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Clinical Pharmacokinetics Apr 2023The pharmacokinetic variability of ampicillin-sulbactam in adults has not been extensively described, particularly in patients with a reduced renal function (i.e.,...
BACKGROUND
The pharmacokinetic variability of ampicillin-sulbactam in adults has not been extensively described, particularly in patients with a reduced renal function (i.e., < 60 mL/min).
OBJECTIVE
This study investigated the population pharmacokinetics of ampicillin and sulbactam in patients with a wide range of renal functions and sought to define dosing approaches that have a high likelihood for optimising drug exposure.
METHODS
Serial blood samples were collected from 16 adult patients receiving intravenous ampicillin-sulbactam in general wards. Total ampicillin and sulbactam concentrations were measured by chromatographic assay and pharmacokinetic parameters were estimated using Pmetrics. Monte Carlo simulations were used to evaluate the probability of target attainment (PTA) of free ampicillin and sulbactam concentrations exceeding the minimum inhibitory concentration (MIC) for 60% and 100% of the dosing interval. Fractional target attainment (FTA) was calculated against MIC distributions of common hospital pathogens. A threshold of ≥ 90% and ≥ 95% was used to define both optimal PTA and FTA, respectively.
RESULTS
The median (range) age, weight, and serum creatinine of the study population was 68 (40-82) years, 62 (40-82) kg, and 1.4 (0.6-6.4) mg/dL, respectively. The pharmacokinetics of ampicillin and sulbactam were best described by a two-compartment model with serum creatinine most closely associated with clearance for both drugs. The estimated ampicillin and sulbactam clearances were 5.58 L/h and 4.79 L/h, respectively, while the volumes of distribution were 12.6 L and 15.36 L, respectively. Approved dosing regimens of ampicillin-sulbactam were sufficient against MICs ≤ 8 and ≤ 4 mg/L, respectively. A 4-h infusion enabled optimal PTA at higher MICs. For both dosing targets, optimal FTAs were obtained against Streptococcus pneumoniae.
CONCLUSION
Optimal FTAs were obtained against the susceptible MIC distributions of Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii. Applying a 4-h infusion will enhance PTA and FTA, particularly at higher MICs.
Topics: Humans; Adult; Aged; Aged, 80 and over; Sulbactam; Anti-Bacterial Agents; Creatinine; Ampicillin; Microbial Sensitivity Tests
PubMed: 36853585
DOI: 10.1007/s40262-023-01219-5 -
Bone Concentration of Ampicillin/Sulbactam: A Pilot Study in Patients with Osteonecrosis of the Jaw.International Journal of Environmental... Nov 2022Osteonecrosis of the jaw (ONJ) occurs typically after irradiation of the head and neck area or after the intake of antiresorptive agents. Both interventions can lead to...
Osteonecrosis of the jaw (ONJ) occurs typically after irradiation of the head and neck area or after the intake of antiresorptive agents. Both interventions can lead to compromised bone perfusion and can ultimately result in infection and necrosis. Treatment usually consists of surgical necrosectomy and prolonged antibiotic therapy, usually through beta-lactams such as ampicillin/sulbactam. The poor blood supply in particular raises the question as to whether this form of antibiosis can achieve sufficient concentrations in the bone. Therefore, we investigated the antibiotic concentration in plasma and bone samples in a prospective study. Bone samples were collected from the necrosis core and in the vital surrounding bone. The measured concentrations in plasma for ampicillin and sulbactam were 126.3 ± 77.6 and 60.2 ± 35.0 µg/mL, respectively. In vital bone and necrotic bone samples, the ampicillin/sulbactam concentrations were 6.3 ± 7.8/1.8 ± 2.0 µg/g and 4.9 ± 7.0/1.7 ± 1.7 µg/g, respectively. These concentrations are substantially lower than described in the literature. However, the concentration seems sufficient to kill most bacteria, such as and , which are mostly present in the biofilm of ONJ. We, therefore, conclude that intravenous administration of ampicillin/sulbactam remains a valuable treatment in the therapy of ONJ. Nevertheless, increasing resistance of towards beta-lactam antibiotics have been reported and should be considered.
