Meropenem Monotherapy Research Articles

Expert perspectives on the clinical use of meropenem monotherapy in the management of various antibiotic-resistant pathogens in Indian settings

Background: To gather expert perspectives on the clinical use of meropenem monotherapy in managing multidrug-resistant (MDR), extensively drug-resistant (XDR), and pan-drug-resistant (PDR) pathogens in Indian settings. Methods: This cross-sectional study used a 20-item questionnaire to gather clinician opinions on prescription practices, clinical observations, and preferences regarding meropenem monotherapy. Descriptive statistics were employed to analyze the responses, presenting frequencies as percentages. Results: A total of 353 clinicians participated in this study, with 37% reporting a 6-10% prevalence of MDR, XDR, and PDR pathogens in their practice. Complicated intra-abdominal infections (cIAIs) were the most common conditions treated with meropenem, reported by 54.96% of respondents. The majority (91.5%) of the respondents preferred combination therapy for resistant infections, with tigecycline (54%) and colistin (33.43%) being common choices. Key pathogens included Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii, Escherichia coli, and Staphylococcus aureus. Most participants (58%) favored administering 1g of IV meropenem in 2 to 3 divided doses. Bloodstream infections, meningitis, and ventilator-associated pneumonia (VAP) were noted as primary indications for meropenem use. Additionally, 68% of participants stated meropenem was the most prescribed antibiotic for complicated urinary tract infections (cUTIs), while 77% indicated it as the preferred treatment for Gram-negative MDR pathogens. Conclusion: Meropenem remains a critical option for treating MDR, XDR, and PDR infections in India, particularly in combination with tigecycline or colistin. Clinicians preferred its use in cIAIs and VAP, especially in elderly patients. The findings highlight the importance of continuously monitoring resistance patterns to optimize treatment strategies.

Piperacillin/Tazobactam is associated with a higher risk of acute kidney injury compared to cefepime and meropenem

This retrospective study investigated whether piperacillin/tazobactam (PIPC/TAZ) monotherapy affects renal function compared to cefepime (CFPM) or meropenem (MEPM) monotherapy. Hospitalized patients who received PIPC/TAZ, CFPM, or MEPM monotherapy between April 2021 and December 2022 were enrolled in this study. We used inverse probability of treatment weighting (IPTW) to balance baseline characteristics and compare the incidence of acute kidney injury (AKI). Overall, 259, 104, and 98 patients were enrolled in the PIPC/TAZ, CFPM, and MEPM groups, respectively. After applying IPTW, PIPC/TAZ administration was found to be significantly associated with an increased risk of AKI (odds ratio [OR]: 6.75, 95% confidence interval [CI]: 1.30–34.8, p = 0.023 compared to CFPM; and OR: 7.71, 95% CI: 1.00–59.2, p = 0.049 compared to MEPM). PIPC/TAZ monotherapy may be associated with a higher risk of AKI than CFPM or MEPM monotherapy.

PKPD modelling and simulation of longitudinal meropenem in vivo effects against Escherichia coli and Klebsiella pneumoniae strains with high MIC

BackgroundCarbapenem-resistant bacteria pose a threat to public health. Characterizing the pharmacokinetics-pharmacodynamics (PKPD) of meropenem longitudinally in vivo against resistant bacteria could provide valuable information for development and translation of carbapenem-based therapies. ObjectivesTo assess the time course of meropenem effects in vivo against strains with high MIC to predict PK/PD indices and expected efficacy in patients using a modelling approach. MethodsA PKPD model was built on longitudinal bacterial count data to describe meropenem effects against six Escherichia coli and Klebsiella pneumoniae strains (MIC values 32-128 mg/L) in a 24h mouse thigh infection model. The model was used to derive PK/PD indices from simulated studies in mice and to predict the efficacy of different infusion durations with high-dose meropenem (2 g q8h/q12h for normal/reduced kidney function) in patients. ResultsData from 592 mice were available for model development. The estimated meropenem concentration-dependent killing rate was not associated with differences in MIC. The fraction of time that unbound concentrations exceeded EC50 (fT>EC50, EC50=1.01 mg/L) showed higher correlations than fT>MIC. For all investigated strains, bacteriostasis at 24h was predicted for prolonged infusions of high-dose meropenem monotherapy in >90% of patients. ConclusionsThe developed PKPD model successfully described bacterial growth and meropenem killing over time in the thigh infection model. For the investigated strains the MIC, determined in vitro, or MIC-based PK/PD indices, did not predict in vivo response. Simulations suggested prolonged infusions of high-dose meropenem to be efficacious in patients infected by the studied strains.

