Meropenem use and therapeutic drug monitoring in clinical practice: a literature review.

WHAT IS KNOWN AND OBJECTIVE: Meropenem, a carbapenem antibiotic, is widely prescribed for the treatment of life-threatening infections. The main parameter associated with its therapeutic success is the percentage of time that the levels remain above the minimum inhibitory concentration. Inadequate levels of meropenem can lead to therapeutic failure and increase the possibility of microbial resistance. The employment of strategies involving dose regimens and drug pharmacodynamics has become increasingly important to optimize therapies. In the present study, we conducted a review with the purpose of assembling information about the clinical use of meropenem and therapeutic drug monitoring. METHODS: A literature review emphasizing the application of therapeutic drug monitoring (TDM) of meropenem in clinical practice has been done. To identify articles related to the topic, we performed a standardized search from January 21, 2020 to December 21, 2020, using specific descriptors in PubMed, Lilacs and Embase. RESULTS AND DISCUSSION: In total, 35 studies were included in the review. The daily dose of meropenem commonly ranged from 3 to 6 g/day. Critically ill patients and those with impaired renal function appear to be the most suitable patients for the application of meropenem TDM, in order to guide therapy. We observed that most of the studies recommend TDM and that, in nine locations, the TDM of meropenem and of other beta-lactams is a routine practice. TDM data can help to maximize the clinical outcomes of the treatment with meropenem. It can also improve the patient care by providing suitable levels of meropenem, guiding the most appropriate dose regimens, which is the main parameter associated with therapeutic success. WHAT IS NEW AND CONCLUSION: The findings from this review suggest that the therapeutic monitoring of meropenem can be beneficial, since it adjusts the treatment and aids clinical outcomes. It does so by indicating the appropriate dosage and preventing failure, toxicity and possible antimicrobial resistance. The multidisciplinary effort, basic knowledge and communication among the medical team are also essential.

Comparison of two empirical prolonged infusion dosing regimens for meropenem in patients with septic shock: A two-center pilot study.

BACKGROUND: Due to high pharmacokinetic variability, standard doses of meropenem are frequently inadequate in septic patients. Therapeutic drug monitoring of meropenem is not widely available; therefore, improved empiric dosing recommendations are needed. OBJECTIVES: This study aimed to compare the attainment of pharmacologic targets for two common empirical dosing regimens for meropenem in patients with septic shock. METHODS: Two empiric dosing schemes for meropenem were compared using extended infusions (120 minutes) in 32 patients with septic shock in the intensive care units at two different hospitals. One regimen was 3 × 2 g meropenem/24 h for two days, followed by 3 × 1 g meropenem/24 h; the other regimen was 4 × 1 g meropenem/24 h. Serum meropenem concentrations were measured for the first 72 h of therapy, and pharmacokinetic modelling was performed to define the percentage of time the free drug concentration was above various target MICs for each regimen (%fT>MIC). RESULTS: Both regimens led to a sufficiently high %fT>MIC for pathogens with target MICs < 4 mg/L. When higher MICs were targeted, the %fT>MIC of 4 × 1 g meropenem decreased faster than that of 3 × 2 g meropenem. At high MICs of 32 mg/L, both dosing regimens failed to provide appropriate drug concentrations. Renal function was a significant covariate of target attainment. CONCLUSIONS: The results of this study can guide clinicians in their choice of an empirical dosing regimen for meropenem. If pathogens with low MICs (< 4 mg/L) are targeted, both dosing regimens are adequate, whereas more resistant strains require higher doses.

Efficacy of generic meropenem products in combination with colistin in carbapenemase-producing Klebsiella pneumoniae experimental osteomyelitis.

Guidelines for the management of carbapenemase-producing Enterobacterales (CPE) infections recommend a combination of two active agents, including meropenem if the minimum inhibitory concentration (MIC) is ≤8 mg/L. The therapeutic equivalence of meropenem generics has been challenged. We compared the bactericidal activity of meropenem innovator (AstraZeneca) and four generic products (Actavis, Kabi, Mylan and Panpharma), both in vitro and in vivo, in association with colistin. In vitro time-kill studies were performed at 4 × MIC. An experimental model of KPC-producing Klebsiella pneumoniae osteomyelitis was induced in rabbits by tibial injection of a sclerosing agent followed by 2 × 108 CFU of K. pneumoniae KPC-99YC (meropenem MIC = 4 mg/L; colistin MIC = 1 mg/L). At 14 days after inoculation, treatment for 7 days started in seven groups of ≥10 rabbits, including a control group, a colistin group, and one group for each meropenem product (i.e. the innovator and four generics), in combination with colistin. In vitro, meropenem + colistin was bactericidal with no viable bacteria after 6 h, and this effect was similar with all meropenem products. In the osteomyelitis model, there was no significant difference between meropenem generics and the innovator when combined with colistin. Colistin-resistant strains were detected after treatment with colistin + meropenem innovator (n = 3) and generics (n = 3). The efficacy of four meropenem generics did not differ from the innovator in vitro and in an experimental rabbit model of KPC-producing K. pneumoniae osteomyelitis in terms of bactericidal activity and the emergence of resistance.

OTAC: Optimization of Antibiotic Therapy in Critically ill Patients. Using beta-lactam antibiotics by continuous infusion.

