ABSTRACT
. The overlap Stevens-Johnson syndrome due to meropenem administration. Clinical case and nursing care. A case of overlap Stevens-Johnson syndrome caused by meropenem administration is described. It is a rare cutaneous reaction due to delayed hypersensitivity to drugs characterised by the destruction and separation of the skin epithelium and mucous membranes, affecting between 10% and 29% of the body surface area. The clinical description of the case and a detailed description of nursing management and interventions based on the available literature are reported.
Subject(s)
Anti-Bacterial Agents , Meropenem , Stevens-Johnson Syndrome , Stevens-Johnson Syndrome/nursing , Stevens-Johnson Syndrome/etiology , Humans , Meropenem/administration & dosage , Meropenem/adverse effects , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/adverse effects , Female , Male , Thienamycins/administration & dosage , Thienamycins/adverse effectsABSTRACT
A 43-year-old man was admitted to our department due to fever and headache. The cerebrospinal fluid analysis confirmed bacterial meningitis. Campylobacter species were isolated from blood cultures on the third day of admission. The patient was treated with meropenem (MEPM) and discharged on the 17th day. However, he experienced a recurrence of meningitis and was readmitted on the 68th day, initiating MEPM therapy. Campylobacter fetus was isolated from cerebrospinal fluid cultures on the 74th day. MEPM was continued until the 81st day, followed by one month of minocycline (MINO) therapy. The patient had an uneventful recovery without further recurrence. This case highlights the potential for recurrence of Campylobacter fetus meningitis approximately two months after the resolution of the initial infection. In addition to carbapenem therapy for at least two weeks, the adjunctive administration of MINO may be beneficial.
Subject(s)
Anti-Bacterial Agents , Campylobacter Infections , Campylobacter fetus , Meningitis, Bacterial , Meropenem , Minocycline , Recurrence , Humans , Male , Adult , Campylobacter fetus/isolation & purification , Campylobacter Infections/drug therapy , Campylobacter Infections/complications , Campylobacter Infections/diagnosis , Campylobacter Infections/microbiology , Meropenem/administration & dosage , Meningitis, Bacterial/drug therapy , Meningitis, Bacterial/microbiology , Meningitis, Bacterial/diagnosis , Anti-Bacterial Agents/administration & dosage , Time Factors , Minocycline/administration & dosage , Treatment Outcome , Thienamycins/administration & dosage , Drug Therapy, CombinationABSTRACT
BACKGROUND: Biapenem (BIPM) exhibited a less efficient substrate for various metallo-ß-lactamase (MBL) than other carbapenems. OBJECTIVE: We aimed to evaluate in vitro susceptibility data of BIPM and optimal dose based on Monte Carlo simulation to extend treatment options. METHODS: We collected 192 carbapenem-resistant Klebsiella pneumoniae (CRKP) clinical isolates from unique patients among multicentres in Thailand, from June 2019 to March 2023. BIPM disk diffusion and broth-microdilution testing were performed to obtain minimum inhibitory concentration (MIC). Each BIPM regimen was simulated using the Monte Carlo technique to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR). RESULTS: The most common genotypes among 192 CRKP isolates were blaOXA-48 (62.3%), blaOXA-48+blaNDM (22.6%) and blaNDM (15.1%). BIPM showed 22.4 and 28.6% susceptible rate when interpreted at clinical breakpoints of 1 and 2 mg/L. The MIC50 and MIC90 of BIPM against CRKP were 8 and 32 mg/L. The BIPM dosing regimens of 300 mg q 6 h infused 6 h and 600 mg q 8 h infused 8 h met the PTA target of %fTime >MIC at 50%, 75% and 100% against isolates MICs of ≤2 mg/L. Based on CFR ≥90%, no BIPM regimens were effective against all the studied CRKP isolates. CONCLUSION: BIPM exhibited a partially susceptible rate among the CRKP isolates in Thailand. The current suggested dose of BIPM with prolonged infusion appears appropriate regimen against CRKP MICs of ≤2 mg/L. However, the empirical use of BIPM for severe CRE infection is not recommended unless the susceptibility has been confirmed.