Impact of Continuous Infusion Meropenem PK/PD Target Attainment on C-Reactive Protein Dynamics in Critically Ill Patients With Documented Gram-Negative Hospital-Acquired or Ventilator-Associated Pneumonia.

Population pharmacokinetic/pharmacodynamic (PK/PD) modelling of antibiotics including C-reactive protein (C-RP) dynamics could be helpful in predicting the efficacy of antimicrobials. We developed a PK/PD model for assessing the impact of continuous infusion (CI) meropenem PK/PD target attainment on C-RP dynamics in critically ill patients with documented Gram-negative hospital- (HAP) or ventilator-acquired pneumonia (VAP). Patients were grouped according to the type of antibiotic treatment received [meropenem monotherapy; meropenem plus empirical anti-MRSA (methicillin-resistant Staphylococcus aureus) therapy; meropenem in combination with another anti-Gram-negative active agent; meropenem plus a targeted anti-MRSA therapy]. A one-compartment population PK model of CI meropenem was developed by including all patients. A full C-RP production inhibition model was developed for fitting the PD data by including only patients receiving meropenem monotherapy or meropenem plus empirical anti-MRSA therapy. Monte Carlo simulations explored the relationship between the type of PK/PD target attainment of CI meropenem, defined as optimal (steady-state plasma concentration [Css] to minimum inhibitory concentration [MIC] ratio = 4-8), quasi-optimal (Css/MIC = 1-4) and sub-optimal (Css/MIC < 1) and the magnitude of C-RP production inhibition over time. A total of 64 patients providing 211 meropenem concentrations were included in the PK analysis, whereas 47 patients providing 328 C-RP data were included in the PD model. Simulations showed that optimal PK/PD target attainment was associated with the highest and most rapid C-RP production inhibition (44% and 56% at days 2 and 4, respectively). Conversely, sub-optimal PK/PD target attainment was shown to be almost ineffective (< 5% at day 4 and < 10% at day 10). Our PK/PD model predicted that attaining optimal PK/PD target with CI meropenem may grant prompt and intense C-RP decrease among critically ill patients receiving targeted monotherapy for Gram-negative HAP/VAP, thus anticipating efficacy.

Anticancer agent 5-fluorouracil reverses meropenem resistance in carbapenem-resistant Gram-negative pathogens

The global increasing incidence of clinical infections caused by carbapenem-resistant Gram-negative pathogens requires urgent and effective treatment strategies. Antibiotic adjuvants represent a promising approach to enhance the efficacy of meropenem against carbapenem-resistant bacteria. This study shows that the anticancer agent 5-fluorouracil (5-FU, 50 µM) significantly reduced the minimum inhibitory concentration of meropenem against blaNDM-5 positive Escherichia coli by 32-fold through cell-based high-throughput screening. Further pharmacological studies indicated that 5-FU exhibited potentiation effects on carbapenem antibiotics against 42 Gram-negative bacteria producing either metallo-β-lactamases (MBLs), such as NDM and IMP, or serine β-lactamases (Ser-BLs), like KPC and OXA. These bacteria included E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter spp., 32 of which were obtained from human clinical samples. Mechanistic investigations revealed that 5-FU inhibited the transcription and expression of the blaNDM-5 gene. In addition, 5-FU combined with meropenem enhanced bacterial metabolism, and stimulated the production of reactive oxygen species (ROS), thereby rendering bacteria more susceptible to meropenem. In a mouse systemic infection model, 5-FU combined with meropenem reduced bacterial loads and effectively elevated the survival rate of 83.3%, compared with 16.7% with meropenem monotherapy. Collectively, these findings indicate the potential of 5-FU as a novel meropenem adjuvant to improve treatment outcomes against infections caused by carbapenem-resistant bacteria.

