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Antimicrobial Agents and Chemotherapy Mar 2021There is insufficient data on the relationship between antibiotic dosing and plasma concentrations in patients treated with continuous renal replacement therapy (CRRT).... (Observational Study)
Observational Study
There is insufficient data on the relationship between antibiotic dosing and plasma concentrations in patients treated with continuous renal replacement therapy (CRRT). In this prospective observational study, we explored the variability in plasma concentrations of meropenem and piperacillin in critically ill patients treated with CRRT and the correlation between concentrations and CRRT intensity. Antibiotic concentrations were measured at the middle and end of the dosing interval and repeated after 2 to 3 days when feasible. Measured concentrations were compared to the clinical susceptible breakpoints for , 16 and 2 mg/liter for piperacillin and meropenem, respectively. CRRT intensity was estimated by delivered, time-averaged, total effluent flow (), corrected for predilution. Concentrations were also compared between patients with different residual diuresis. We included 140 meropenem concentrations from 98 patients and 47 piperacillin concentrations from 37 patients. Concentrations at the middle of the dosing interval were above target at all occasions for both antibiotics. For meropenem, 6.5% of trough concentrations were below target, and for piperacillin, 22%. Correlations between and antibiotic concentrations or the concentration half-life () were either statistically not significant or weak. Meropenem concentrations and values differed between patients with different residual diuresis. Thus, when treating intensive care patients with CRRT and recommended doses of meropenem or piperacillin, both low, suboptimal plasma concentrations and unnecessarily high, potentially toxic, plasma concentrations are common. Plasma concentrations cannot be predicted from CRRT intensity. Residual diuresis is associated with lower meropenem concentrations, but the correlation is weak. Concentration measurement is probably the most useful approach to avoid suboptimal treatment.
Topics: Anti-Bacterial Agents; Continuous Renal Replacement Therapy; Critical Illness; Humans; Meropenem; Piperacillin; Renal Replacement Therapy
PubMed: 33495227
DOI: 10.1128/AAC.02029-20 -
Antimicrobial Agents and Chemotherapy Aug 2021Meropenem-vaborbactam is a broad-spectrum carbapenem-beta-lactamase inhibitor combination approved in the United States and Europe to treat patients with complicated...
Meropenem-vaborbactam is a broad-spectrum carbapenem-beta-lactamase inhibitor combination approved in the United States and Europe to treat patients with complicated urinary tract infections and in Europe for other serious bacterial infections, including hospital-acquired and ventilator-associated pneumonia. Population pharmacokinetic (PK) models were developed to characterize the time course of meropenem and vaborbactam using pooled data from two phase 1 and two phase 3 studies. Multicompartment disposition model structures with linear elimination processes were fit to the data using NONMEM 7.2. Since both drugs are cleared primarily by the kidneys, estimated glomerular filtration rate (eGFR) was evaluated as part of the base structural models. For both agents, a two-compartment model with zero-order input and first-order elimination best described the pharmacokinetic PK data, and a sigmoidal Hill-type equation best described the relationship between renal clearance and eGFR. For meropenem, the following significant covariate relationships were identified: clearance (CL) decreased with increasing age, CL was systematically different in subjects with end-stage renal disease, and all PK parameters increased with increasing weight. For vaborbactam, the following significant covariate relationships were identified: CL increased with increasing height, volume of the central compartment () increased with increasing body surface area, and CL, , and volume of the peripheral compartment were systematically different between phase 1 noninfected subjects and phase 3 infected patients. Visual predictive checks demonstrated minimal bias, supporting the robustness of the final models. These models were useful for generating individual PK exposures for pharmacokinetic-pharmacodynamic (PK-PD) analyses for efficacy and Monte Carlo simulations to evaluate PK-PD target attainment.
Topics: Anti-Bacterial Agents; Boronic Acids; Drug Combinations; Heterocyclic Compounds, 1-Ring; Humans; Meropenem
PubMed: 34097490
DOI: 10.1128/AAC.02606-20 -
Microbiology Spectrum Jun 2022Debate continues as to the role of combination antibiotic therapy for the management of Pseudomonas aeruginosa infections. We studied the extent of bacterial killing by...