Subject(s)
Anti-Bacterial Agents , Bacterial Proteins , Klebsiella Infections , Klebsiella pneumoniae , Microbial Sensitivity Tests , Monte Carlo Method , beta-Lactamases , Klebsiella pneumoniae/drug effects , Klebsiella pneumoniae/genetics , Klebsiella pneumoniae/enzymology , Klebsiella pneumoniae/isolation & purification , beta-Lactamases/genetics , beta-Lactamases/metabolism , Humans , Thailand , Klebsiella Infections/microbiology , Klebsiella Infections/drug therapy , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/administration & dosage , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Middle Aged , Male , Aged , Female , Genotype , Carbapenem-Resistant Enterobacteriaceae/drug effects , Carbapenem-Resistant Enterobacteriaceae/genetics , Carbapenem-Resistant Enterobacteriaceae/isolation & purification , ThienamycinsABSTRACT
BACKGROUND: Clinical trials of treatments for serious infections commonly use the primary endpoint of all-cause mortality. However, many trial participants survive their infection and this endpoint may not truly reflect important benefits and risks of therapy. The win ratio uses a hierarchical composite endpoint that can incorporate and prioritize outcome measures by relative clinical importance. METHODS: The win ratio methodology was applied post hoc to outcomes observed in the MERINO trial, which compared piperacillin-tazobactam with meropenem. We quantified the win ratio with a primary hierarchical composite endpoint, including all-cause mortality, microbiological relapse, and secondary infection. A win ratio of 1 would correspond to no difference between the 2 antibiotics, while a ratio <1 favors meropenem. Further analyses were performed to calculate the win odds and to introduce a continuous outcome variable in order to reduce ties. RESULTS: With the hierarchy of all-cause mortality, microbiological relapse, and secondary infection, the win ratio estimate was 0.40 (95% confidence interval [CI], .22-.71]; P = .002), favoring meropenem over piperacillin-tazobactam. However, 73.4% of the pairs were tied due to the small proportion of events. The win odds, a modification of the win ratio accounting for ties, was 0.79 (95% CI, .68-.92). The addition of length of stay to the primary composite greatly minimized the number of ties (4.6%) with a win ratio estimate of 0.77 (95% CI, .60-.99; P = .04). CONCLUSIONS: The application of the win ratio methodology to the MERINO trial data illustrates its utility and feasibility for use in antimicrobial trials.
Subject(s)
Anti-Bacterial Agents , Klebsiella Infections , Klebsiella pneumoniae , Meropenem , Piperacillin, Tazobactam Drug Combination , Piperacillin , Humans , Meropenem/therapeutic use , Meropenem/pharmacology , Piperacillin, Tazobactam Drug Combination/therapeutic use , Piperacillin, Tazobactam Drug Combination/pharmacology , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/pharmacology , Klebsiella pneumoniae/drug effects , Piperacillin/therapeutic use , Piperacillin/pharmacology , Klebsiella Infections/drug therapy , Klebsiella Infections/mortality , Bacteremia/drug therapy , Bacteremia/microbiology , Bacteremia/mortality , Escherichia coli/drug effects , Escherichia coli Infections/drug therapy , Escherichia coli Infections/microbiology , Escherichia coli Infections/mortality , Penicillanic Acid/analogs & derivatives , Penicillanic Acid/therapeutic use , Penicillanic Acid/pharmacology , Ceftriaxone/therapeutic use , Ceftriaxone/pharmacology , Male , Female , Middle Aged , Thienamycins/therapeutic use , Thienamycins/pharmacology , Aged , Treatment OutcomeABSTRACT
The emergence and dissemination of carbapenem-resistant species of Acinetobacter and Pseudomonas have become a serious health concern. Routine antimicrobial disk susceptibility tests in clinical laboratories cannot distinguish between isolates that are highly carbapenem-resistant and those that are moderately carbapenem-resistant. The present study describes antimicrobial susceptibility tests using disks containing high doses (1000 µg) of meropenem. The diameters of inhibition zones were significantly negatively correlated with the MICs of Pseudomonas and Acinetobacter species for meropenem (R2: 0.93 and 0.91, respectively) and imipenem (R2: 0.75 and 0.84, respectively). Double disk synergy tests using clavulanic acid or sodium mercaptoacetate can detect ESBL or MBL producers. Susceptibility tests using disks containing high doses of meropenem can easily detect highly carbapenem-resistant isolates in a quantitative manner. These disks may be useful in bacteriological laboratories because of their technical ease, stability, and relatively low cost.