In-vitro safety assessment of meropenem on human retinal pigment epithelium (RPE)

PurposeEndophthalmitis is a severe infection accompanied by inflammation that affects the anterior and posterior parts of the eye. It is typically treated with a combination of antibiotics that cover various microorganisms. However, retinal pigment epithelium (RPE) cells are highly susceptible to damage from intravitreal injection therapy. This study aimed to investigate the impact of clinically relevant concentrations of meropenem (alone or in combination with vancomycin) on the viability and inflammation of RPE cells. DesignIn-vitro Study. MethodsRPE cells from passages 5–7 were treated with different concentrations of meropenem (1/4x, x, and 4x; [x = 16 mg/L]), vancomycin (30 mg/L), and meropenem (x) plus vancomycin for 24 h. The morphology assessment and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay were performed to evaluate cytotoxicity due to drug treatment. Real-time PCR was used to measure the relative expression of apoptotic genes (BCL-2 and BAX) and inflammation biomarkers (IL-1b and IL-6). ResultsMeropenem (alone or in combination with vancomycin) did not have any significant effect on RPE cell morphology, density, and viability. Gene expression analysis confirmed these results, showing no significant changes in the BCL-2/BAX ratio in drug-treated RPE cells compared to controls. Treatment with meropenem significantly induced the expression of IL-1b at all studied concentrations. Additionally, at concentrations of x and 4x, it also significantly increased the expression of IL-6, which was dose-dependent. However, this effect was not observed with vancomycin alone or in combination with meropenem. ConclusionsThe results of this study suggest that meropenem, either alone or in combination with vancomycin, does not induce RPE cytotoxicity. There was an upregulation of IL-1b and IL-6 in meropenem monotherapy, the clinical implication of which should be elucidated in future in-vivo or clinical studies.

Comparative Impact of an Optimized PK/PD Target Attainment of Piperacillin-Tazobactam vs. Meropenem on the Trend over Time of SOFA Score and Inflammatory Biomarkers in Critically Ill Patients Receiving Continuous Infusion Monotherapy for Treating Documented Gram-Negative BSIs and/or VAP.

(1) Background: The advantage of using carbapenems over beta-lactam/beta-lactamase inhibitor combinations in critically ill septic patients still remains a debated issue. We aimed to assess the comparative impact of an optimized pharmacokinetic/pharmacodynamic (PK/PD) target attainment of piperacillin-tazobactam vs. meropenem on the trend over time of both Sequential Organ Failure Assessment (SOFA) score and inflammatory biomarkers in critically ill patients receiving continuous infusion (CI) monotherapy with piperacillin-tazobactam or meropenem for treating documented Gram-negative bloodstream infections (BSI) and/or ventilator-associated pneumonia (VAP). (2) Methods: We performed a retrospective observational study comparing critically ill patients receiving targeted treatment with CI meropenem monotherapy for documented Gram-negative BSIs or VAP with a historical cohort of critical patients receiving CI piperacillin-tazobactam monotherapy. Patients included in the two groups were admitted to the general and post-transplant intensive care unit in the period July 2021-September 2023 and fulfilled the same inclusion criteria. The delta values of the SOFA score between the baseline of meropenem or piperacillin-tazobactam treatment and those at 48-h (delta 48-h SOFA score) or at 7-days (delta 7-days SOFA) were selected as primary outcomes. Delta 48-h and 7-days C-reactive protein (CRP) and procalcitonin (PCT), microbiological eradication, resistance occurrence, clinical cure, multi-drug resistant colonization at 90-day, ICU, and 30-day mortality rate were selected as secondary outcomes. Univariate analysis comparing primary and secondary outcomes between critically ill patients receiving CI monotherapy with piperacillin-tazobactam vs. meropenem was carried out. (3) Results: Overall, 32 critically ill patients receiving CI meropenem monotherapy were compared with a historical cohort of 43 cases receiving CI piperacillin-tazobactam monotherapy. No significant differences in terms of demographics and clinical features emerged at baseline between the two groups. Optimal PK/PD target was attained in 83.7% and 100.0% of patients receiving piperacillin-tazobactam and meropenem, respectively. No significant differences were observed between groups in terms of median values of delta 48-h SOFA (0 points vs. 1 point; p = 0.89) and median delta 7-days SOFA (2 points vs. 1 point; p = 0.43). Similarly, no significant differences were found between patients receiving piperacillin-tazobactam vs. meropenem for any of the secondary outcomes. (4) Conclusion: Our findings may support the contention that in critically ill patients with documented Gram-negative BSIs and/or VAP, the decreases in the SOFA score and in the inflammatory biomarkers serum levels achievable with CI piperacillin-tazobactam monotherapy at 48-h and at 7-days may be of similar extent and as effective as to those achievable with CI meropenem monotherapy provided that optimization on real-time by means of a TDM-based expert clinical pharmacological advice program is granted.