Debate continues as to the role of combination antibiotic therapy for the management of Pseudomonas aeruginosa infections. We studied the extent of bacterial killing by and the emergence of resistance to meropenem and amikacin as monotherapies and as a combination therapy against susceptible and resistant P. aeruginosa isolates from bacteremic patients using the dynamic hollow-fiber infection model. Three P. aeruginosa isolates (meropenem MICs of 0.125, 0.25, and 64 mg/L) were used, simulating bacteremia with an initial inoculum of ~1 × 10 CFU/mL and the expected pharmacokinetics of meropenem and amikacin in critically ill patients. For isolates susceptible to amikacin and meropenem (isolates 1 and 2), the extent of bacterial killing was increased with the combination regimen compared with the killing by monotherapy of either antibiotic. Both the combination and meropenem monotherapy were able to sustain bacterial killing throughout the 7-day treatment course, whereas regrowth of bacteria occurred with amikacin monotherapy after 12 h. For the meropenem-resistant P. aeruginosa isolate (isolate 3), only the combination regimen demonstrated bacterial killing. Given that tailored antibiotic regimens can maximize potential synergy against some isolates, future studies should explore the benefit of combination therapy against resistant P. aeruginosa. Current guidelines recommend that aminoglycosides should be used in combination with β-lactam antibiotics as initial empirical therapy for serious infections, and otherwise, patients should receive β-lactam antibiotic monotherapy. Given the challenges associated with studying the clinical effect of different antibiotic strategies on patient outcomes, useful data for subsequent informed clinical testing can be obtained from models like the hollow-fiber infection model (HFIM). Based on the findings of our HFIM, we propose that the initial use of combination therapy with meropenem and amikacin provides some bacterial killing against carbapenem-resistant P. aeruginosa isolates. For susceptible isolates, combination therapy may only be of benefit in specific patient populations, such as critically ill or immunocompromised patients. Therefore, clinicians may want to consider using the combination therapy for the initial management and ceasing the aminoglycosides once antibiotic susceptibility results have been obtained.
Topics: Amikacin; Aminoglycosides; Anti-Bacterial Agents; Bacteremia; Critical Illness; Humans; Meropenem; Microbial Sensitivity Tests; Pseudomonas Infections; Pseudomonas aeruginosa
PubMed: 35442072
DOI: 10.1128/spectrum.00525-22 -
BMJ Case Reports Sep 2021Meropenem is a broad-spectrum carbapenem widely used to treat both Gram-positive and negative bacterial infections, including extended-spectrum beta-lactamase-producing...
Meropenem is a broad-spectrum carbapenem widely used to treat both Gram-positive and negative bacterial infections, including extended-spectrum beta-lactamase-producing microbes. We describe the occurrence of thrombocytopenia and hypersensitivity in a boy receiving intravenous meropenem for intra-abdominal sepsis secondary to perforated appendicitis. The patient developed a pruritic maculopapular rash with occasional petechiae, associated with severe thrombocytopenia, after 7 days of meropenem administration. Investigations for other causes of thrombocytopenia, including possible line sepsis, were unfruitful, and the thrombocytopenia did not resolve until cessation of meropenem. Drug-induced reactions should be considered in children receiving meropenem who present with a rash and thrombocytopenia.
Topics: Anti-Bacterial Agents; Bacterial Infections; Child; Humans; Male; Meropenem; Thienamycins; Thrombocytopenia
PubMed: 34479885
DOI: 10.1136/bcr-2021-243443 -
The Journal of Antimicrobial... Apr 2022To evaluate the in vitro and in vivo efficacy of the FDA-approved drug disulfiram in combination with meropenem against MBL-expressing carbapenem-resistant Acinetobacter...
OBJECTIVES
To evaluate the in vitro and in vivo efficacy of the FDA-approved drug disulfiram in combination with meropenem against MBL-expressing carbapenem-resistant Acinetobacter baumannii.
METHODS
Chequerboard and antibiotic resistance reversal analysis were performed using 25 clinical isolates producing different MBLs. Three representative strains harbouring NDM, IMP or non-MBL genes were subjected to a time-kill assay to further evaluate this synergistic interaction. Dose-dependent inhibition by disulfiram was assessed to determine IC50 for NDM-1, IMP-7, VIM-2 and KPC-2. Further, to test the efficacy of meropenem monotherapy and meropenem in combination with disulfiram against NDM- and IMP-harbouring A. baumannii, an experimental model of systemic infection and pneumonia was developed using BALB/c female mice.
