Pharmacokinetics of Sulbactam/Ampicillin in Humans: A Review

Foulds, George

doi:10.1093/clinids/8.supplement_5.503

Cited by 119 publications

(88 citation statements)

References 29 publications

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“…Antimicrobial susceptibility testing was performed by using CLSI methods or the Epsilometer test according to the manufacturer's instructions (bioMérieux, Durham, NC) (8). Time-kill assays were performed in duplicate using an initial bacterial inoculum of 10 6 CFU/ml in LuriaBertani broth (LB) supplemented with 50 mg/liter calcium, with antibiotic concentrations chosen to encompass readily achievable serum levels of each agent during clinical treatment regimens (9)(10)(11)(12)(13). Quantitative bacterial counts were determined at 0, 6, and 24 h of incubation at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Ceftaroline Restores Daptomycin Activity against Daptomycin-Nonsusceptible Vancomycin-Resistant Enterococcus faecium

Sakoulas

Rose

Nonejuie

et al. 2014

Antimicrob Agents Chemother

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c Daptomycin-nonsusceptible vancomycin-resistant Enterococcus faecium (VRE) strains are a formidable emerging threat to patients with comorbidities, leaving few therapeutic options in cases of severe invasive infections. Using a previously characterized isogenic pair of VRE strains from the same patient differing in their daptomycin susceptibilities (Etest MICs of 0.38 mg/liter and 10 mg/liter), we examined the effect of ceftaroline, ceftriaxone, and ampicillin on membrane fluidity and susceptibility of VRE to surface binding and killing by daptomycin and human cathelicidin antimicrobial peptide LL37. Synergy was noted in vitro between daptomycin, ampicillin, and ceftaroline for the daptomycin-susceptible VRE strain, but only ceftaroline showed synergy against the daptomycin-nonsusceptible VRE strain (ϳ2 log 10 CFU reduction at 24 h). Ceftaroline cotreatment increased daptomycin surface binding with an associated increase in membrane fluidity and an increase in the net negative surface charge of the bacteria as evidenced by increased poly-L-lysine binding. Consistent with the observed biophysical changes, ceftaroline resulted in increased binding and killing of daptomycin-nonsusceptible VRE by human cathelicidin LL37. Using a pair of daptomycinsusceptible/nonsusceptible VRE strains, we noted that VRE is ceftaroline resistant, yet ceftaroline confers significant effects on growth rate as well as biophysical changes on the cell surface of VRE that can potentiate the activity of daptomycin and innate cationic host defense peptides, such as cathelicidin. Although limited to just 2 strains, these finding suggest that additional in vivo and in vitro studies need to be done to explore the possibility of using ceftaroline as adjunctive anti-VRE therapy. Loss of susceptibility to daptomycin is an increasing concern among vancomycin-resistant Enterococcus faecium (VRE) (1). When faced with invasive infections by daptomycin-nonsusceptible VRE, clinicians have limited therapeutic options. Of great concern are the lack of a bactericidal agent, antibiotic-associated side effects such as linezolid-induced thrombocytopenia and quinupristin-dalfopristin (QD)-associated myalgias, and drug-drug interactions such as microsomal P450 effects of QD and serotonin syndrome concerns with linezolid and concomitant serotonin reuptake inhibitors. Therefore, a great need exists for infectiousdisease physicians practicing in tertiary medical centers with patients at high risk for VRE infections, e.g., bone marrow and liver transplant recipients, to develop innovative pharmacotherapies to treat such patients (2, 3). The clinical dilemma faced by physicians treating these patients is further compounded by the facts that novel therapeutics targeting VRE are lacking and that single or combination antibiotics with in vitro activity against VRE have not been clinically validated by appropriate trials (4).Our group has previously shown a perhaps counterintuitive effect of ampicillin in converting daptomycin from a bacteriostatic to a bactericidal an...

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Section: Methodsmentioning

confidence: 99%

Ceftaroline Restores Daptomycin Activity against Daptomycin-Nonsusceptible Vancomycin-Resistant Enterococcus faecium

Sakoulas

Rose

Nonejuie

et al. 2014

Antimicrob Agents Chemother

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“…The PK of both ampicillin and sulbactam were previously described by a two compartment model [3][4][5][6]12]. The parameterization with clearance (CL), central volume (V1), inter-compartment clearance (Q), and peripheral volume (V2) was used, though the other models such as one and three compartment models were also tested in advance.…”

Section: Population Pharmacokinetic Analysismentioning

confidence: 99%

“…Ampicillin and sulbactam have been shown to have similar pharmacokinetics (PK) with extensive distribution in the extracellular fluids and tissues being achieved for both drugs [3]. Ampicillin has been found to be approximately 28% reversibly bound to human serum protein and sulbactam approximately 38% reversibly bound [4]. Both drugs are primarily eliminated in urine, principally via glomerular filtration and tubular excretion [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

“…Ampicillin has been found to be approximately 28% reversibly bound to human serum protein and sulbactam approximately 38% reversibly bound [4]. Both drugs are primarily eliminated in urine, principally via glomerular filtration and tubular excretion [3][4][5]. The halflives of ampicillin and sulbactam are approximately 1 h in healthy subjects [3,6] and 1.6-3.7 h in subjects with abnormal renal function [7].…”