Comparison of Culture Proven Enteric Fever Treatment with Meropenem Alone Vs Combination of Meropenem and Azithromycin

Background: Enteric fever, primarily caused by Salmonella enterica serotypes Typhi and Paratyphi, remains a significant global health challenge, particularly in regions with limited access to clean water and sanitation. The emergence of multidrug-resistant strains has prompted the exploration of effective antibiotic regimens. While Meropenem has become a critical treatment option, the potential benefit of combining it with Azithromycin is not well established. Objective: The study aimed to compare the efficacy of Meropenem alone versus a combination of Meropenem and Azithromycin in the treatment of culture-proven enteric fever, focusing on fever resolution time and hospital stay duration. Methods: Conducted at the Combined Military Hospital, Peshawar, this study involved 81 patients diagnosed with enteric fever. They were randomly divided into two groups: Group 1 (n=40) received Meropenem alone, and Group 2 (n=41) received a combination of Meropenem and Azithromycin. Key parameters evaluated included gender distribution, age, duration of defervescence, and length of hospital stay. Statistical significance was assessed using appropriate tests. Results: The study found no significant difference in the duration of fever resolution (P=0.571) and hospital stay (P=0.466) between the two groups. The mean defervescence time was 5.325 days for Group 1 and 5.4878 days for Group 2. The average hospital stay was 6.4 days for Group 1 and 6.6098 days for Group 2. Gender distribution and age profile were comparable across both groups. Conclusion: The study concludes that there is no significant difference in the effectiveness of treating enteric fever with Meropenem alone compared to a combination of Meropenem and Azithromycin. This finding supports the use of Meropenem monotherapy as a suitable treatment for enteric fever, potentially reducing treatment protocols and addressing concerns about antibiotic overuse.

Metabolomics reveals the mechanism of action of meropenem and amikacin combined in the treatment of Pseudomonas aeruginosa.

The treatment of Pseudomonas aeruginosa infection often involves the combined use of β-lactam and aminoglycoside antibiotics. In this study, we employed metabolomic analysis to investigate the mechanism responsible for the synergistic activities of meropenem/amikacin combination therapy against multidrug-resistant P. aeruginosa strains harboring OXA-50 and PAO genes. Antibiotic concentrations for meropenem (2 mg/L) monotherapy, amikacin (16 mg/L) monotherapy, and meropenem/amikacin (2/16 mg/L) combination therapy were selected based on clinical breakpoint considerations. Metabolomic analysis revealed significant alterations in relevant metabolites involved in bacterial cell membrane and cell wall synthesis within 15 min of combined drug administration. These alterations encompassed various metabolic pathways, including fatty acid metabolism, peptidoglycan synthesis, and lipopolysaccharide metabolism. Furthermore, at 1 h and 4 h, the combination therapy exhibited significant interference with amino acid metabolism, nucleotide metabolism, and central carbon metabolism pathways, including the tricarboxylic acid cycle and pentose phosphate pathway. In contrast, the substances affected by single drug administration at 1 h and 4 h demonstrated a noticeable reduction. Meropenem/amikacin combination resulted in notable perturbations of metabolic pathways essential for survival of P. aeruginosa, whereas monotherapies had comparatively diminished impacts.

Pharmacokinetic/Pharmacodynamic Target Attainment of Continuous Infusion Piperacillin-Tazobactam or Meropenem and Microbiological Outcome among Urologic Patients with Documented Gram-Negative Infections.