RESULTS
Chequerboard and antibiotic reversal assay displayed a synergistic interaction against MBL-expressing A. baumannii strains with 4- to 32-fold reduction in MICs of meropenem. In time-kill analysis, meropenem and disulfiram exhibited synergy against NDM- and IMP-producing carbapenem-resistant A. baumannii (CRAb) isolates. In vitro dose-dependent inhibition analysis showed that disulfiram inhibits NDM-1 and IMP-7 with IC50 values of 1.5 ± 0.6 and 16.25 ± 1.6 μM, respectively, with slight or no inhibition of VIM-2 (<20%) and KPC-2. The combination performed better in the clearance of bacterial load from the liver and spleen of mice infected with IMP-expressing CRAb. In the pneumonia model, the combination significantly decreased the bacterial burden of NDM producers compared with monotherapy.
CONCLUSIONS
These results strongly suggest that the combination of disulfiram and meropenem represents an effective treatment option for NDM- and IMP-associated CRAb infections.
Topics: Animals; Female; Mice; Acinetobacter baumannii; Anti-Bacterial Agents; beta-Lactamases; Carbapenems; Disulfiram; Meropenem; Microbial Sensitivity Tests
PubMed: 35199158
DOI: 10.1093/jac/dkac057 -
Enfermedades Infecciosas Y... Dec 2023Prolonged intravenous infusion of beta-lactams increase the clinical cure rate compared to conventional administration in critical or septic patients. This study aimed...
INTRODUCTION
Prolonged intravenous infusion of beta-lactams increase the clinical cure rate compared to conventional administration in critical or septic patients. This study aimed to determine chemical stability and physical compatibility of meropenem at conditions used in clinical practice to evaluate the stability of the preparation during its administration and the possibility of anticipated preparation.
METHODS
Admixtures in study were: (i) meropenem 6g in 0.9% sodium chloride (NS) in infusor of 2mL/h 50mL or 10mL/h 240mL; (ii) meropenem 1 or 2g in NS in infusion bag of 250mL. Temperatures of study were: (i) infusor: 4.5°C, 32°C or 12h at 4.5°C followed by 32°C; (ii) Infusion bag: 4.5°C, 24.5°C or 6h at 4.5°C followed by 24.5°C. Time of study was 5-6 days in infusor and 1 day in infusion bag. Chemical stability was evaluated by high performance liquid chromatography and physical compatibility by measuring pH and visual inspection.
RESULTS
Chemical stability and physical compatibility of meropenem in admixtures in infusors were reduced at high meropenem concentration and high temperature. Admixtures in infusion bag show chemical stability and physical compatibility for at least 1 day.
CONCLUSION
Administration of meropenem 6g in infusion of 24h in 240mL of 0.9% NaCl in infusor of 10mL/h could be possible if the admixture is infused at 4.5°C. Extended infusion of meropenem 1 or 2g in 0.9% NaCl in infusion bag (250mL) in 3-4h is also feasible. Anticipated preparation of the admixtures in infusion bag is possible with a stability of 24h.
Topics: Humans; Infusions, Intravenous; Meropenem; Saline Solution
PubMed: 36707284
DOI: 10.1016/j.eimce.2022.07.010 -
International Journal of Antimicrobial... Aug 2023Device-related infections are difficult to treat due to biofilms. In this setting, optimizing antibiotic efficacy is difficult as most pharmacokinetic/pharmacdynamic...
INTRODUCTION
Device-related infections are difficult to treat due to biofilms. In this setting, optimizing antibiotic efficacy is difficult as most pharmacokinetic/pharmacdynamic (PK/PD) studies have been performed on planktonic cells, and therapies are limited when multi-drug-resistant bacteria are involved. This study aimed to analyse the PK/PD indices of meropenem predicting anti-biofilm efficacy against meropenem-susceptible and meropenem-resistant strains of Pseudomonas aeruginosa.
MATERIALS AND METHODS
Pharmacodynamics of meropenem dosages mimicking those of clinical practice (intermittent bolus of 2 g every 8 h; extended infusion of 2 g over 4 h every 8 h), with and without colistin, were evaluated with the CDC Biofilm Reactor in-vitro model for susceptible (PAO1) and extensively-drug-resistant (XDR-HUB3) P. aeruginosa. Efficacy was correlated with the PK/PD indices for meropenem.
RESULTS
For PAO1, both meropenem regimens were bactericidal, with higher killing for extended infusion [∆log colony-forming units (CFU)/mL 54-0h=-4.66±0.93 for extended infusion vs ∆log CFU/mL 54-0h=-3.4±0.41 for intermittent bolus; P<0.001]. For XDR-HUB3, the intermittent bolus regimen was non-active, but extended infusion showed bactericidal effect (∆log CFU/mL 54-0h=-3.65±0.29; P<0.001). Time above minimum inhibitory concentration (f%T) had the best correlation with efficacy for both strains. The addition of colistin always improved meropenem activity, and resistant strains did not emerge.
