Combination Of Meropenem Research Articles

Pharmacokinetic/pharmacodynamic analysis of meropenem and fosfomycin combinations in in vitro time-kill and hollow-fibre infection models against multidrug-resistant and carbapenemase-producing Klebsiella pneumoniae.

MDR Gram-negative bacteria, such as ESBL-producing and carbapenemase-producing Klebsiella pneumoniae, represent major global health threats. Treatment options are limited due to increasing resistance and slowed development of novel antimicrobials, making it necessary to apply effective combination therapies based on approved antibiotics. To quantitatively evaluate the synergistic potential of meropenem and fosfomycin against carbapenem-resistant K. pneumoniae strains isolated from clinics. We evaluated four MDR K. pneumoniae strains, each expressing KPC-2 or KPC-3, using static time-kill assays that accounted for measured meropenem degradation. This was followed by pharmacokinetic/pharmacodynamic (PK/PD) interaction modelling, which estimated meropenem degradation rate constants and identified perpetrator-victim relationships in PD interactions. Dynamic hollow-fibre infection model (HFIM) experiments were used to confirm synergy. Static time-kill assays demonstrated high killing effects and suppressed regrowth for the combination of meropenem and fosfomycin, compared with the failure of monotherapy. Meropenem degradation was significantly higher in the presence of bacteria, attributable to carbapenemase activity. Pharmacometric models indicated a synergistic interaction primarily driven by meropenem as the perpetrator, enhancing the potency of fosfomycin. HFIM experiments confirmed in vitro synergy, demonstrating continuous bacterial suppression of the combination therapy. Meropenem and fosfomycin exhibited additive or synergistic potential against carbapenemase-expressing single- or double-resistant K. pneumoniae at clinically achievable concentrations. This combination therapy may offer a strategy against MDR infections, possibly improving clinical treatment outcomes. Further in vivo research is needed to translate these findings into clinical practice, emphasizing the importance of PK/PD modelling in rationalizing antibiotic use.

In Vitro Dynamic Model Evaluation of Meropenem Alone and in Combination with Avibactam Against Carbapenemase-Producing Klebsiella pneumoniae.

Background: A potential strategy to maintain the efficacy of carbapenems against carbapenemase-producing Klebsiella pneumoniae (CPKP) is their combination with carbapenemase inhibitors. To address these issues, the effectiveness of a novel combination of meropenem with avibactam against CPKP was studied. Additionally, the applicability of a pharmacokinetically-based approach to antibiotic/inhibitor minimum inhibitory concentration (MIC) determinations to better predict efficacy was examined. Methods: CPKP strains were exposed to meropenem alone or in combination with avibactam in an in vitro hollow-fiber infection model. Treatment effects were correlated with simulated antibiotic and antibiotic/inhibitor combination ratios of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC). All MICs were determined at standard and at high inocula; combination MICs were determined using the conventional approach with fixed avibactam concentration or using the pharmacokinetic (PK)-based approach with a fixed meropenem-to-avibactam concentration ratio, equal to the respective drug therapeutic AUC ratios. Results: Meropenem alone was not effective even against a "susceptible" CPKP strain. The addition of avibactam significantly improved both meropenem MICs and its effectiveness. The effects of meropenem alone and in combination with avibactam (merged data) correlated well with AUC/MIC ratios only when MICs were determined at high inocula and using the PK-based approach (r2 0.97); the correlation was worse with the conventional approach (r2 0.73). Conclusions: The effectiveness of meropenem/avibactam against CPKP is promising. A single "effect-AUC/MIC" relationship useful for predicting meropenem efficacy (alone or in combination with avibactam) was obtained using MICs at high inocula and combination MICs determined using a PK-based approach.

Closing the Gaps: Testing the Efficacy of Carbapenem and Cephalosporin Treatments of Late-Stage Anthrax in Rabbits.

Anthrax is a fatal zoonotic disease caused by exposure to Bacillus anthracis spores. The CDC's guidelines divide anthrax treatment into three categories according to disease progression: post-exposure prophylaxis (PEP), systemic, and systemic with a suspicion of CNS infection. While the prognosis for PEP or the early treatment of systemic anthrax is very good, ingress of the bacteria into the CNS poses a substantial clinical challenge. Here, we use rabbits to test the efficacy of a combined treatment of meropenem and doxycycline, which is the first choice in the CDC recommendations for treating systemic patients with an indication of CNS infection. In addition, we test the efficacy of the first-generation cephalosporin, cefazolin, in treating different stages of the disease. We found that the combination of doxycycline and meropenem is highly effective in treating rabbits in our inhalation model. Cefazolin was efficient only for PEP or systemic-stage treatment and not for CNS-infected animals. Our findings support the CDC recommendation of using a combination of doxycycline and meropenem for systemic patients with or without indications of CNS infection. We found that cefazolin is a decent choice for PEP or early-stage systemic disease but recommend considering using this antibiotic only if all other options are not available.