Subject(s)
Acinetobacter , Anti-Infective Agents , Meropenem/pharmacology , Pseudomonas , Thienamycins/pharmacology , Carbapenems/pharmacology , Microbial Sensitivity Tests , Anti-Bacterial Agents/pharmacology , beta-LactamasesABSTRACT
Roseomonas mucosa is difficult to identify using routine analytical techniques. We herein report a case of peritoneal dialysis (PD)-related peritonitis caused by R. mucosa identified using matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) mass spectrometry (MS). A 70-year-old woman was admitted to our hospital with PD-related peritonitis. Blood agar medium of dialysate culture derived colony pale pink in color, and the organism was identified as R. mucosa using MALDI-TOF MS. She was successfully treated with ciprofloxacin and meropenem without catheter removal. To our knowledge, this is the first case of R. mucosa peritonitis in which technique failure has been avoided.
Subject(s)
Ciprofloxacin , Methylobacteriaceae , Peritonitis , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Humans , Aged , Female , Peritonitis/diagnosis , Peritonitis/etiology , Peritonitis/microbiology , Methylobacteriaceae/isolation & purification , Ciprofloxacin/therapeutic use , Meropenem/therapeutic use , Gram-Negative Bacterial Infections/diagnosis , Gram-Negative Bacterial Infections/drug therapy , Anti-Bacterial Agents/therapeutic use , Peritoneal Dialysis/adverse effects , Treatment Outcome , Thienamycins/therapeutic useABSTRACT
PURPOSE: The aim of this study is to characterize the concentration-time profile, pharmacokinetics parameters, and therapeutic target attainment of meropenem in pediatric post-liver transplant patients according to the duration of infusion. METHODS: This is a prospective cohort of pediatric transplant recipients with preserved renal function receiving meropenem 40 mg/kg every 8 hours. The patients were stratified into 2 groups based on infusion duration: G1 (15 minutes of intermittent infusion) and G1 (3 hours of extended infusion). Two blood samples per child were collected during the same interval within 48 hours of starting the antimicrobial. Meropenem concentrations were determined by high-performance liquid chromatography with tandem mass spectrometry. Pharmacokinetic parameters were assessed using a noncompartmental analysis. The therapeutic target was defined as 100% of the time above the minimum inhibitory concentration. FINDINGS: Fourteen patients with 28 measured meropenem concentrations were included. Lower values of volume of distribution and meropenem clearance compared with other critically ill pediatric populations were found. All patients achieved the therapeutic target against gram-negative pathogens with a minimum inhibitory concentration of ≤8 mg/L. Patients receiving a 15-minute infusion had higher values of peak and trough concentrations, resulting in unnecessary increased total drug exposure when compared to patients receiving a 3-hour infusion (P < .05). CONCLUSIONS: Meropenem at 120 mg/kg/d attained the therapeutic target against sensitive microorganisms in pediatric liver transplant recipients. The extended infusion should be preferred for patient safety. Because of the pharmacokinetic changes resulting from liver transplantation, individualized meropenem dosing regimens may be necessary.
Subject(s)
Anti-Bacterial Agents , Liver Transplantation , Humans , Child , Meropenem , Anti-Bacterial Agents/therapeutic use , Liver Transplantation/adverse effects , Thienamycins/therapeutic use , Prospective Studies , Infusions, Intravenous , Critical Illness/therapy , Microbial Sensitivity TestsABSTRACT
Aim: This study aimed to investigate the in vitro antimicrobial effect of gold nanoparticles capped with meropenem and imipenem against various strains and to evaluate the cytotoxic effect of gold nanoparticles on healthy human colon epithelial cells. Materials & methods: Gold nanoparticles were synthesized via the Turkevich method and tested for antimicrobial effects using broth microdilution. Cell culture studies were performed using a cytotoxicity assay with alamarBlue™. Results & conclusion: Nanoparticles (10-20 nm) with antibiotic coating were more effective against Escherichia coli, Proteus spp. and Serratia marcescens than pure antibiotics. They had a cytotoxic effect on cells at high concentrations but were safe at low concentrations.