(1) Objectives: To describe the relationship between pharmacokinetic/pharmacodynamic (PK/PD) target attainment of continuous infusion (CI) piperacillin-tazobactam or meropenem monotherapy and microbiological outcome in a case series of urological patients with documented Gram-negative infections. (2) Methods: Patients admitted to the urology ward who were treated with CI piperacillin-tazobactam or meropenem monotherapy for documented Gram-negative infections and underwent real-time therapeutic drug monitoring (TDM)-guided expert clinical pharmacological advice (ECPA) program from June 2021 to May 2023 were retrospectively retrieved. Average steady-state (Css) piperacillin-tazobactam and meropenem concentrations were determined, and the free fractions (fCss) were calculated. Optimal PK/PD target attainments were defined as an fCss/MIC ratio >4 for CI meropenem and an fCss/MIC ratio of piperacillin >4 coupled with an fCss/CT ratio for tazobactam >1 for piperacillin-tazobactam (joint PK/PD target). The relationship between beta-lactam PK/PD targets and microbiological outcome was explored. (3) Results: Sixteen urologic patients with documented Gram-negative infections (62.5% complicated urinary tract infections (cUTI)) had 30 TDM-guided ECPAs. At first TDM assessment, beta-lactam dosing adjustments were recommended in 11 out of 16 cases (68.75%, of which 62.5% decreases and 6.25% increases). Overall, beta-lactam dosing adjustments were recommended in 14 out of 30 ECPAs (46.6%). Beta-lactam PK/PD target attainments were optimal in 100.0% of cases. Microbiological failure occurred in two patients, both developing beta-lactam resistance. (4) Conclusion: A TDM-guided ECPA program may allow for optimizing beta-lactam treatment in urologic patients with documented Gram-negative infections, ensuring microbiological eradication in most cases.

Mortality in KPC-producing Klebsiella pneumoniae bloodstream infections: a changing landscape.

To assess the impact of carbapenem resistance on mortality in Klebsiella pneumoniae bloodstream infection (BSI) in the era of novel β-lactam/β-lactamase inhibitor combinations. Retrospective study of patients with K. pneumoniae BSI between January and August 2020 in 16 centres (CARBANEW study within the MULTI-SITA project). Overall, 426 patients were included: 107/426 (25%) had carbapenem-resistant K. pneumoniae (CR-Kp) BSI and 319/426 (75%) had carbapenem-susceptible K. pneumoniae (CS-Kp) BSI. Crude cumulative 30 day mortality was 33.8% and 20.7% in patients with, respectively, CR-Kp BSI and CS-Kp BSI (P = 0.027). Carbapenemase production or carbapenemase-encoding genes were detected in 84/98 tested CR-Kp isolates (85.7%), mainly KPC (78/84; 92.9%). Ceftazidime/avibactam was the most frequently used appropriate therapy for CR-Kp BSI (80/107; 74.7%). In multivariable analyses, variables showing an unfavourable association with mortality after correction for multiple testing were age-adjusted Charlson comorbidity index (HR 1.20; 95% CI 1.10-1.31, P < 0.001) and Pitt score (HR 1.33; 95% CI 1.15-1.55, P < 0.001), but not carbapenem resistance (HR 1.28, 95% CI 0.74-2.22, P = 0.410). In a propensity score-matched analysis, there was no difference in mortality between patients appropriately treated with ceftazidime/avibactam for CR-Kp BSI and patients appropriately treated with other agents (mainly meropenem monotherapy or piperacillin/tazobactam monotherapy) for CS-Kp BSI (HR 1.07; 95% CI 0.50-2.29, P = 0.866). Our results suggest that the increased mortality in CR-Kp BSI compared with CS-Kp BSI is not (or no longer) dependent on the type of therapy in areas where ceftazidime/avibactam-susceptible KPC-producing isolates are the most prevalent type of CR-Kp.

Improving the efficacy for meropenem therapy requires a high probability of target attainment in critically ill infants and children.