Outcome of carbapenem or colistin resistant Klebsiella pneumoniae bacteremia in the intensive care unit

Carbapenem-resistant Klebsiella pneumoniae (CRKp) infections continue to be an important cause of mortality. In this retrospective study, the effect of carbapenem or colistin resistance on mortality in Klebsiella pneumoniae bacteremia and combined meropenem + colistin administration in CRKp bacteremia was evaluated. In addition to that, a mathematical model is applied to explore the relationships between the resistance and mortality. A total of 139 adult patients diagnosed with K. pneumoniae bacteremia(73 carbapenem sensitive and 66 carbapenem resistant) between 01/01/2000 and 31/07/2019 were included in the study. The 30-day mortality in entire cohort were 19.4%. 30-day mortality was significantly higher in the carbapenem resistant-colistin sensitive group and in the carbapenem resistant-colistin resistant group compared to the carbapenem susceptible group. Meropenem + colistin combination was administered to 37 (95%) of carbapenem resistant–colistin sensitive (n = 39) and 25 (93%) of carbapenem resistant–colistin resistant patients(n = 27). Notably, mortality was not significantly affected regardless of whether CRKp was colistin sensitive and whether a high dose and prolonged infusion of meropenem was administered. Mortality is higher in carbapenem resistant Klebsiella pneumoniae bacteremia compared to carbapenem susceptible group. In cases of combined meropenem and colistin administration, high dose and prolonged infusion of meropenem is not superior to standard dose and infusion in both carbapenem resistant–colistin sensitive and carbapenem resistant–colistin resistant K. pneumoniae bacteremia.

Development of a new Acinetobacter baumannii pneumonia rabbit model for the preclinical evaluation of future anti-infective strategies.

Carbapenem-resistant Acinetobacter baumannii (CRAB) is an emerging cause of hospital-acquired pneumonia (HAP). Preclinical large models are warranted to predict the efficacy and the resistance profile of anti-infectives and mimic how they will be used in the human treatment of CRAB-HAP. Here we reported on the development of an Acinetobacter baumannii experimental pneumonia model in immunocompromised rabbits, receiving a 48-h human-simulated regimen. The efficacy of meropenem (2 g/q8h i.v. over prolonged 3-h perfusion), rifampin (25 mg/kg/q8h, i.v.), or the combination of meropenem and rifampin was assessed in rabbits infected with the carbapenem-susceptible ATCC 17978 reference strain or the CRAB Turc 2 clinical strain. The emergence of rifampin mutants was also investigated. Meropenem demonstrated a strong pulmonary bacterial reduction in animals infected with the ATCC 17978 strain (unlike the CRAB strain). The high rifampin dosage was associated with a 1.3 Log10 bacterial killing on average but induced the emergence of high-level resistant mutants in 80%-100% of animals, depending on the strain. The adjunction of rifampin to meropenem did not improve the bioburden in the lungs but partially reduced the number of animals exhibiting resistant mutants, whatever the tested strain. However, this adjunctive treatment was insufficient to overcome the emergence of resistance since mutation prevention concentration-related pharmacodynamic indices were unattainable at this dose. This CRAB pneumonia rabbit model represents an innovative tool to evaluate the efficacy of new or existing therapies and will provide informative data on how they can meet the resistance pharmacodynamic targets, which now need to be investigated before deciding on clinical therapeutic regimens.IMPORTANCEWithin intensive care unit settings, carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a frequent cause of hospital-acquired pneumonia (HAP) with poor clinical outcomes. This multidrug-resistant pathogen remains very challenging to study in clinical trials, and the U.S. Food and Drug Administration highlighted the limitations of existing small animal models for evaluating antibacterial or prophylactic strategies against such critical infections. These limitations include the difficulty in anticipating the risk of the emergence of resistance during treatment. Here we developed a new Acinetobacter baumannii pneumonia rabbit model using high inoculum. We demonstrated the emergence of resistance with rifampin, an existing antibiotic debated as a rescuing option to treat CRAB infections; and even intensified rifampin doses failed to close the mutant selection window. This CRAB pneumonia rabbit model represents a valuable tool to evaluate the efficacy of new or existing therapies and provides supportive data in antimicrobial resistance pharmacodynamics.