CONCLUSION
f%T was the PK/PD index that best correlated with the anti-biofilm efficacy of meropenem; it was better optimized when using the extended infusion regimen, allowing recovery of bactericidal activity in monotherapy, including activity against meropenem-resistant P. aeruginosa. Combining meropenem by extended infusion with colistin offered the most effective therapy for both strains. Optimizing meropenem dosing by extended infusion should be encouraged when treating biofilm-related infections.
Topics: Humans; Meropenem; Colistin; Pseudomonas aeruginosa; Pseudomonas Infections; Anti-Bacterial Agents; Microbial Sensitivity Tests
PubMed: 37211260
DOI: 10.1016/j.ijantimicag.2023.106856 -
Orthopaedic Surgery Dec 2021To investigate the biomechanical and elution properties of meropenem-loaded bone cement.
OBJECTIVE
To investigate the biomechanical and elution properties of meropenem-loaded bone cement.
METHODS
Bone cement (Palacos LV) with 5% (2 g/4 0g), 10% (4 g/40 g), and 15% (6 g/40 g) meropenem; 5% (2 g/40 g) and 10% (4 g/40 g) vancomycin; and blank bone cement were prepared in a total of six groups named A2, A4, A6, B2, B4, and A0 (antibiotic-free). 36 cylinder specimens (6-mm diameter and 12-mm height) of all six groups were molded for a compression test. After the compression test, because of mechanical properties below the ISO standard requirements, groups B2, B4 were not subjected to a bending test. So a total of 24 rectangular strip specimens (10-mm width, 75-mm length, and 3.3-mm thickness) for groups A2, A4, A6 and A0 were molded for the bending test. Between-group differences of compressive strength, bending strength and bending modulus were analyzed. The meropenem standard was prepared as a series of standard solutions to calculate the standard curve. At a constant temperature of 37 °C, separately, meropenem-loaded bone cement cylinder specimens (12 mm in diameter and 17 mm in length) of A2, A4 and A6 were serially immersed in saline solution without stirring. The eluent drug concentration at 24, 48, 72 h and 6, 12, 24 days was measured and the drug concentration-time curve of meropenem was constructed.
RESULTS
With the exception of groups B2 and B4, all cements compressive strength values were well above the minimum requirement of the ISO 5833 standard (70 MPa). The compressive strength and bending strength values of group A4 were higher than those of group A0 (P < 0.05), but no difference was found between the A0, A2 and A6 groups (P > 0.05). There were no intergroup differences of bending modulus between the A0, A2, A4 and A6 groups (P > 0.05). A standard curve of meropenem was obtained and a regression equation was constructed: Y = 15.0265 X + 13.5218, r = 1.00. At 37 °C, the release of meropenem was rapid during the first 48 h for all A2, A4, A6 samples, and subsequent release continued to decrease.
CONCLUSION
When adding up to 15% (6 g/40 g) meropenem to the bone cement, the biomechanical properties were not reduced, and bone cement with 10% (4 g/40 g) meropenem had the best performance. At a constant temperature of 37°C, meropenem can be released from bone cement for up to 24 days.
Topics: Anti-Bacterial Agents; Biomechanical Phenomena; Bone Cements; Compressive Strength; Humans; Materials Testing; Meropenem; Polymethyl Methacrylate; Powders; Vancomycin
PubMed: 34734478
DOI: 10.1111/os.13139 -
Microbiology Spectrum Feb 2023Carbapenems are a common first-line therapy for serious Gram-negative infections, but carbapenem-resistant (CRE) isolates have become an urgent health concern....