Subject(s)
Anti-Infective Agents , Metal Nanoparticles , Humans , Meropenem/pharmacology , Imipenem/pharmacology , Gold , Thienamycins/pharmacology , Microbial Sensitivity Tests , Anti-Bacterial Agents/pharmacologyABSTRACT
BACKGROUND: The standard meropenem (MEPM) regimen allowed by insurance in Japan is 0.5 g two or three times a day. Differences in dosages and administration schedules in Japan were evaluated. METHODS: Patients with bacteremia for whom MEPM was used as the initial treatment at our institution between 2016 and 2021 were included. We retrospectively investigated patients classified into two groups: those treated according to severe infections (high-dose groupand others (low-dose group). After propensity score matching, we compared the probability of achieving free drug blood levels above the minimum inhibitory concentration (MIC) in 24 h (%fT > MIC) and outcomes. RESULTS: The probability of 100% fT > MIC was significantly higher in the high-dose group (96.4% vs 74.5%, odds ratio [OR] = 0.3, 95% confidence interval [CI] = 0.2-0.4, P = < 0.001). Regarding outcomes, the 30-day mortality rate was significantly lower in the high-dose group (1.4% vs. 11.4%, OR = 8.0, 95% CI = 1.5-43.7, P = 0.019). CONCLUSIONS: To improve outcomes in patients with bacteremia treated with MEPM, support for appropriate antimicrobial use is necessary for compliance with the dosage and administration schedule according to severe infections in initial treatment.
Subject(s)
Anti-Infective Agents , Bacteremia , Humans , Meropenem , Anti-Bacterial Agents/pharmacology , Retrospective Studies , Bacteremia/drug therapy , Microbial Sensitivity Tests , Thienamycins/therapeutic useABSTRACT
PURPOSE: Creatinine clearance (CCr) and pharmacokinetic parameters are markedly affected by pathophysiological changes in patients with sepsis. However, only a few reports have assessed renal function in patients with sepsis using the measured CCr. Furthermore, the administration regimen has not been sufficiently evaluated using a population PK (PPK) model across renal function broad ranges. Therefore, this study was performed to construct a meropenem PPK model for patients with sepsis using the measured CCr and evaluate the optimized meropenem dosing regimen based on the CCr. METHODS: Patients with sepsis who received intravenous meropenem at the Showa University Hospital were enrolled in this prospective observational study. The PPK model was constructed using blood samples and clinical information of patients. The probability of target attainment (PTA) indicates the likelihood of achieving 50% time above the minimum inhibitory concentration (% T > MIC) based on 10,000 virtual patients using Monte Carlo simulations. The PTA for each meropenem regimen was 50% T > MIC based on different renal functions using the Monte Carlo simulation. RESULTS: One hundred samples were collected from 31 patients. The final PPK model incorporating the measured CCr as a covariate in CL displayed the best fit. The recommended dosing regimen to achieve a PTA of 50% T > MIC of 4 mcg/mL was 1 g every 8 hours as a 3-hour prolonged infusion for patients with CCr 85-130 mL/min and 1 g every 8 hours as an 8-hour continuous infusion for patients with CCr ≥ 130 mL/min. CONCLUSIONS: This model precisely predicted meropenem concentrations in patients with sepsis by accurately evaluating renal function using the measured CCr. Extended dosing was demonstrated to be necessary to achieve a PTA of 50% T > MIC for patients with CCr ≥ 85 mL/min. Meropenem effectiveness can be maximized in patients with sepsis by selecting the appropriate dosing regimen based on renal function and the MIC.
Subject(s)
Anti-Bacterial Agents , Sepsis , Humans , Meropenem/pharmacokinetics , Creatinine , Thienamycins , Sepsis/drug therapy , Microbial Sensitivity Tests , Critical IllnessABSTRACT
STUDY OBJECTIVE: The aim of this study was to investigate the impact of therapeutic plasma exchange (TPE) on the plasma concentrations and pharmacokinetic (PK) patterns of meropenem. DESIGN: Prospective, open-label, PK study. SETTING: Academic tertiary care medical center. PATIENTS: Eleven patients who underwent TPE. MEASUREMENTS: A single-center PK study was conducted on adult patients who underwent TPE. All patients received two phases of meropenem administration for research purposes. Meropenem PK studies were carried out after the administration of a single dose of 1 g of meropenem in the patients during TPE (phase 1) and compared with meropenem 1 g administration in the same patients without TPE (phase 2), which served as the control phase with an at least 72-h wash-out period separating the phases. MAIN RESULTS: The total clearance (CL) of meropenem during TPE was greater than the values obtained from the same patients without TPE (13.37 ± 6.23 L/h during TPE vs. 8.42 ± 2.84 L/h without TPE). The mean drug fraction eliminated during TPE was 14.22 ± 11.03%, and the mean amount of drug removed by the TPE was 142.23 ± 110.31 mg. CONCLUSIONS: These results indicate that the TPE had an impact on the elimination of meropenem in patients during the exchange procedure. The CL of meropenem during TPE was greater than the values obtained from the control phase without TPE.