The use of dual β-lactams to restore susceptibility of Mycobacterium avium complex.

The Mycobacterium avium complex (MAC) are non-tuberculous mycobacteria responsible for chronic and debilitating conditions. Guideline-recommended therapy for MAC is a combination of clarithromycin/azithromycin, ethambutol and a rifamycin. However, culture conversion rates with this regimen are 67%. Alternative treatment options are needed. Recent findings of β-lactam combinations in the treatment of other mycobacterial diseases have been promising. The proposed mechanism is an additive inhibition of multiple enzymes in the peptidoglycan synthesis pathway by the β-lactam combinations. Given the similarity in cell wall structures of MAC and M. abscessus, we hypothesize that using dual β-lactams will result in interruption of peptidoglycan synthesis in MAC and reduction of MIC. In this study, we sought to determine the MIC of meropenem in combination with ceftaroline, cefdinir and cefuroxime in MAC. A total of 31 clinical MAC isolates were used for susceptibility testing using broth microdilution method. MICs were tested for meropenem, ceftaroline, cefdinir and cefuroxime, alone, as well as combinations of meropenem plus ceftaroline, cefdinir, or cefuroxime. In vitro MAC susceptibility to meropenem was significantly enhanced with the addition of ceftaroline, cefdinir, and cefuroxime. This effect was most significant with addition of ceftaroline and cefdinir, with a change of meropenem MIC50/MIC90 from 16/32 to 0.125/0.5 and 0.125/4 mg/L, respectively (P value ≤0.0001, Wilcoxon signed-rank test). This study demonstrates that the susceptibility of MAC to meropenem is restored with the addition of ceftaroline and cefdinir. These findings underscore the potential effectiveness of combining β-lactams as an alternative therapeutic strategy for MAC infections.

Antibacterial Effects of Basil (Ocimum sanctum) Leaf Extract in Combination with Meropenem against Extended Spectrum Beta-Lactamase (ESBL) Producing Klebsiella pneumoniae

Highlights: O. sanctum leaf extract does not significantly increase its antibacterial effects when combined with meropenem against ESBL-producing K. pneumonia. O. sanctum leaf extract has different antibacterial effects depending on geological and environmental factors. Abstract Introduction: Antibiotic usage for bacterial infections causes antibiotic resistance in bacteria. One is extended-spectrum beta-lactamase (ESBL), which produces Klebsiella pneumoniae, a pathogen responsible for increased antibiotic resistance. Basil (Ocimum sanctum) is a candidate for combination therapy. It has been proven to have antibacterial effects. However, its combination with antibiotics is rarely researched. This study evaluated the antibacterial effects of O. sanctum leaf extract and meropenem combination against ESBL-producing K. pneumoniae. Methods: This study used the disk diffusion method. The extract was tested for each experiment at 6%, 4%, 2%, 1%, and 0.5% concentration. The research was divided into two experiments to evaluate the antibacterial effects of O. sanctum leaf extract (n = 18) and its combination with meropenem against ESBL-producing K. pneumoniae (n = 18). The data was analyzed using the International Business Machines Corporation (IBM) Statistical Package for the Social Sciences (SPSS) version 26.0 for Windows. A probability (p) value of < 0.050 was considered significant. Results: The first experiment showed that the extract had the largest antibacterial effect at 0.5% concentration (n = 18, p = 0.007). Meanwhile, the second experiment showed that the combination of the extract and meropenem did not have significant antibacterial effects (n = 18, p = 0.597). Conclusion: O. sanctum leaf extract has viable antibacterial effects, but its combination with meropenem does not significantly improve its antibacterial effects against ESBL-producing K. pneumonia.