Topics: Humans; Sulbactam; Pilot Projects; Prospective Studies; Ampicillin; Anti-Bacterial Agents; Osteonecrosis; Escherichia coli
PubMed: 36429636
DOI: 10.3390/ijerph192214917 -
British Medical Journal (Clinical... Feb 1983
Topics: Ampicillin; Humans; Kinetics
PubMed: 6402157
DOI: 10.1136/bmj.286.6365.583 -
International Journal of Molecular... May 2022Cefotaximase-Munich (CTX-M) extended-spectrum beta-lactamases (ESBLs) are commonly associated with Gram-negative, hospital-acquired infections worldwide. Several...
Cefotaximase-Munich (CTX-M) extended-spectrum beta-lactamases (ESBLs) are commonly associated with Gram-negative, hospital-acquired infections worldwide. Several beta-lactamase inhibitors, such as clavulanate, are used to inhibit the activity of these enzymes. To understand the mechanism of CTX-M-15 activity, we have determined the crystal structures of CTX-M-15 in complex with two specific classes of beta-lactam compounds, desfuroylceftiofur (DFC) and ampicillin, and an inhibitor, clavulanic acid. The crystal structures revealed that Ser70 and five other residues (Lys73, Tyr105, Glu166, Ser130, and Ser237) participate in catalysis and binding of those compounds. Based on analysis of steady-state kinetics, thermodynamic data, and molecular docking to both wild-type and S70A mutant structures, we determined that CTX-M-15 has a similar affinity for all beta-lactam compounds (ceftiofur, nitrocefin, DFC, and ampicillin), but with lower affinity for clavulanic acid. A catalytic mechanism for tested β-lactams and two-step inhibition mechanism of clavulanic acid were proposed. CTX-M-15 showed a higher activity toward DFC and nitrocefin, but significantly lower activity toward ampicillin and ceftiofur. The interaction between CTX-M-15 and both ampicillin and ceftiofur displayed a higher entropic but lower enthalpic effect, compared with DFC and nitrocefin. DFC, a metabolite of ceftiofur, displayed lower entropy and higher enthalpy than ceftiofur. This finding suggests that compounds containing amine moiety (e.g., ampicillin) and the furfural moiety (e.g., ceftiofur) could hinder the hydrolytic activity of CTX-M-15.
Topics: Ampicillin; Anti-Bacterial Agents; Cephalosporins; Clavulanic Acid; Microbial Sensitivity Tests; Molecular Docking Simulation; beta-Lactamases
PubMed: 35563620
DOI: 10.3390/ijms23095229 -
IARC Monographs on the Evaluation of... 1990
Review
Topics: Ampicillin; Animals; Carcinogens; Female; Humans; Molecular Structure; Reproduction
PubMed: 2292797
DOI: No ID Found -
The Journal of Antimicrobial... Feb 2022This study aimed to simultaneously investigate the pharmacokinetics of ampicillin and gentamicin, currently the WHO standard of care for treating neonatal sepsis. (Clinical Trial)
Clinical Trial
OBJECTIVES
This study aimed to simultaneously investigate the pharmacokinetics of ampicillin and gentamicin, currently the WHO standard of care for treating neonatal sepsis.
METHODS
Pharmacokinetic data were collected in 59 neonates receiving ampicillin and gentamicin for suspected or proven sepsis in the NeoFosfo trial (NCT03453177). A panel of 23 clinical Escherichia coli isolates from neonates with sepsis, resistant to either ampicillin, gentamicin or both, were tested for susceptibility using chequerboards. Pharmacokinetic/pharmacodynamic (PKPD) modelling and simulations were used to compare single-agent (EUCAST MIC) and combination (chequerboard MIC) target attainment with standard dosing regimens.
