-infusion-based regimens, with a focus on major areas in which the clinical laboratory can support the clinical use of these regimens.

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“…Nevertheless, different meta-analyses evaluating CI versus STI of various time-dependent antimicrobials have failed to convincingly demonstrate improved clinical outcomes on mortality and clinical cure (1)(2)(3)(4)(5)(6). It is noteworthy, however, that in the majority of studies included in these metaanalyses, the total daily dose of antimicrobials was lower for patients treated with EI or CI (1,2,5).…”

mentioning

confidence: 89%

Continuous versus Short-Term Infusion of Cefuroxime: Assessment of Concept Based on Plasma, Subcutaneous Tissue, and Bone Pharmacokinetics in an Animal Model

Tøttrup

Bibby

Hardlei

et al. 2015

Antimicrob Agents Chemother

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The relatively short half-lives of most ␤-lactams suggest that continuous infusion of these time-dependent antimicrobials may be favorable compared to short-term infusion. Nevertheless, only limited solid-tissue pharmacokinetic data are available to support this theory. In this study, we randomly assigned 12 pigs to receive cefuroxime as either a short-term or continuous infusion. Measurements of cefuroxime were obtained every 30 min in plasma, subcutaneous tissue, and bone. For the measurements in solid tissues, microdialysis was applied. A two-compartment population model was fitted separately to the drug concentration data for the different tissues using a nonlinear mixed-effects regression model. Estimates of the pharmacokinetic parameters and time with concentrations above the MIC were derived using Monte Carlo simulations. Except for subcutaneous tissue in the short-term infusion group, the tissue penetration was incomplete for all tissues. T he relatively short half-lives of most ␤-lactams suggest that extended infusion (EI) or continuous infusion (CI) of these time-dependent antimicrobials may be favorable compared to short-term infusion (STI). Nevertheless, different meta-analyses evaluating CI versus STI of various time-dependent antimicrobials have failed to convincingly demonstrate improved clinical outcomes on mortality and clinical cure (1-6). It is noteworthy, however, that in the majority of studies included in these metaanalyses, the total daily dose of antimicrobials was lower for patients treated with EI or CI (1, 2, 5). In a subset of randomized controlled trials (RCTs) in which the total daily dose was equivalent in the two intervention arms, the clinical failure rate was lower for patients treated with CI (1).Inferences about the dosing regimens of antimicrobials are commonly based on plasma pharmacokinetics-pharmacodynamics (PK-PD) indices, despite the fact that the majority of bacterial pathogens reside in the interstitial space of solid tissues. However, incomplete and uneven tissue distribution was eventually demonstrated in a number of studies for different combinations of drug and tissue (7-13). As the gap between steady-state plasma concentrations and MICs may be rather limited using CI, incomplete tissue penetration may partly explain why improved clinical outcomes for CI have been difficult to demonstrate, particularly when the total daily dose is reduced.Deep-seated orthopedic infections, like osteomyelitis and implant-associated infections (IAI), are difficult to treat, often requiring extensive surgical debridement and long-lasting antimicrobial therapy (14). In a recent porcine study, we demonstrated substantially impaired bone and subcutaneous tissue (SCT) penetration of cefuroxime (15). The pharmacokinetic profiles suggested that EI or CI of the drug might attain increased time with tissue concentrations above the MIC (TϾMIC) for relevant microorganisms.Ultimately, the dosing regimens of antimicrobials should be based on results of RCTs for a specific combination of drug, bug...

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Does prolonged β-lactam infusions improve clinical outcomes compared to intermittent infusions? A meta-analysis and systematic review of randomized, controlled trials

Cited by 84 publications

References 33 publications

Combination Therapy for Treatment of Infections with Gram-Negative Bacteria

Combination Therapy for Treatment of Infections with Gram-Negative Bacteria

Continuous and Prolonged Intravenous β-Lactam Dosing: Implications for the Clinical Laboratory

Continuous versus Short-Term Infusion of Cefuroxime: Assessment of Concept Based on Plasma, Subcutaneous Tissue, and Bone Pharmacokinetics in an Animal Model

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