Subject(s)
Plasma Exchange , Thienamycins , Adult , Anti-Bacterial Agents , Humans , Meropenem , Prospective StudiesABSTRACT
Meropenem is a broad spectrum carbapenem used for the treatment of cerebral infections. There is a need for data describing meropenem pharmacokinetics (PK) in the brain tissue to optimize therapy in these infections. Here, we present a meropenem PK model in the central nervous system and simulate dosing regimens. This was a population PK analysis of a previously published prospective study of patients admitted to the neurointesive care unit between 2016 and 2019 who received 2 g of meropenem intravenously every 8 h. Meropenem concentration was determined in blood, cerebrospinal fluid (CSF), and brain microdialysate. Meropenem was described by a six-compartment model: two compartments in the blood, two in the CSF, and two in the brain tissue. Creatinine clearance and brain glucose were included as covariates. The median elimination rate constant was 1.26 h-1, the central plasma volume was 5.38 L, and the transfer rate constants from the blood to the CSF and from the blood to the brain were 0.001 h-1 and 0.02 h-1, respectively. In the first 24 h, meropenem 2 g, administered every 8 h via intermittent and extended infusions achieved good target attainment in the CSF and brain, but continuous infusion (CI) was better at steady-state. Administering a 3 g loading dose (LD) followed by 8 g CI was beneficial for early target attainment. In conclusion, a meropenem PK model was developed using blood, CSF, and brain microdialysate samples. An 8 g CI may be needed for good target attainment in the CSF and brain. Giving a LD prior to the CI improved the probability of early target attainment.
Subject(s)
Anti-Bacterial Agents , Brain , Anti-Bacterial Agents/pharmacokinetics , Critical Illness , Humans , Meropenem/pharmacokinetics , Monte Carlo Method , Prospective Studies , Thienamycins/pharmacokineticsABSTRACT
Morbidity and mortality related to ventriculitis in neurocritical care patients remain high. Antibiotic dose optimization may improve therapeutic outcomes. In this study, a population pharmacokinetic model of meropenem in infected critically ill patients was developed. We applied the final model to determine optimal meropenem dosing regimens required to achieve targeted cerebrospinal fluid exposures. Neurocritical care patients receiving meropenem and with a diagnosis of ventriculitis or extracranial infection were recruited from two centers to this study. Serial plasma and cerebrospinal fluid samples were collected and assayed. Population pharmacokinetic modeling and Monte Carlo dosing simulations were performed using Pmetrics. We sought to determine optimized dosing regimens that achieved meropenem cerebrospinal fluid concentrations above pathogen MICs for 40% of the dosing interval, or a higher target ratio of meropenem cerebrospinal fluid trough concentrations to pathogen MIC of ≥1. In total, 53 plasma and 34 cerebrospinal fluid samples were obtained from eight patients. Meropenem pharmacokinetics were appropriately described using a three-compartment model with linear plasma clearance scaled for creatinine clearance and cerebrospinal fluid penetration scaled for patient age. Considerable interindividual pharmacokinetic variability was apparent, particularly in the cerebrospinal fluid. Percent coefficients of variation for meropenem clearance from plasma and cerebrospinal fluid were 41.7% and 89.6%, respectively; for meropenem, the volume of distribution in plasma and cerebrospinal fluid values were 63.4% and 58.3%, respectively. High doses (up to 8 to 10 g/day) improved attainment of meropenem cerebrospinal fluid target exposures, particularly for less susceptible organisms (MICs, ≥0.25 mg/L). Standard meropenem doses of 2 g every 8 h may not achieve effective concentrations in cerebrospinal fluid in all critically ill patients. Higher doses, or alternative dosing methods (e.g., loading dose followed by continuous infusion) may be required to optimize cerebrospinal fluid exposures. Doses of up to 8 to 10 g/day either as intermittent boluses or continuous infusion would be suitable for patients with augmented renal clearance; lower doses may be considered for patients with impaired renal function as empirical suggestions. Ongoing dosing should be tailored to the individual patient circumstances. Notably, the study population was small and dosing recommendations may not be generalizable to all critically ill patients.