Towards evidence-based empiric antibiotic recommendations for spontaneous infections in patients with cirrhosis

BackgroundWith the emergence of multidrug-resistant infections, healthcare professionals must evaluate the effectiveness of empiric antibiotic treatments. AimsTo assess the antibiotic susceptibility patterns of microorganisms causing spontaneous infections in patients with cirrhosis and to evaluate the suitability of empiric antibiotic treatments based on major clinical guidelines. MethodsThis cross-sectional study utilized two datasets from prospective studies of patients with cirrhosis and culture-positive spontaneous bacterial infections in Argentina and Uruguay. We estimated susceptibility to commonly used antibiotics and assessed coverage following European and American recommendations. ResultsWe analyzed 238 episodes of culture-positive spontaneous infections in 229 patients. When implementing the recommendations for empiric treatment of community-acquired spontaneous infections, ceftazidime would result in 39 % coverage, whereas ceftriaxone would reach 70 %. Cefepime, which is not included in the recommendations, would have provided coverage of 74 %. Using ertapenem for nosocomial infections would have only covered 56 % of these episodes, whereas meropenem or imipenem reached 73 % coverage. Only the combination of meropenem or imipenem plus vancomycin would achieve a coverage surpassing 85 % in healthcare-associated or nosocomial spontaneous bacterial infections. ConclusionsOur study uncovers inadequate coverage in specific clinical scenarios when adhering to recommendations, underscoring the necessity of guidelines based on local epidemiological data.

Fighting XDR Typhoid: A Hospital Based Study on Clinical Aspects and Treatment Outcome in Tertiary Care Hospital

Objective: The main aim of this study is to find Clinical Aspects and Treatment Outcome in drug resistant Typhoid. Methodology: Total 120 patients participated in this study. Individuals who received a diagnosis of XDR S.Typhi through a blood culture test were identified from the registry of both healthcare facilities. The medical data of patients suffering from typhoid fever who received treatment as either a hospital inpatient or outpatient between April 1, 2022, and June 30, 2022, were examined for the purpose of screening for inclusion in this investigation. Only typhoid patients who tested positive for S.Typhi in a test to culture blood and the manifestation of insusceptibility to the five classifications of antimicrobials (ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, fluoroquinolone, and 3rd generation cephalosporin (ceftriaxone or cefixime) were examined for potential incorporation in this inquiry. Results: Among the 120 cases of XDR Typhoid, n= 35 (29.16%) were managed exclusively with azithromycin, while 40 (33.33%) were solely administered meropenem. The remaining 45(37.5%) received a combination of both azithromycin and meropenem. Two patients could not recover after receiving Azithromycin. Full recovery seen in Meropenem. Four patients couldn’t recover from combination therapy. Conclusion: Escalating antibiotic resistance in Salmonella enterica has rendered it a complex ailment to address. Measures ought to be implemented to enhance antibiotic prescription protocols and establish consistent recommendations for the management of highly resistant strains of Salmonella enterica.

Synergy of lytic phage pB23 and meropenem combination against carbapenem-resistant Acinetobacter baumannii.

Phage-antibiotic combination treatment is a novel noteworthy drug delivery method in anti-infection. In the current study, we have isolated a new phage, pB23, against carbapenem-resistant Acinetobacter baumannii 2023. Synergistic antibacterial effect between phage pB23 and meropenem combination could be more stable, using moderate doses of phage (multiplicity of infection ranging from 0.1 to 1,000) based on results of in vitro antibacterial activity. Phage pB23 and meropenem combination could effectively clear mature biofilms and prevent biofilm formation of carbapenem-resistant Acinetobacter baumannii in vitro. Phage pB23 and meropenem combination also has good synergistic antibacterial effects against carbapenem-resistant Acinetobacter baumannii in different growth phases under static culture conditions. The pig skin explant model shows that phage pB23 and meropenem combination has a synergistic effect to remove bacteria from wounds ex vivo. Phage pB23 and meropenem combination also exhibited a synergistic antibacterial effect in vivo using a zebrafish infection mode. The potential promotion of phage proliferation by meropenem and the sensitivity recovery of phage-resistant bacteria to meropenem might elucidate the mechanism of the synergistic antimicrobial activity. In summary, our study illustrates that phage pB23 and meropenem combination could produce synergistic antibacterial effects against carbapenem-resistant Acinetobacter baumannii under static growth conditions. This study also demonstrates that phage-antibiotic combination will become an effective strategy to enhance antibacterial activity of individual drug and provide a new idea of the drug development for the treatment of infections due to carbapenem-resistant Acinetobacter baumannii and other multidrug-resistant bacteria.

Extensively drug-resistant Salmonella typhi Infection in Adults; Experience from A Tertiary Care Hospital.