RESULTS
A model was established that simultaneously estimated parameters of a one-compartment ampicillin model and a two-compartment gentamicin model. A common clearance for both drugs was used (6.89 L/h/70 kg) relating to glomerular filtration (CLGFR), with an additional clearance term added for ampicillin (5.3 L/h/70 kg). Covariate modelling included a priori allometric weight and post-menstrual age scaling of clearance. Further covariate relationships on renal clearance were postnatal age and serum creatinine.Simulation-based PKPD assessments suggest good Gram-positive (MIC ≤ 0.25 mg/L) cover. However, less than one-quarter of neonates were predicted to receive efficacious coverage against Enterobacterales (MIC ≤ 2 mg/L). The benefit of the ampicillin/gentamicin combination was limited, with only 2/23 E. coli clinical strains showing FIC index < 0.5 (synergy) and most in the range 0.5-1 (suggesting additivity). Simulations showed that feasible dosing strategies would be insufficient to cover resistant strains.
CONCLUSIONS
PKPD simulations showed ampicillin and gentamicin combination therapy was insufficient to cover Enterobacterales, suggesting the need for alternative empirical treatment options for neonatal sepsis.
Topics: Ampicillin; Anti-Bacterial Agents; Escherichia coli; Gentamicins; Humans; Infant, Newborn; Neonatal Sepsis; Sepsis
PubMed: 35107141
DOI: 10.1093/jac/dkab413 -
British Journal of Clinical Pharmacology Jun 19771 The plasma concentration/time curves of ampicillin and mecillinam in normal subjects were measured after oral administration of ampicillin (500 mg) and pivmecillinam...
1 The plasma concentration/time curves of ampicillin and mecillinam in normal subjects were measured after oral administration of ampicillin (500 mg) and pivmecillinam (400 and 600 mg). 2 Similar plasma concentration/time curves of ampicillin and mecillinam in the starved normal subjects followed oral administration of ampicillin (500 mg) and pivmecillinam (600 mg). 3 The plasma concentration/time curve of mecillinam was measured in the same normal subjects after oral administration of pivmecillinam (400 mg) with a reproducible standardized Lundh test meal. 4 There was no statistically significant difference in the plasma concentration/time curve of mecillinam after pivmecillinam/400 mg) and the meal compared with the plasma concentration/time curve after oral pivmecillinam (400 mg) was given to the same subjects when starved. After administration of pivmecillinam (400 mg) with meal, Tasc was significantly delayed beyond the value obtained when the subjects were starved. 5 The pharmacokinetics of pivmecillinam in coeliac disease are normal. This finding contrasts with previous studies on the pharmacokinetics of another pivaloyloxymethylpenicillin ester, pivampicillin, in this condition.
Topics: Adolescent; Adult; Amdinocillin Pivoxil; Ampicillin; Biological Assay; Celiac Disease; Escherichia coli; Food; Humans; Intestinal Absorption; Kinetics; Middle Aged; Penicillanic Acid; Sarcina; Starvation
PubMed: 197981
DOI: 10.1111/j.1365-2125.1977.tb00711.x -
Journal of Microbiology, Immunology,... Jun 2022To investigate antibiotic resistance of pathogens responsible for neonatal invasive bacterial infections (IBIs) in China.
BACKGROUND
To investigate antibiotic resistance of pathogens responsible for neonatal invasive bacterial infections (IBIs) in China.
METHODS
Cross-sectional study of neonates with IBI evaluated in nine hospitals in China (January 2012-August 2019). Antibiotic resistance patterns of pathogens responsible for neonatal IBIs were analyzed.
RESULTS
Of 3770 full-term neonates who were subjected to lumbar puncture and a blood culture, IBIs were diagnosed in 460 neonates (12.2%). Escherichia coli and Group B Streptococcus (GBS) were the leading pathogens, followed by Enterococcus spp, and Staphylococcus aureus. E. coli expressed high resistance to ampicillin (72.0%) and third-generation cephalosporins (cefotaxime, 34.8%; ceftriaxone, 38.1%). The prevalence of extended spectrum beta-lactamase (ESBL)-producing E. coli was 34.1%. The proportions of E. spp resistant to penicillin and ampicillin were 60% and 54.1%. All S. aureus showed resistance to ampicillin and penicillin. The resistance rate of S. aureus to methicillin was 50%. Although all GBS were susceptible to penicillin and ampicillin, the proportions of GBS resistant to erythromycin and clindamycin were 75.9% and 77.3%. Antibiotic susceptibility appeared to improve in 2019. Susceptibility of E. coli to ampicillin, cefotaxime, and ceftriaxone improved to 42.9%, 76.9%, and 71.4% in 2019, compared with 12.5%, 37.5%, and 50% in 2012. The prevalence of ESBL-producing E. coli declined to 20% in 2019, lower than 100% in 2012. Susceptibility of GBS to erythromycin and clindamycin improved from 0% in 2012 to 28.6% and 25% in 2019.
