meropenem and Renal-Insufficiency

Meropenem is a well established carbapenem antibacterial with a wide spectrum of activity against Gram-positive and Gram-negative bacteria, including beta-lactamase producers and Pseudomonas aeruginosa. Because of its clinical and bacteriological efficacy, meropenem is an important antimicrobial drug in the treatment of serious infections in adults and in children. Meropenem is predominately excreted unchanged in the urine, and thus dosage adjustments are necessary in patients with renal insufficiency and those undergoing intermittent haemodialysis (IHD) or various forms of continuous renal replacement therapy (CRRT), such as continuous venovenous haemodialysis, continuous venovenous haemodiafiltration (CVVHDF), continuous venovenous haemofiltration (CVVHF) or continuous ambulatory peritoneal dialysis (CAPD). The half-life of meropenem (approximately 1 hour in healthy volunteers) is prolonged up to 13.7 hours in anuric patients with end-stage renal disease. In patients receiving renal replacement therapy, half-life is influenced by drug-specific factors as well by membrane and treatment modalities (IHD, CRRT or CAPD). Plasma meropenem concentrations reach a peak of between 53 and 62 mg/L after the administration of meropenem 1g intravenously to healthy volunteers, up to 53 mg/L after meropenem 0.5g in haemodialysis patients, and between 18 and 45 mg/L after meropenem 1g during CRRT in critically ill patients. Approximately 50% of meropenem is eliminated by IHD, 25 to 50% by CVVHF and 13 to 53% by CVVHDF. Such differences are not negligible and demonstrate the great influence of the treatment modality on the elimination of the drug during renal replacement therapy. Thus, physicians run the risk of underdosing with this antimicrobial drug because of the quite different recommendations in the literature. Because of the excellent tolerability profile of meropenem, such underadministration should be avoided.

Topics: Adult; Anti-Bacterial Agents; Area Under Curve; Child; Half-Life; Humans; Imipenem; Male; Meropenem; Metabolic Clearance Rate; Renal Dialysis; Renal Insufficiency; Thienamycins

Meropenem, a new carbapenem antibiotic, is more active against gram-negative bacilli and less active against gram-positive cocci than is imipenem, and there are several important structural differences between meropenem and the older carbapenem. These differences may be responsible for the lower potential for the induction of epileptogenic activity observed with meropenem as well as for its increased stability to degradation by dehydropeptidase-I. The pharmacokinetics of meropenem are typical of those of a parenteral beta-lactam antibiotic with low protein binding and predominantly renal excretion. Dosage reduction is required in patients with reduced renal function; no dosage adjustment is required for patients with hepatic impairment. Meropenem has excellent penetration in abdominal tissues, bile, blister fluid, inflammatory exudate, cerebrospinal fluid (in the presence of inflammation), gynecologic tissues, respiratory tract tissues, and urinary tract tissues; tissue levels are generally equal to or above the levels needed for the treatment of patients with susceptible pathogens.

Topics: Adult; Aged; Anti-Bacterial Agents; Bacteria, Anaerobic; Bacterial Infections; Child; Child, Preschool; Cilastatin; Clinical Trials as Topic; Female; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Imipenem; Infant; Infant, Newborn; Kidney; Male; Meropenem; Microbial Sensitivity Tests; Molecular Structure; Renal Insufficiency; Thienamycins

To describe and then compare an investigational carbapenem antibiotic, meropenem, with the only currently available antibiotic in this class, imipenem/cilastatin.. An English language search using MEDLINE (1988-1993); Abstracts of the 31st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 1991; and Abstracts of the 32nd ICAAC, 1992.. All current scientific publications were reviewed for study design and quality. Emphasis was placed on susceptibility and pharmacokinetic analysis. Phase 3 clinical trials are now being completed and have only been published in abstract form. Hence, conclusions derived regarding efficacy were tempered.. Meropenem is active against a broad spectrum of gram-positive and -negative pathogens including beta-lactamase producers. Meropenem appears to be two- to fourfold less active than imipenem against gram-positive organisms. Meropenem is two- to fivefold more active against enterobacteriaceae. The two compounds appear to be equally active against Pseudomonas aeruginosa. Pharmacokinetic disposition is also similar for imipenem and meropenem. Meropenem may exhibit greater tissue penetration. Meropenem is not labile to renal hydrolysis and can be administered without a competitive antagonist of dihydropeptidase, such as cilastatin. In clinical trials, meropenem appears to be as safe and effective as imipenem/cilastatin or ceftazidime in the treatment of infections involving soft tissue, urinary tract, upper respiratory tract, abdominal processes, and febrile neutropenic episodes.. Meropenem is comparable to imipenem in terms of in vitro susceptibility pattern and pharmacokinetic disposition. Overall, meropenem seems to offer promise as the second of the carbapenem class of antibiotics. Clinical data are preliminary, and further data are needed.