Probability of target attainment is the key factor influencing the outcome of meropenem therapy. The objective of the present study was to evaluate the relationship between the time in which the plasma free concentration of meropenem exceeds the minimum inhibitory concentration of pathogens (fT >MIC) during therapy and the clinical outcome of treatment to optimize meropenem therapy. Critically ill children with infections who had received intravenous meropenem monotherapy were included. The relationship between fT >MIC of meropenem and effectiveness and safety were explored. Data from 53 children (mean age ± standard deviation, 26 months ± 38) were available for final analysis. Children with fT >MIC ≥ 5.6 h (n = 14) had a more significant improvement in antibacterial efficacy in terms of decrease in fever (p = 0.02), white blood cell count (p = 0.014), and C-reactive protein (p = 0.02) compared with children with fT >MIC < 5.6 h (n = 39) after meropenem therapy completed. No drug-related adverse events were shown to have a causal association with meropenem therapy. Our study shows the clinical benefits of sufficient target attainment of meropenem therapy. Meeting a suitable pharmacodynamic target attainment of meropenem is required to ensure better antibacterial efficacy in critically ill infants and children. Clinical Trial Registration: clinicaltrials.gov, Identifier NCT03643497.

Carbapenem Combinations for Infections Caused by Carbapenemase-Producing Pseudomonas aeruginosa: Experimental In Vitro and In Vivo Analysis.

In the context of difficult-to-treat carbapenem-resistant Pseudomonas aeruginosa infections, we evaluated imipenem, meropenem, and doripenem combinations against eleven carbapenemase-producing P. aeruginosa isolates. According to the widespread global distribution of high-risk clones and carbapenemases, four representative isolates were selected: ST175 (OXA-2/VIM-20), ST175 (VIM-2), ST235 (GES-5), and ST111 (IMP-33), for efficacy studies using a sepsis murine model. Minimum inhibitory concentration (mg/L) ranges were 64–256 for imipenem and 16–128 for meropenem and doripenem. In vitro, imipenem plus meropenem was synergistic against 72% of isolates and doripenem plus meropenem or imipenem against 55% and 45%, respectively. All combinations were synergistic against the ST175, ST235, and ST155 clones. In vivo, meropenem diminished the spleen and blood bacterial concentrations of four and three isolates, respectively, with better efficacy than imipenem or doripenem. The combinations did not show efficacy compared with the more active monotherapies, except for imipenem plus meropenem, which reduced the ST235 bacterial spleen concentration. Mortality decreased with imipenem plus meropenem or doripenem for the ST175 isolate. Results suggest that carbapenem combinations are not an alternative for severe infections by carbapenemase-producing P. aeruginosa. Meropenem monotherapy showed in vivo efficacy despite its high MIC, probably because its dosage allowed a sufficient antimicrobial exposure at the infection sites.

Pharmacodynamics of Piperacillin-Tazobactam/Amikacin Combination versus Meropenem against Extended-Spectrum β-Lactamase-Producing Escherichia coli in a Hollow Fiber Infection Model.

Carbapenems are recommended for the treatment of urosepsis caused by extended-spectrum β-lactamase (ESBL)-producing, multidrug-resistant Escherichia coli; however, due to selection of carbapenem resistance, there is an increasing interest in alternative treatment regimens including the use of β-lactam-aminoglycoside combinations. We compared the pharmacodynamic activity of piperacillin-tazobactam and amikacin as mono and combination therapy versus meropenem monotherapy against extended-spectrum β-lactamase (ESBL)-producing, piperacillin-tazobactam resistant E. coli using a dynamic hollow fiber infection model (HFIM) over 7 days. Broth-microdilution was performed to determine the MIC of E. coli isolates. Whole genome sequencing was conducted. Four E. coli isolates were tested in HFIM with an initial inoculum of ~107 CFU/mL. Dosing regimens tested were piperacillin-tazobactam 4.5 g, 6-hourly, plus amikacin 30 mg/kg, 24-hourly, as combination therapy, and piperacillin-tazobactam 4.5 g, 6-hourly, amikacin 30 mg/kg, 24-hourly, and meropenem 1 g, 8-hourly, each as monotherapy. We observed that piperacillin-tazobactam and amikacin monotherapy demonstrated initial rapid bacterial killing but then led to amplification of resistant subpopulations. The piperacillin-tazobactam/amikacin combination and meropenem experiments both attained a rapid bacterial killing (~4-5 log10) within 24 h and did not result in any emergence of resistant subpopulations. Genome sequencing demonstrated that all ESBL-producing E. coli clinical isolates carried multiple antibiotic resistance genes including blaCTX-M-15, blaOXA-1, blaEC, blaTEM-1, and aac(6')-Ib-cr. These results suggest that the combination of piperacillin-tazobactam/amikacin may have a potential role as a carbapenem-sparing regimen, which should be tested in future urosepsis clinical trials.