This study aimed to determine the epidemiology, clinical features, and complications of extensively drug-resistant Salmonella typhi (XDR S. typhi) infection in adults. This cross-sectional study enrolled adults with culture-proven XDR S. typhi admitted to Hayatabad Medical Complex, Peshawar from 1st March to 10th September 2022. Their demographic characteristics, clinical features, treatment, and complications were recorded. Out of 84 patients, 68 (80.9%) were male. The mean age of enrolled patients was 25.2 ± 11.3 years. The mean duration of fever at the time of admission was 13.6 ± 8.2 days, respectively. The most common symptom was loose stools (n=25, 29.8%). Most of the patients (n=69, 82.1%) had received empirical treatment before hospitalization. The majority of the patients (n=42, 50%) received meropenem and a combination of meropenem and azithromycin (n=35, 41.7%) during the study. The time to defervescence for both regimens was similar. Five patients (6%) developed complications of enteric fever. There was no mortality among the participants. Diarrhea was the most common associated clinical feature in XDR typhoid fever. Most of the patients received meropenem alone or in combination with azithromycin with a comparable time to defervescence. The majority of the patients recovered uneventfully and there was no mortality among the study participants.

Variables that predict hospital stay and the outcome of Fournier gangrene at King Abdulaziz University Hospital: a retrospective study

BackgroundThe aggressive nature of Fournier gangrene and the associated health issues can result in a more complex clinical course and potentially a longer hospital stay. This study aimed to assess factors that affect the length of hospital stay (LHS) and its relation to the outcome of Fournier gangrene patients.MethodsA retrospective study was performed at King Abdulaziz University Hospital (KAUH), Saudi Arabia, on patients diagnosed with Fournier gangrene between 2017 and 2023. Data about length of hospital stay (LHS), age, BMI, clinical and surgical data and outcome was obtained.ResultsThe mean age of the studied patients was 59.23 ± 11.19 years, the mean body mass index (BMI) was 26.69 ± 7.99 kg/m2, and the mean duration of symptoms was 10.27 ± 9.16 days. The most common presenting symptoms were swelling or induration (64%), 88% had comorbidities with diabetes mellitus (DM) (84%), and 76% had uncontrolled DM. of patients, 24% had a poly-microbial infection, with E. coli being the most common (52%). The mean length of hospital stay (LHS) was 54.56 ± 54.57 days, and 24% of patients had an LHS of more than 50 days. Longer LHS (> 50 days) was associated with patients who did not receive a compatible initial antibiotic, whereas shorter LHS was associated with patients who received Impenem or a combination of vancomycin and meropenem as alternative antibiotics following incompatibility. Reconstruction patients had significantly longer LHS and a higher mean temperature. However, none of the studied variables were found to be predictors of long LHS in the multivariate regression analysis.ConclusionKnowledge of the values that predict LHS allows for patient-centered treatment and may be useful in predicting more radical treatments or the need for additional treatment in high-risk patients. Future multicenter prospective studies with larger sample sizes are needed to assess the needed variables and predictors of long LHS.

Efficacy and safety of antibiotics targeting Gram-negative bacteria in nosocomial pneumonia: a systematic review and Bayesian network meta-analysis

BackgroundMultiple randomized controlled studies have compared numerous antibiotic regimens, including new, recently commercialized antibiotics in the treatment of nosocomial pneumonia (NP). The objective of this Bayesian network meta-analysis (NMA) was to compare the efficacy and the safety of different antibiotic treatments for NP.MethodsWe conducted a systematic search of PubMed, Medline, Web of Science, EMBASE and the Cochrane Library databases from 2000 through 2021. The study selection included studies comparing antibiotics targeting Gram-negative bacilli in the setting of NP. The primary endpoint was 28 day mortality. Secondary outcomes were clinical cure, microbiological cure and adverse events.ResultsSixteen studies encompassing 4993 patients were included in this analysis comparing 13 antibiotic regimens. The level of evidence for mortality comparisons ranged from very low to moderate. No significant difference in 28 day mortality was found among all beta-lactam regimens. Only the combination of meropenem plus aerosolized colistin was associated with a significant decrease of mortality compared to using intravenous colistin alone (OR = 0.43; 95% credible interval [0.17–0.94]), based on the results of the smallest trial included. The clinical failure rate of ceftazidime was higher than meropenem with (OR = 1.97; 95% CrI [1.19–3.45]) or without aerosolized colistin (OR = 1.40; 95% CrI [1.00–2.01]), imipemen/cilastatin/relebactam (OR = 1.74; 95% CrI [1.03–2.90]) and ceftazidime/avibactam (OR = 1.48; 95% CrI [1.02–2.20]). For microbiological cure, no substantial difference between regimens was found, but ceftolozane/tazobactam had the highest probability of being superior to comparators. In safety analyses, there was no significant difference between treatments for the occurrence of adverse events, but acute kidney failure was more common in patients receiving intravenous colistin.ConclusionsThis network meta-analysis suggests that most antibiotic regimens, including new combinations and cefiderocol, have similar efficacy and safety in treating susceptible Gram-negative bacilli in NP. Further studies are necessary for NP caused by multidrug-resistant bacteria.Registration PROSPERO CRD42021226603