Topics: Clinical Trials as Topic; Drug Resistance, Microbial; Drugs, Investigational; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Renal Insufficiency; Thienamycins

Augmented renal clearance (ARC) defined as creatinine clearance (Clcr) above 130 mL/min/1.73m. In this randomized clinical trial, patients with VAP and high risk for ARC were recruited. An 8-h urine collection was performed on the 1st, 3rd, and 5th days of study to measure Clcr. Included patients were divided into three groups: (1) 1 g meropenem, 3-h infusion, (2) 2 g meropenem, 3-h infusion, (3) 1 g meropenem, 6-h infusion. On the 2nd, 3rd, and 5th days of treatment, peak and trough blood samples were collected to undergo HPLC assay. MICs were assessed using microdilution method. Patients were also clinically monitored for 14 days.. Forty-five patients were included. Group 3 showed significanty higher rate of patients achieving fT > MIC > 50% (100% for group 3 versus 40% for group 2 and 13% for group 1; p = 0.0001). Mean fT > MIC% was significantly higher in group 3 (78.77 ± 5.87 for group 3 versus 49.6 ± 7.38 for group 2 and 43.2 ± 7.98 for group 1; p = 0.0001). Statistical analysis showed no significant differences among groups regarding clinical improvement.. According to the findings of this trial, prolonged meropenem infusion is an appropriate strategy compared to dose elevation among ARC patients.

Topics: Anti-Bacterial Agents; Critical Illness; Humans; Meropenem; Microbial Sensitivity Tests; Pneumonia, Ventilator-Associated; Renal Insufficiency

Severe burn injury involves widespread skin and tissue damage leading to systemic inflammation, hypermetabolism and multi-organ failure. The hypermetabolic phase of burn injury has been associated with increased systemic antibiotic clearance; however, critical illness in the absence of burn may also induce similar physiologic changes. Continuous renal replacement therapy (CRRT) is often implemented in critically ill patients and may also affect antibiotic clearance. Although the pharmacokinetics (PK) of meropenem has been described in both the burn and non-burn critically ill populations, direct comparative data is lacking.. For this study, we evaluated PK parameters of meropenem from 23 critically ill patients, burn or non-burn, treated with or without continuous veno-venous haemofiltration (CVVH) to determine the contribution of burn and CVVH to the variability of therapeutic meropenem levels.. A two-compartment model best described the data and revealed creatinine clearance (CrCl) and total burn surface area (TBSA) as significant covariates on clearance (CL) and peripheral volume of distribution (Vp), respectively. Of interest, non-burn patients on CVVH displayed an overall lower inherent CL as compared to burn patients on CVVH (6.43 vs. 12.85 L/h). Probability of target attainment (PTA) simulations revealed augmented renal clearance (ARC) may necessitate dose adjustments, but TBSA and CVVH would not.. We recommend a standard dose of 1000 mg every 8 hours; however, if ARC is suspected, or the severity of illness requires a more stringent therapeutic target, we recommend a loading dose of 1000-2000 mg infused over 30 minutes to 1 hour followed by continuous infusion (3000-6000 mg over 24 hours), or intermittent infusion of 2000 mg every 8 hours.