Evaluating Mono- and Combination Therapy of Meropenem and Amikacin against Pseudomonas aeruginosa Bacteremia in the Hollow-Fiber Infection Model.

ABSTRACTDebate 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 in vitro 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 × 105 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.IMPORTANCE 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 in vitro 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.

Disulfiram enhances meropenem activity against NDM- and IMP-producing carbapenem-resistant Acinetobacter baumannii infections.

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. 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. 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. These results strongly suggest that the combination of disulfiram and meropenem represents an effective treatment option for NDM- and IMP-associated CRAb infections.

Antimicrobial Peptides Epinecidin-1 and Beta-Defesin-3 Are Effective against a Broad Spectrum of Antibiotic-Resistant Bacterial Isolates and Increase Survival Rate in Experimental Sepsis.

The antimicrobial peptides human Beta-defensin-3 (hBD-3) and Epinecidin-1 (Epi-1; by Epinephelus coioides) could be a promising tool to develop novel antibacterials to combat antibiotic resistance. The antibacterial activity of Epi-1 + vancomycin against methicillin-resistant Staphylococcus aureus (22 isolates) and Epi-1 + hBD-3 against carbapenem-resistant isolates of Klebsiella pneumoniae (n = 23), Klebsiella aerogenes (n = 17), Acinetobacter baumannii (n = 9), and Pseudomonas aeruginosa (n = 13) was studied in vitro. To evaluate the in vivo efficacy of hBD-3 and Epi-1, ICR (CD-1) mice were injected intraperitoneally with a lethal dose of K. pneumoniae or P. aeruginosa. The animals received a single injection of either sterile saline, hBD-3 monotherapy, meropenem monotherapy, hBD-3 + meropenem, or hBD-3 + Epi-1. Studied peptides showed antibacterial activity in vitro against all studied clinical isolates in a concentration of 2 to 32 mg/L. In both experimental models of murine sepsis, an increase in survival rate was seen with hBD-3 monotherapy, hBD-3 + meropenem, and hBD-3 + Epi-1. For K. pneumoniae-sepsis, hBD-3 was shown to be a promising option in overcoming the resistance of Klebsiella spp. to carbapenems, though more research is needed. In the P. aeruginosa-sepsis model, the addition of Epi-1 to hBD-3 was found to have a slightly reduced mortality rate compared to hBD-3 monotherapy.

Carbapenem-resistant K. pneumoniae exhibiting clinically undetected amikacin and meropenem heteroresistance leads to treatment failure in a murine model of infection

Heteroresistance is a poorly understood mechanism of resistance which refers to a phenomenon where there are different subpopulations of seemingly isogenic bacteria which exhibit a range of susceptibilities to a particular antibiotic.In the current study, we identified a multidrug-resistant, carbapenemase-positive K. pneumoniae strain SWMUF35 which was classified as susceptible to amikacin and resistant to meropenem by clinical diagnostics yet harbored different subpopulations of phenotypically resistant cells, and has the ability to form biofilm. Population analysis profile (PAP) indicated that SWMUF35 showed heteroresistance towards amikacin and meropenem which was considered as co-heteroresistant K. pneumoniae strain. In vitro experiments such as dual PAP, dual Times-killing assays and checkerboard assay showed that antibiotic combination therapy (amikacin combined with meropenem) can effectively combat SWMUF35. Importantly, using an in vivo mouse model of peritonitis, we found that amikacin or meropenem monotherapy was unable to rescue mice infected with SWMUF35. Antibiotic combination therapy could be a rational strategy to use clinically approved antibiotics when monotherapy would fail.Furthermore, our data warn that antibiotic susceptibility testing results may be unreliable due to undetected heteroresistance which can lead to treatment failure and the detection of this phenotype is a prerequisite for a proper choice of antibiotic to support a successful treatment outcome.