Wide use of broad-spectrum antibiotics in very low birth weight infants with spontaneous focal intestinal perforation—is it really justified?

PurposeVery low birth weight (VLBW) infants are at a risk of spontaneous focal intestinal perforation (FIP). Treatment includes supportive care, antibiotics, and drainage with/without surgery. Broad-spectrum antibiotic agents like carbapenems are applied frequently, although their use is not well-supported by the limited evidence of causal pathogens. We hypothesize that the use of carbapenems may not be necessary in VLBW infants with FIP. Our primary objective was to evaluate the antimicrobial use in VLBW infants with FIP in a cohort of the German Neonatal Network (GNN). The secondary objective was to characterize a subset in detail as a benchmark for future targets of stewardship.MethodsData on VLBW infants with FIP was collected prospectively within the GNN, a collaboration of 68 neonatal intensive care units (NICU). With regards to the primary objective, patient characteristics and antimicrobial treatment were extracted from the predefined GNN database. To address our secondary objective, an additional on-site assessment of laboratory and microbiological culture results were performed.ResultsIn the GNN cohort, 613/21,646 enrolled infants (2.8%) developed FIP requiring surgery. They were frequently treated with carbapenems (500/613 (81.6%)) and vancomycin (497/613 (81.1%)). In a subset of 124 VLBW infants, 77 (72.6%) had proof of gram-positive bacteria in the abdominal cavity, coagulase-negative staphylococci (CoNS) predominantly. Despite the low prevalence of gram-negative bacteria (n = 6 (4.8%)), the combination of meropenem and vancomycin was prescribed most frequently (n = 96 (78.0%)).ConclusionThe use of carbapenems as broad-spectrum antimicrobials agents might not be justified in most VLBW infants with FIP. Knowledge on the development of the neonatal gut microbiota, local resistance patterns and individual microbiological findings should be taken into consideration when implementing antimicrobial stewardship programs (ASPs).

In vitro pharmacokinetics/pharmacodynamics of FL058 (a novel beta-lactamase inhibitor) combined with meropenem against carbapenemase-producing Enterobacterales.

Objective: FL058 is a novel beta-lactamase inhibitor with a broad spectrum of activity and a favorable safety profile. The objective of this study was to evaluate pharmacokinetic/pharmacodynamic (PK/PD) relationships for the combination of FL058 and meropenem in an in vitro infection model. Methods: By simulating human concentration-time profiles in the in vitro model, meropenem combined with FL058 when administered 1g/0.5 g, 1g/1g, 2g/1g, and 2g/2g q8h by 3-h infusion achieved approximately 2- and 4-log10 kill to KPC/OXA-producing Klebsiella pneumoniae and Escherichia coli; the combination therapy could not inhibit NDM-producing K. pneumoniae but could maintain NDM-producing E. coli around a baseline. Results: The PK/PD indexes that best described the bacterial killing from baseline in log10CFU/mL at 24h were the percent time of free drug above the minimal inhibitory concentration (MIC) (%fT > MIC, MIC with FL058 at 4mg/L) for meropenem and the percent time of free drug above 1mg/L (%fT > 1mg/L) for FL058. The targets for achieving a static effect and the 1- and 2-log10 kill were 74, 83, and 99 for %fT > MIC of meropenem and 40, 48, and 64 for %fT > 1mg/L of FL058, respectively. The PK/PD index of %fT > 1mg/L can provide a basis for evaluating clinical dosing regimens for FL058 combined with meropenem. Conclusion: FL058 combined with meropenem might be a potential treatment for KPC- and/or OXA-48-producing Enterobacterales infection.