Topics: Anti-Bacterial Agents; Burns; Continuous Renal Replacement Therapy; Critical Illness; Humans; Meropenem; Renal Insufficiency

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 recom

Topics: Anti-Bacterial Agents; Cerebral Ventriculitis; Critical Illness; Humans; Meropenem; Prospective Studies; Renal Insufficiency; Thienamycins

Topics: Humans; Kinetics; Meropenem; Renal Insufficiency; Voriconazole

Topics: Antifungal Agents; Humans; Inflammation; Meropenem; Renal Insufficiency; Voriconazole

Meropenem plasma concentration above a pathogen's MIC over the whole dosing interval (100% ƒT>MIC) is a determinant of outcome in severe infections. Significant variability of meropenem pharmacokinetics is reported in ICU patients.. To characterize meropenem pharmacokinetics in variable CLCR or renal replacement therapy and assess the appropriateness of recommended regimens for MIC coverage.. A pharmacokinetic analysis (NONMEM) was conducted with external model validation. Patient characteristics were tested on meropenem clearance estimates, differentiated according to the presence/absence of continuous renal replacement therapy (CRRT, CLCRRT or CLno-CRRT). Simulations evaluated the appropriateness of recommended dosing for achieving 100% fT>MIC in 90% of patients.. A total of 101 patients were studied: median 63 years (range 49-70), 56% male, SAPS II 38 (27-48). 32% had a CLCR >60 mL/min, 49% underwent CRRT and 32% presented severe sepsis or septic shock. A total of 127 pathogens were documented: 76% Gram-negatives, 24% Gram-positives (meropenem MIC90 2 mg/L, corresponding to EUCAST susceptibility breakpoint). Three hundred and eighty plasma and 129 filtrate-dialysate meropenem concentrations were analysed: two-compartment modelling best described the data. Predicted meropenem CLno-CRRT was 59% lower in impaired (CLCR 30 mL/min) compared to normal (CLCR 100 mL/min) renal function. Simulations showed that recommended regimens appropriately cover MIC90 in patients with CLCR <60 mL/min. Patients with CLCR of 60 to <90 mL/min need 6 g/day to achieve appropriate coverage. In patients with CLCR ≥90 mL/min, appropriate exposure is achieved with increased dose, frequency of administration and infusion duration, or continuous infusion.. Recommended meropenem regimens are suboptimal in ICU patients with normal or augmented renal clearance. Modified dosing or infusion modalities achieve appropriate MIC coverage for optimized antibacterial efficacy in meropenem-susceptible life-threatening infections.

Topics: Aged; Anti-Bacterial Agents; Bacterial Infections; Computer Simulation; Critical Illness; Female; Humans; Male; Meropenem; Metabolic Clearance Rate; Middle Aged; Plasma; Prospective Studies; Renal Insufficiency; Renal Replacement Therapy

A critically ill patient with multiple postoperative infections repeatedly required profound voriconazole dose reductions whenever high-dose meropenem was added. Subsequent in vitro assessment confirmed inhibition of cytochrome P450 (CYP) 2C19 and CYP3A4 by meropenem, suggesting that during meropenem treatment, narrow therapeutic index drugs metabolized by these CYPs require close monitoring.

Topics: Aged; Cytochrome P-450 CYP2C19 Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Drug Monitoring; Humans; Male; Meropenem; Renal Insufficiency; Thienamycins; Voriconazole

The US Food and Drug Administration reported seizures associated with the use of cefepime (primarily in patients with renal impairment who did not receive appropriate dose adjustments of cefepime).. The maximum dose of cefepime in the USA (6 g per day) is higher than that in Japan (4 g per day). We investigated the prevalence of convulsions associated with the use of cefepime by comparing it with that of meropenem.. A retrospective study was undertaken in 183 patients treated with cefepime and 745 patients treated with meropenem over 2 years at Ehime University Hospital. Cefepime or meropenem-associated convulsions were defined according to the following criteria: (1) administration or dose escalation of diazepam, phenytoin, phenobarbital and thiamylal given via the intravenous route (2) convulsions recorded in medical records during administration of cefepime or meropenem.. The prevalence of convulsions was significantly greater in the cefepime treated group than in the meropenem-treated group. Among the patients who had cefepime-associated convulsions, none had renal failure. Cefepime-associated convulsions occurred only in patients with brain disorders.. Cefepime-associated convulsions should be recognized as potential complications even in patients with normal renal function. Brain disorders may increase the risk of cefepime-associated convulsions.