CONCLUSIONS
The prevalence of antibiotic resistance is high in neonates in China, although there is a favorable declining trend in recent years.
Topics: Ampicillin; Anti-Bacterial Agents; Cefotaxime; Ceftriaxone; China; Clindamycin; Cross-Sectional Studies; Drug Resistance, Bacterial; Drug Resistance, Microbial; Erythromycin; Escherichia coli; Humans; Infant, Newborn; Microbial Sensitivity Tests; Penicillins; Staphylococcus aureus; Streptococcus agalactiae
PubMed: 34059443
DOI: 10.1016/j.jmii.2021.05.004 -
The Journal of International Medical... 2001Ampicillin/sulbactam is an effective solution to the emergence of beta-lactamase-mediated resistance among common pediatric pathogens, and is a widely recognized... (Review)
Review
Ampicillin/sulbactam is an effective solution to the emergence of beta-lactamase-mediated resistance among common pediatric pathogens, and is a widely recognized treatment option for a variety of pediatric infections. Recent antimicrobial surveillance data confirm the continued susceptibility of many Gram-positive and Gram-negative aerobes and anaerobes to ampicillin/sulbactam. Pharmacokinetic studies have demonstrated high drug concentrations at a variety of infection sites, including cerebrospinal fluid and bone. Furthermore, clinical studies have shown that ampicillin/sulbactam, administered intravenously, intramuscularly or orally (as the mutual prodrug sultamicillin), is clinically and bacteriologically effective against upper and lower respiratory tract infections, urinary tract infections, skin, bone and soft-tissue infections, and meningitis, and provides effective surgical prophylaxis. Sultamicillin has an excellent tolerability profile, which is associated with a low rate of treatment discontinuation. Accordingly, ampicillin/sulbactam and sultamicillin should be considered first-choice options for the management of a variety of pediatric infections.
Topics: Ampicillin; Bacterial Infections; Child; Drug Therapy, Combination; Drug Tolerance; Humans; Meningitis, Bacterial; Respiratory Tract Infections; Sulbactam; Urinary Tract Infections
PubMed: 11675898
DOI: 10.1177/147323000102900401 -
BMC Microbiology Jan 2023Enterococcus faecalis remains one of the most common pathogens causing infection in surgical patients. Our goal was to evaluate the antibiotic resistance of E. faecalis,...
BACKGROUND
Enterococcus faecalis remains one of the most common pathogens causing infection in surgical patients. Our goal was to evaluate the antibiotic resistance of E. faecalis, causing infections in a surgical clinic, against two antibacterial drugs, ampicillin and teicoplanin. One commonly administered in the past for such infections, ampicillin, and another newer, teicoplanin, which demonstrated exceptionally good efficacy.
METHODS
Data from 1882 isolates were retrieved from the microbiology department database during two 5-year periods. Standard biochemical methods were employed for the identification of the isolates. The prevalence of E. faecalis among patients with clinical evidence of infection in a surgical oncology ward was assessed. Confidence interval (CI) as well as standard error (SE) were calculated. Moreover, the annual incidence of E. faecalis infections in this surgical ward was recorded. The susceptibility of E. faecalis to ampicillin and teicoplanin was studied and compared using Fisher's exact test.
RESULTS AND CONCLUSION
Results showed that the incidence of E. faecalis infections in the surgical clinic was increasing. Ampicillin, in the later year period, was not statistically different from teicoplanin in treating E. faecalis infections. Consequently, ampicillin seems currently to be an effective antibiotic against such infections that could be used as empiric therapy.
Topics: Humans; Teicoplanin; Enterococcus faecalis; Microbial Sensitivity Tests; Anti-Bacterial Agents; Ampicillin
PubMed: 36609223
DOI: 10.1186/s12866-022-02753-1