The Triple Combination of Meropenem, Avibactam, and a Metallo-β-Lactamase Inhibitor Optimizes Antibacterial Coverage Against Different β-Lactamase Producers

This work explores the potential of a triple combination of meropenem (MEM), a novel metallo-β-lactamase (MBL) inhibitor (indole-2-carboxylate 58 (InC58)), and a serine-β-lactamase (SBL) inhibitor (avibactam (AVI)) for broad-spectrum activity against carbapenemase-producing bacteria. A diverse panel comprising MBL- and SBL-producing strains was used for susceptibility testing of the triple combination using the agar dilution method. The frequency of resistance (FoR) to MEM combined with InC58 was investigated. Mutants were sequenced and tested for cross resistance, fitness, and the stability of the resistance phenotype. Compared with the double combinations of MEM plus an SBL or MBL inhibitor, the triple combination extended the spectrum of activity to most of the isolates bearing SBLs (oxacillinase-48 (OXA-48) and Klebsiella pneumoniae carbapenemase-2 (KPC-2)) and MBLs (New Delhi metallo-β-lactamases (NDMs)), although it was not effective against Verona integron-encoded metallo-β-lactamase (VIM)-carrying Pseudomonas aeruginosa (P. aeruginosa) and OXA-23-carrying Acinetobacter baumannii (A. baumannii). The FoR to MEM plus InC58 ranged from 2.22 × 10−7 to 1.13 × 10−6. The resistance correlated with mutations to ompC and comR, affecting porin C and copper permeability, respectively. The mutants manifested a fitness cost, a decreased level of resistance during passage without antibiotic pressure, and cross resistance to another carbapenem (imipenem) and a β-lactamase inhibitor (taniborbactam). In conclusion, compared with the dual combinations, the triple combination of MEM with InC58 and AVI showed a much wider spectrum of activity against different carbapenemase-producing bacteria, revealing a new strategy to combat β-lactamase-mediated antimicrobial resistance.

The Biofilm Inhibition Properties of Glucosamine Gold Nanoparticles in Combination with Meropenem against Pseudomonas aeruginosa on the Endotracheal Tube: A Model of Biofilm-Related Ventilator-Associated Pneumonia.

Biofilm-related infections play a significant role in the development and persistence of ventilator-associated pneumonia. Pseudomonas aeruginosa (P. aeruginosa) frequently causes biofilm-related infections associated with ventilator tubing. Glucosamine gold nanoparticles (AuNPs) may exhibit antibiofilm properties; however, more studies, including combinatorial therapy with antibiotics, are needed to explore their potential applications in clinical settings. This study aims to investigate the biofilm inhibition properties of glucosamine AuNPs in combination with meropenem against P. aeruginosa ATCC 9027 on the endotracheal tube. A biofilm inhibition assay of glucosamine AuNPs at 0.02 mg/mL, both singly and in combination with meropenem at 1 mg/mL, was carried out against P. aeruginosa ATCC 9027 on an endotracheal tube using the tissue culture plate method. Scanning electron microscopy was performed for visualization. Glucosamine AuNPs at 0.02 mg/mL combined with meropenem at 1 mg/mL showed greater biofilm inhibition (72%) on the endotracheal tube than glucosamine nanoparticles at 0.02 mg/mL alone (26%) (p = 0.001). The scanning electron microscopic visualization revealed that the untreated P. aeruginosa biofilm was denser than the glucosamine nanoparticles-treated biofilm, whether combined with meropenem or using glucosamine nanoparticles alone. The combination of glucosamine AuNPs and meropenem may have the synergistic effect of inhibiting biofilm production of P. aeruginosa on the endotracheal tubes of patients with mechanical ventilation. Conducting additional experiments to explore the impact of combining glucosamine-coated gold nanoparticles (AuNPs) with meropenem on the inhibition of biofilm production by clinical P. aeruginosa isolates would be beneficial.

Repurposing DNase I and alginate lyase to degrade the biofilm matrix of dual-species biofilms of Staphylococcus aureus and Pseudomonas aeruginosa grown in artificial sputum medium: In-vitro assessment of their activity in combination with broad-spectrum antibiotics