OBJECTIVE: To determine the percentage of patients given standard doses of piperacillin/tazobactam or meropenem by continuous  infusion who achieved the target pharmacokinetic/pharmacodynamic  (PK/PD) index, which was defined as free concentrations four times  more than the minimum inhibitory concentration (CMI) for 100% of the  dosing interval (100% fT≥ 4 x MIC). METHOD: Preliminary data from a larger prospective clinical study  analysing the PK/PD behaviour of ß-lactams antibiotics continuous  infusion (CI) in critical patients. The study was conducted in the  intensive care units of a tertiary university hospital for adults (June  2015-May 2017). Inclusion criteria: normal renal function (glomerular  renal function (GFR) CKD-EPI formula ≥ 60 mL/min/1.73 m2) and  treatment with standard dose ß-lactams CI. Concentrations at steady  state (Css) conditions were determined using UHPLC-MS/MS. We  selected the highest susceptible MIC for all likely organisms according to  European Commitee on Antimicrobial Susceptibility Testing's (i.e.  piperacillin/tazobactam: 8 mg/L for enterobacteriaceae and 16 mg/L for  Pseudomonas aeruginosa; meropenem: 2 mg/L for any  microorganism). In addition, a subanalysis of patients was conducted using actual MIC values. RESULTS: 61 patients were enrolled (25 to meropenem and 36 to  piperacillin/tazobactam). Average age was 59 (15) years and median  GFR rate was 95 mL/min/1.73 m2 (83-115). Median meropenem and  piperacillin free concentrations were 16 mg/L (11-29) and 40 mg/L (21- 51), respectively. 88% of patients treated with meropenem reached the  PK/PD target, without differences between both microorganisms. For  piperacillin/tazobactam, 61% and 11% of patients reached the target,  with enterobacteriaceae and Pseudomonas as suspected  microorganisms, respectively. The pathogen was isolated in 35 (57%)  patients: 94% reached the target PK/PD, without differences between  both antibiotic therapies. CONCLUSIONS: Standard doses of meropenem CI are sufficient to  achieve a PK/PD target of 100% fT≥ 4 x MIC in suspected infections  with high MICs (Pseudomonas aeruginosa or enterobacteriaceae).  However, higher doses of piperacillin/tazobactam could be considered to  achieve this goal. In patients with isolated microorganisms, a  standard dose of both antibiotic therapies would be sufficient to achieve  the target. Therapeutic drug monitoring is highly recommended for  therapeutic optimization.

Objetivo: Determinar el porcentaje de pacientes, a los que se les  administró dosis estándar de piperacilina/tazobactam o meropenem en  perfusión continua, que alcanzaban el índice  farmacocinético/farmacodinámico diana definido como el 100% del  intervalo de administración en que las concentraciones de antibiótico  libre fueron cuatro veces iguales o superiores a la concentración mínima  inhibitoria (100% fT ≥ 4 x CMI).Método: Datos preliminares obtenidos de un estudio clínico prospectivo que analiza el comportamiento  farmacocinético/farmacodinámico de los antibióticos betalactámicos  administrados en perfusión continua en pacientes críticos. Se realizó en  unidades de cuidados intensivos de un hospital universitario de tercer  nivel, desde junio de 2015 a mayo de 2017. Criterios de inclusión:  adultos con función renal correcta (filtrado glomerular según la fórmula  CKD-EPI ≥ 60 ml/min/1,73 m2) y tratados con dosis estándar de  antibióticos betalactámicos en perfusión continua. Las concentraciones  en estado de equilibrio estacionario fueron determinadas mediante  cromatografía líquida acoplada a espectrometría de masas (UHPLC- MS/MS). Se utilizaron valores de concentración mínima  inhibitoria  teóricos para microorganismos más resistentes (piperacilina/ tazobactam: 16 mg/l para Pseudomonas aeruginosa y 8 mg/l para Enterobacteriaceae; meropenem: 2 mg/l, independientemente del  microorganismo). Además, se realizó un subanálisis de los pacientes con aislamiento microbiológico (concentraciones mínimas inhibitorias  reales).Resultados: Se incluyeron 61 pacientes (25 meropenem y 36  piperacilina/ tazobactam). Edad media 59 años (15), mediana de  filtrado glomerular 95 ml/min/1,73 m2 (83-115). Mediana de  concentraciones en estado de equilibrio estacionario libre: 16 mg/l (11- 29) meropenem y 40 mg/l (21-51) piperacilina. El 88% de los pacientes  tratados con meropenem alcanzaron el objetivo  farmacocinético/farmacodinámico, sin diferencias entre Enterobacteriaceae y Pseudomonas. En el caso de  piperacilina/tazobactam, el 61% y el 11% de los pacientes alcanzaron la  diana, considerando Enterobacteriaceae y Pseudomonas como  microorganismo sospechoso. Un total de 35 (57%) pacientes  presentaron aislamiento microbiológico. El 94% de ellos alcanzaron la  diana, sin diferencias entre los dos antibióticos.Conclusiones: Ante la sospecha de infecciones por microorganismos con concentraciones mínimas inhibitorias elevadas  (Pseudomonas aeruginosa o enterobacterias), se observa que dosis  convencionales de meropenem en perfusión continua son suficientes  para lograr la diana 100% fT≥ 4 x MIC. Sin embargo, se requerirían  dosis superiores de piperacilina/tazobactam. En casos de aislamiento  microbiológico, dosis estándar de ambos antibióticos fueron suficientes  para lograr la diana. La monitorización farmacocinética es altamente  recomendable para la optimización terapéutica.