Subject(s)
Cerebral Ventriculitis , Renal Insufficiency , Anti-Bacterial Agents , Critical Illness , Humans , Meropenem/pharmacokinetics , Prospective Studies , ThienamycinsABSTRACT
Imipenem cilastatin sodium, as a member of a new generation of ß-lactam antibiotics, has a broad spectrum of antibacterial activity and a very wide range of application. Thrombocytopenia has been reported as a rare adverse event in several studies of patients treated with imipenem cilastatin sodium. In this study, we present a case of thrombocytopenia associated with imipenem cilastatin sodium in an older patient. The 78-year-old male patient with pulmonary infection was initiated on anti-infection therapy with imipenem cilastatin sodium. On the 9th day after imipenem cilastatin sodium administration, the patient experienced a sudden and dramatic decrease in platelet count. Similarly, on the 4th day after the re-administration of imipenem cilastatin sodium for anti-infection therapy, the patient's platelet count showed a remarkable downward trend again. A time correlation between the drug therapy and the occurrence of platelet reaction was found. The patient's platelet count gradually returned to the normal level on the 6th day after the first drug withdrawal and the 13th day after the second drug withdrawal, respectively. Considering the widespread use of imipenem cilastatin sodium, healthcare providers should improve the notification of thrombocytopenia associated with imipenem cilastatin sodium.
Subject(s)
Bacterial Infections , Thrombocytopenia , Aged , Anti-Bacterial Agents/adverse effects , Bacterial Infections/drug therapy , Cilastatin/adverse effects , Cilastatin, Imipenem Drug Combination/therapeutic use , Drug Combinations , Humans , Imipenem/adverse effects , Male , Thienamycins/therapeutic use , Thrombocytopenia/chemically induced , Thrombocytopenia/diagnosis , Thrombocytopenia/drug therapySubject(s)
Critical Illness , Piperacillin , Anti-Bacterial Agents/therapeutic use , Humans , Infusions, Intravenous , Meropenem , Renal Dialysis , ThienamycinsSubject(s)
Critical Illness , Piperacillin , Anti-Bacterial Agents/therapeutic use , Humans , Infusions, Intravenous , Meropenem , Renal Dialysis , ThienamycinsABSTRACT
One of the resistance mechanisms of superbugs is to hydrolyze antibiotics by producing metallo-ß-lactamases (MßLs). To verify how MßLs evolved to increase in activity in response to various ß-lactam antibiotics, the mutation and evolution of CphA from Aeromonas hydrophila (Zn2+-dependent MßL) was investigated in a medium with a continuous biapenem (BIA) concentration gradient. The results showed that a single-base mutation M1 and two frameshift mutations M3 and M4 were observed. Furthermore, a nonsense mutation M2 was observed. Compared with wild-type (WT), the minimum inhibitory concentrations (MICs) of the M3 and M4 increased by more than 128 times, and the catalytic efficiency of BIA by the M3 and M4 increased by 752% and 376% respectively. In the mutants, the carbon skeleton migration caused by the outward motion of the loop3 near the entrance of the binding pocket increased the cavity volume of the binding pocket and was more conducive to the entry and expulsion of BIA and its hydrolytic product in the binding pocket. The conformational change effect originated from mutations is transmitted to the binding pocket through the interactions between the side chain amino acid residues of the C-terminal and those of the loop3, thus affecting the binding and hydrolysis capability of the mutants to BIA in the binding pocket. All these indicated that during the repeated drug-endurance and -resistance, the CphA completed its mutation and conformational change and evolved to the mutants with a more delicate structure and stronger hydrolysis ability by a genetic mutation.
Subject(s)
Thienamycins , beta-Lactamases , Anti-Bacterial Agents , Bacterial Proteins/chemistry , Mutation , Thienamycins/chemistry , Thienamycins/metabolism , beta-Lactamases/metabolismABSTRACT
PURPOSE: The aim of this prospective cohort study was to evaluate the therapeutic target attainment of 3-hour extended infusion of meropenem in patients with septic burns in the early and late periods of septic shock. METHODS: Meropenem serum levels were determined by liquid chromatography from blood samples collected within 48 hours (early period) of therapy and 10 to 14 days afterward (late period). Pharmacokinetic properties were investigated by noncompartmental analysis, and the therapeutic target was defined as 100% of the time above the MIC (100%fT> MIC). FINDINGS: Fifteen patients with 90 measured meropenem concentrations were included. Throughout the entire course of antimicrobial therapy, the therapeutic target was attained against gram-negative pathogens with an MIC ≤ 2 mg/L. Pathogens with intermediate susceptibility to meropenem were only covered in the early phase of therapy. IMPLICATIONS: Higher-dose regimens or continuous infusions may be necessary to guarantee antimicrobial coverage of meropenem against less sensitive pathogens in patients with septic burns.