Carbapenems are a common first-line therapy for serious Gram-negative infections, but carbapenem-resistant (CRE) isolates have become an urgent health concern. Klebsiella pneumoniae serine carbapenemases (KPCs) now have been disseminated worldwide and are endemic in many hospitals globally. Isolates producing metallo-β-lactamases (MBLs) or class D OXA-48 carbapenemases are also increasingly common in Europe, although they are less common in the United States. Meropenem-vaborbactam is a combination of the carbapenem meropenem and vaborbactam, which is a β-lactamase inhibitor with activity against serine carbapenemases, including KPC-producing isolates. We examined the susceptibility of U.S. multidrug-resistant (MDR) isolates to meropenem-vaborbactam. A total of 1,697 MDR isolates were collected in 31 U.S. medical centers in 2016 to 2020. Susceptibility testing was performed using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method. Whole-genome sequencing was performed for all CRE strains (MIC values of >2 mg/L for imipenem or meropenem). The rate of susceptibility of all MDR strains to meropenem-vaborbactam was 99.1%, and 86.2% of the isolates were susceptible to meropenem. There were 222 CRE isolates (13.1%). KPC was the most common carbapenemase (81.1%). Thirteen CRE isolates produced NDM (= 7), VIM (= 3), and/or OXA-48-like (= 4) carbapenemases; 29 CRE isolates (13.1%) had no detected carbapenemase. The rate of susceptibility of all CRE strains to meropenem-vaborbactam was 93.2%, and the rate of susceptibility of the KPC-producing isolates to meropenem-vaborbactam was 98.9%. The primary carbapenemase in the United States continues to be KPC, while MBL and OXA-48-like carbapenemases remain uncommon. Overall, the rate of susceptibility of these U.S. MDR organisms to meropenem-vaborbactam was 99.1%, indicating that meropenem-vaborbactam is a valuable treatment option for Gram-negative infections caused by U.S. MDR organisms. Carbapenems are a common first-line therapy for serious Gram-negative infections, but CRE isolates have become an urgent health concern. Meropenem-vaborbactam is a combination of the carbapenem meropenem and vaborbactam, which is a β-lactamase inhibitor with activity against serine carbapenemases, including KPC-producing isolates. We examined the susceptibility of U.S. MDR Gram-negative isolates to meropenem-vaborbactam. A total of 1,697 U.S. MDR isolates collected in 2016 to 2020 were tested. Susceptibility testing was performed using the CLSI broth microdilution method. Whole-genome sequencing was performed for all CRE strains (MIC values of >2 mg/L for imipenem or meropenem). The rate of susceptibility of all MDR strains to meropenem-vaborbactam was 99.1%, and 86.2% of the isolates were susceptible to meropenem. A total of 13.1% of the isolates were CRE strains, and KPC was the most common carbapenemase. Overall, the rate of susceptibility of these U.S. MDR organisms to meropenem-vaborbactam indicates that meropenem-vaborbactam is a valuable treatment option for Gram-negative infections caused by U.S. MDR Gram-negative pathogens.
Topics: United States; Meropenem; Carbapenems; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Bacterial Proteins; Imipenem; beta-Lactamases; Gram-Negative Bacteria; Gammaproteobacteria; Serine; Microbial Sensitivity Tests
PubMed: 36622238
DOI: 10.1128/spectrum.04507-22 -
BMC Microbiology May 2023Acinetobacter baumannii is one of the main causes of healthcare-associated infections that threaten public health, and carbapenems, such as meropenem, have been a...
BACKGROUND
Acinetobacter baumannii is one of the main causes of healthcare-associated infections that threaten public health, and carbapenems, such as meropenem, have been a therapeutic option for these infections. Therapeutic failure is mainly due to the antimicrobial resistance of A. baumannii, as well as the presence of persister cells. Persisters constitute a fraction of the bacterial population that present a transient phenotype capable of tolerating supra-lethal concentrations of antibiotics. Some proteins have been suggested to be involved in the onset and/or maintenance of this phenotype. Thus, we investigated the mRNA levels of the adeB (AdeABC efflux pump component), ompA, and ompW (outer membrane proteins) in A. baumannii cells before and after exposure to meropenem.
RESULTS
We found a significant increase (p-value < 0.05) in the expression of ompA (> 5.5-fold) and ompW (> 10.5-fold) in persisters. However, adeB did not show significantly different expression levels when comparing treated and untreated cells. Therefore, we suggest that these outer membrane proteins, especially OmpW, could be part of the mechanism of A. baumannii persisters to deal with the presence of high doses of meropenem. We also observed in the Galleria mellonella larvae model that persister cells are more virulent than regular ones, as evidenced by their LD values.
CONCLUSIONS
Taken together, these data contribute to the understanding of the phenotypic features of A. baumannii persisters and their relation to virulence, as well as highlight OmpW and OmpA as potential targets for drug development against A. baumannii persisters.
Topics: Meropenem; Acinetobacter baumannii; Virulence; Anti-Bacterial Agents; Membrane Proteins; Microbial Sensitivity Tests; Bacterial Proteins
PubMed: 37246220
DOI: 10.1186/s12866-023-02904-y