Meropenem Monotherapy is a Valid Alternative in Community Acquired Adult Acute Bacterial Meningitis (ABM)

Background: Meropenem (Merrem®, Meropenem®) is a broad-spectrum antibacterial carbapenem with indication for Acute Bacterial Meningitis (ABM). We wanted to specifically evaluate the effect of meropenem monotherapy, compared to standard recommended therapy. Method: A Swedish ongoing internet based quality register for ABM was started 1994 and covers the whole country with roughly 30 infectious disease clinics. After ethical approval data were extracted from the database and evaluated using conventional statistical methods (IBM SPSS Statistics 23). Results: The register contained 1708 patients altogether. All 770 patients (45%) given meropenem or cefotaxime/ampicillin were selected for this study. The age of the studied population was from 18-91 with a mean of 55 and median 60. Overall ABM mortality was 12.1% (197/1708). In the meropenem and cefotaxime/ampicillin subgroup 7.8% (60/770) died, p=0,035 and in the non-selected group 14,6 % (137/938), p&lt;0.001. For meningococci the mortality was only 2% and for pneumococci 9% (p=0,025) and are record low figures in this selected population. The mortality increased 1.3 times (Odd’s ratio 1.3, p&lt;0.001) with each decade of life and 1.5 times with each RLS stratification level (Odd’s ratio 1.5, p&lt;0.001). Conclusion: There was no statistical significance in mortality (p=0.67) or sequelae rate between meropenem and cefotaxime/ampicillin treatment. Favourable outcome depends on speedy and correct antibiotic therapy as well as inclusion of betamethasone. Age, RLS and bacterial species, are factors, which cannot be influenced. Meropenem is a valid antibiotic choice in the Swedish population (with limited resistance problems).

A New Method for Optimizing Sepsis Therapy by Nivolumab and Meropenem Combination: Importance of Early Intervention and CTL Reinvigoration Rate as a Response Marker.

Background: Recently, there has been a growing interest in applying immune checkpoint blockers (ICBs), so far used to treat cancer, to patients with bacterial sepsis. We aimed to develop a method for predicting the personal benefit of potential treatments for sepsis, and to apply it to therapy by meropenem, an antibiotic drug, and nivolumab, a programmed cell death-1 (PD-1) pathway inhibitor.Methods: We defined an optimization problem as a concise framework of treatment aims and formulated a fitness function for grading sepsis treatments according to their success in accomplishing the pre-defined aims. We developed a mathematical model for the interactions between the pathogen, the cellular immune system and the drugs, whose simulations under diverse combined meropenem and nivolumab schedules, and calculation of the fitness function for each schedule served to plot the fitness landscapes for each set of treatments and personal patient parameters.Results: Results show that treatment by meropenem and nivolumab has maximum benefit if the interval between the onset of the two drugs does not exceed a dose-dependent threshold, beyond which the benefit drops sharply. However, a second nivolumab application, within 7–10 days after the first, can extinguish a pathogen which the first nivolumab application failed to remove. The utility of increasing nivolumab total dose above 6 mg/kg is contingent on the patient's personal immune attributes, notably, the reinvigoration rate of exhausted CTLs and the overall suppression rates of functional CTLs. A baseline pathogen load, higher than 5,000 CFU/μL, precludes successful nivolumab and meropenem combination therapy, whereas when the initial load is lower than 3,000 CFU/μL, meropenem monotherapy suffices for removing the pathogen.Discussion: Our study shows that early administration of nivolumab, 6 mg/kg, in combination with antibiotics, can alleviate bacterial sepsis in cases where antibiotics alone are insufficient and the initial pathogen load is not too high. The study pinpoints the role of precision medicine in sepsis, suggesting that personalized therapy by ICBs can improve pathogen elimination and dampen immunosuppression. Our results highlight the importance in using reliable markers for classifying patients according to their predicted response and provides a valuable tool in personalizing the drug regimens for patients with sepsis.