Subject(s)
Burns , Shock, Septic , Anti-Bacterial Agents , Burns/drug therapy , Critical Illness , Humans , Infusions, Intravenous , Meropenem/pharmacokinetics , Microbial Sensitivity Tests , Prospective Studies , Shock, Septic/drug therapy , Thienamycins/pharmacokineticsABSTRACT
OBJECTIVES: In difficult-to-treat infections such as nosocomial ventriculitis, meropenem exposure in the infected compartment is often uncertain but crucial for antibacterial effects. The aim of this study was to investigate the cerebrospinal fluid (CSF) penetration of meropenem in patients with nosocomial ventriculitis and to derive a nomograph to predict effective meropenem doses as a function of clinical parameters. METHODS: Retrospective patient data including meropenem serum and CSF levels as well as CSF inflammation markers were analyzed using NONMEM to assess the general pharmacokinetics and CSF penetration. Monte Carlo simulations were used to evaluate different meropenem dosing regimens. Probability of target attainment (PTA) in CSF was assessed, and a nomograph to achieve a target twice the minimal inhibitory concentration (MIC) during the dosing interval (100 %fT > 2x MIC) was developed. RESULTS: A one-compartment model with meropenem clearance dependent on the estimated glomerular filtration rate (CKD-EPI eGFR, p < 0.001) best described meropenem serum pharmacokinetics of 51 critically ill patients. CSF penetration ratio was correlated with the amount of protein in CSF (p < 0.001), with higher CSF protein levels accounting for higher penetration ratios. Preserved renal function (CKD-EPI eGFR >50 mL/min/1.73 m2) and low CSF protein levels (<500 mg/L) resulted in 80% PTA 100 %fT >2xMIC) for a meropenem dose of 6 g/24 h. DISCUSSION: High interindividual variability in meropenem CSF concentration was observed in patients with nosocomial ventriculitis. A nomograph to predict the daily meropenem dose required for target attainment for a given eGFR and CSF protein count was developed.
Subject(s)
Cerebral Ventriculitis , Cross Infection , Renal Insufficiency, Chronic , Anti-Bacterial Agents/therapeutic use , Cerebral Ventriculitis/drug therapy , Critical Illness , Cross Infection/drug therapy , Humans , Meropenem , Microbial Sensitivity Tests , Monte Carlo Method , Renal Insufficiency, Chronic/drug therapy , Retrospective Studies , ThienamycinsABSTRACT
Carbapenems are antibiotics of last resort in the clinic. Owing to their potency and broad-spectrum activity, they are an important part of the antibiotic arsenal. The vital role of carbapenems is exemplified by the approval acquired by Merck from the US Food and Drug Administration (FDA) for the use of an imipenem combination therapy to treat the increased levels of hospital-acquired and ventilator-associated bacterial pneumonia that have occurred during the COVID-19 pandemic1. The C6 hydroxyethyl side chain distinguishes the clinically used carbapenems from the other classes of ß-lactam antibiotics and is responsible for their low susceptibility to inactivation by occluding water from the ß-lactamase active site2. The construction of the C6 hydroxyethyl side chain is mediated by cobalamin- or B12-dependent radical S-adenosylmethionine (SAM) enzymes3. These radical SAM methylases (RSMTs) assemble the alkyl backbone by sequential methylation reactions, and thereby underlie the therapeutic usefulness of clinically used carbapenems. Here we present X-ray crystal structures of TokK, a B12-dependent RSMT that catalyses three-sequential methylations during the biosynthesis of asparenomycin A. These structures, which contain the two metallocofactors of the enzyme and were determined in the presence and absence of a carbapenam substrate, provide a visualization of a B12-dependent RSMT that uses the radical mechanism that is shared by most of these enzymes. The structures provide insight into the stereochemistry of initial C6 methylation and suggest that substrate positioning governs the rate of each methylation event.