Section: Introductionmentioning

confidence: 99%

“…Based on the result, the high dose was approved in 2012. While the PK profile for ampicillin/sulbactam in healthy and renally impaired subjects is well known [3][4][5][6]12], there is no published account of high dose ampicillin/sulbactam PK in Japanese patients with CAP.…”

Section: Introductionmentioning

confidence: 99%

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Population pharmacokinetics of ampicillin and sulbactam in patients with community-acquired pneumonia: evaluation of the impact of renal impairment

Soto

Shoji

Muto

et al. 2014

Br J Clin Pharmacol

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AIMSThe aims of this study were to develop a population pharmacokinetic (PK) model of ampicillin and sulbactam, to identify patient characteristics influencing the PK, and to explore the relationship between dose regimen and degree of renal impairment with exposure and time above minimum inhibitory concentration (MIC). METHODSThis analysis was performed on PK data for ampicillin and sulbactam and MIC data from a clinical trial in Japanese patients with community acquired pneumonia. Simulations were performed to investigate the effects of different dosing intervals on exposure and time above MIC in various degrees of renal impairment. RESULTSThe plasma concentrations from 47 patients were adequately described by a two compartment model with simultaneous fit of ampicillin and sulbactam PK data, where creatinine clearance on clearance and body weight on volume in the peripheral compartment were identified as covariates for both drugs. Creatinine clearance contributed to reducing inter-individual variability of clearance by 16%. Mean clearance (inter-individual variability) for ampicillin and sulbactam was estimated to be 10.7 l h −1 (14.8%) and 10.4 l h −1 (15.2%), respectively. The time above MIC for each pathogen was generally > 50% of the treatment period. Simulations for exposure and time above MIC supported currently recommended dose adjustments. CONCLUSIONSThis study provided a PK model for ampicillin and sulbactam, the time above MICs for identified pathogens and associated simulation results. These findings provide useful information and augment evidence for the established dosage regimens in patients with various degrees of renal impairment.

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Comparison of Ampicillin‐Sulbactam and Ticarcillin‐Clavulanic Acid in Patients With Chronic Renal Failure: Effects of Differential Pharmacokinetics on Serum Bactericidal Activity

Hardin,

Butler,

Ross

et al. 1994

Pharmacotherapy

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Study Objectives. To evaluate the pharmacodynamic antibacterial activity of ticarcillin‐clavulanic acid (T‐C) and ampicillin‐sulbactam (A‐S) combinations against reference bacterial strains in patients with end‐stage renal disease maintained on long‐term hemodialysis.Design. Randomized, crossover, controlled study.Setting. National Institutes of Health‐funded general clinical research unit in a Veterans Administration Medical Center.Patients. Nine adult men with end‐stage renal disease maintained on long‐term hemodialysis. Two subjects did not complete the study due to problems of vascular access, and another withdrew for personal reasons.Interventions. On a nondialysis day, each subject was randomly administered either T‐C 3.1 g or A‐S 3 g as a slow intravenous infusion over 30 minutes. Serial blood samples were collected for measurement of antibiotic serum concentrations and determination of serum bactericidal titers. Following a washout period, the study was repeated with the alternative antibiotic combination.Measurements and Main Results. The mean observed apparent β‐half‐life of clavulanic acid was substantially shorter than that for the other three drugs. The bactericidal activity of both A‐S and T‐C against non‐β‐lactamase‐producing (Nβ‐LP) strains of S. aureus and E. coli was consistently high, as indicated by geometric mean SBTs of at least 1:5 at 24 hours. Against β‐lactamase‐producing (β‐LP) S. aureus, the geometric mean SBTs for A‐S were at least 1:25 throughout the study period, while the geometric mean SBTs for T‐C decreased over 24 hours from 1:29 to 1:6. Against β‐LP E. coli, the bactericidal activities for both A‐S and T‐C were poor, with geometric mean peak SBTs of only 1:6 and 1:3, respectively. The geometric mean SBT for T‐C against this E. coli strain had declined to 1:1 at 6 hrs.Conclusion. Increasing the dosing interval for T‐C in patients with end‐stage renal disease may lead to periods of insufficient clavulanic acid to protect ticarcillin from β‐lactamase degradation.

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Pharmacokinetics of Sulbactam/Ampicillin in Humans: A Review

Cited by 119 publications

References 29 publications

Ceftaroline Restores Daptomycin Activity against Daptomycin-Nonsusceptible Vancomycin-Resistant Enterococcus faecium

Ceftaroline Restores Daptomycin Activity against Daptomycin-Nonsusceptible Vancomycin-Resistant Enterococcus faecium

Population pharmacokinetics of ampicillin and sulbactam in patients with community-acquired pneumonia: evaluation of the impact of renal impairment

Comparison of Ampicillin‐Sulbactam and Ticarcillin‐Clavulanic Acid in Patients With Chronic Renal Failure: Effects of Differential Pharmacokinetics on Serum Bactericidal Activity

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