Topics: Adult; Aged; Anti-Bacterial Agents; Brain Diseases; Cefepime; Cephalosporins; Female; Hospitals, University; Humans; Infusions, Intravenous; Japan; Male; Meropenem; Neurotoxicity Syndromes; Prevalence; Pseudomonas aeruginosa; Pseudomonas Infections; Renal Insufficiency; Retrospective Studies; Risk; Seizures; Staphylococcal Infections; Staphylococcus aureus; Thienamycins

To describe a case of severe cellulitis, successfully treated with high-dose daptomycin plus continuous infusion meropenem, in a patient with morbid obesity and renal failure, in whom drug exposure over time was optimized by means of real-time therapeutic drug monitoring (TDM).. A 63-year-old man with morbid obesity (body mass index 81.6 kg/m²) and renal failure was admitted to the emergency department because of severe cellulitis. The patient had an admission Laboratory Risk Indicator for Necrotizing Fasciitis score of 9, and broad-spectrum antimicrobial therapy with daptomycin and meropenem was started. Because of rapidly changing renal function, dosage adjustments were guided by an intensive program of TDM (daptomycin ranging from 1200 mg every 48 hours over 30 minutes to 1200 mg every 36 hours over 30 minutes; meropenem ranging from 0.25 g every 8 hours over 6 hours to 500 mg every 4 hours by continuous infusion). Clinical response was observed within 72 hours. However, a sudden increase of serum creatine kinase (SCK) raised questions about the need for discontinuation of daptomycin. The drug concentrations were not toxic; therefore, we decided to continue therapy. Significant clinical improvement, with SCK normalization, was observed within a few days. Antimicrobial therapy was switched on day 29 to amoxicillin/clavulanate plus levofloxacin, and then discontinued at discharge on day 53.. High-dose daptomycin plus continuous infusion meropenem may ensure adequate empiric antimicrobial coverage in patients with possible early necrotizing fasciitis. However, in patients with morbid obesity and changing renal function, significant challenges may arise because of the hydrophilic nature of these drugs and the inaccuracy of standard methods of estimating renal function.. Real-time TDM may represent an invaluable approach in optimizing drug exposure with high-dose daptomycin plus continuous infusion meropenem in patients with severe cellulitis, morbid obesity, and changing renal function.

Topics: Anti-Bacterial Agents; Cellulitis; Creatine Kinase; Daptomycin; Drug Monitoring; Drug Therapy, Combination; Fasciitis, Necrotizing; Humans; Male; Meropenem; Middle Aged; Obesity, Morbid; Renal Insufficiency; Severity of Illness Index; Thienamycins; Treatment Outcome

Topics: Anti-Bacterial Agents; Cefepime; Cephalosporins; Creatinine; Critical Pathways; Drug Administration Schedule; Humans; Meropenem; Pneumonia, Ventilator-Associated; Quality Assurance, Health Care; Renal Insufficiency; Thienamycins

Cardiovascular dysfunction in patients with hemolytic-uremic syndrome (HUS) may be related to secondary issues such as volume overload, hypertension or electrolyte disturbances including hyperkalemia. Additionally, primary myocardial involvement has been increasingly recognized as a potential comorbid feature of HUS. We report a 9-month-old child with HUS who developed clinical signs of poor myocardial function with depressed myocardial function noted by echocardiography. Supportive care including mechanical ventilation and inotropic agents were necessary for approximately 10 days. Follow-up echocardiography revealed return of normal ventricular function. Previous reports of primary cardiac involvement with HUS have included thrombotic microangiopathy of the coronary vasculature resulting in myocardial ischemia, myocardial infarction or depressed myocardial function, myocarditis, congestive heart failure with dilated cardiomyopathy and pericardial effusion with tamponade. Given the potential for morbidity and mortality during the preoperative period in patients with HUS, anesthesiologists involved in the care of such patients should be aware of the potential for myocardial involvement in this disease process. Preoperatively, the routine evaluation of myocardial function may be indicated.

Topics: Anemia; Anti-Bacterial Agents; Cardiomyopathies; Cardiotonic Agents; Dopamine; Electrocardiography; Hemolytic-Uremic Syndrome; Humans; Infant; Intubation, Intratracheal; Male; Meropenem; Milrinone; Natriuretic Agents; Natriuretic Peptide, Brain; Oliguria; Peritoneal Dialysis; Renal Dialysis; Renal Insufficiency; Respiration, Artificial; Thienamycins; Vancomycin