BackgroundBiofilm-associated pulmonary infections pose therapeutic challenges in cystic fibrosis patients, especially when involving multiple bacterial species. Enzymatic degradation of the biofilm matrix may offer a potential solution to enhance antibiotic efficacy. This study investigated the repurposing of DNase I, commonly used for its mucolytic activity in cystic fibrosis, to target extracellular DNA within biofilms, as well as potential synergies with alginate lyase and broad-spectrum antibiotics in dual-species biofilms of Pseudomonas aeruginosa and Staphylococcus aureus. MethodsDual-species biofilms were grown in artificial sputum medium using S. aureus and P. aeruginosa isolated by pairs from the same patients and exposed to various combinations of enzymes, meropenem, or tobramycin. Activity was assessed by measuring biofilm biomass and viable counts. Matrix degradation and decrease in bacterial load were visualized using confocal microscopy. Biofilm viscoelasticity was estimated by rheology. ResultsNearly complete destruction of the biofilms was achieved only if combining the enzymatic cocktail with the two antibiotics, and if using supratherapeutic levels of DNase I and high concentrations of alginate lyase. Biofilms containing non-pigmented mucoid P. aeruginosa required higher antibiotic concentrations, despite low viscoelasticity. In contrast, for biofilms with pigmented mucoid P. aeruginosa, a correlation was observed between the efficacy of different treatments and the reduction they caused in elasticity and viscosity of the biofilm. ConclusionsIn this complex, highly drug-tolerant biofilm model, enzymes prove useful adjuvants to enhance antibiotic activity. However, the necessity for high enzyme concentrations emphasizes the need for thorough concentration-response evaluations and safety assessments before considering clinical applications.

The synergic and addictive activity of biogenic silver nanoparticle associated with meropenem against carbapenem-resistant Acinetobacter baumannii.

Antibiotic management of infections caused by Acinetobacter baumannii often fails due to antibiotic resistance (especially to carbapenems) and biofilm-forming strains. Thus, the objective here was to evaluate in vitro the antibacterial and antibiofilm activity of biogenic silver nanoparticle (Bio-AgNP) combined with meropenem, against multidrug-resistant isolates of A. baumannii. In this study, A. baumannii ATCC® 19606™ and four carbapenem-resistant A. baumannii (Ab) strains were used. The antibacterial activity of Bio-AgNP and meropenem was evaluated through broth microdilution. The effect of the Bio-AgNP association with meropenem was determined by the checkboard method. Also, the time-kill assay and the integrity of the bacterial cell membrane were evaluated. Furthermore, the antibiofilm activity of Bio-AgNP and meropenem alone and in combination was determined. Bio-AgNP has antibacterial activity with minimum inhibitory concentration (MIC) and minimum bactericidal concentration ranging from 0.46 to 1.87 μg ml-1. The combination of Bio-AgNP and meropenem showed a synergistic and additive effect against Ab strains, and Bio-AgNP was able to reduce the MIC of meropenem from 4- to 8-fold. Considering the time-kill of the cell, meropenem and Bio-AgNP when used in combination reduced bacterial load to undetectable levels within 10 min to 24 h after treatment. Protein leakage was observed in all treatments evaluated. When combined, meropenem/Bio-AgNP presents biofilm inhibition for Ab2 isolate and ATCC® 19606™, with 21% and 19%, and disrupts the biofilm from 22% to 50%, respectively. The increase in nonviable cells in the biofilm can be observed after treatment with Bio-AgNP and meropenem in carbapenem-resistant A. baumannii strains. The combination of Bio-AgNP with meropenem can be a therapeutic option in the treatment of infections caused by carbapenem-resistant A. baumannii.

Covid-19 Pneumonia Presenting as a ‘Typical Radiological Bronchopneumonia’ Pattern in Clinical-Radiological-Pathological Phenotype with Transient Hyperglycemia

Radiological phenotypes are radiological patterns or observable characteristics of COVID19 pneumonia. Various phenotypic classifications have been reported in literature. CT severity radiological phenotypes are widely used and universally accepted radiological phenotypic methods. Radiological CT severity phenotypic differentiation has documented very crucial role in initial assessment and during triaging of these cases in indoor and outdoor setting. Typical COVID-19 lung parenchymal involvement described as predominant ground glass opacities (GGOs) and consolidations in peripheral and subpleural portion of any lobe, predominantly involving lower lobes. Atypical Radiological patterns in COVID-19 has been documented as bronchopneumonia, multifocal consolidations, necrotizing pneumonia, cavitations with GGOs with or without consolidations. In present case report, 43-year male, presented with acute febrile respiratory illness with acute hypoxic respiratory failure documented as oxygen saturation of 80% at room air with tachypnea and respiratory distress. HRCT thorax was showing Pleural based, peripheral, central, multifocal patchy, confluent & ill-defined GGOs and consolidations in bilateral lung fields in upper, middle and lower lobes. These typical radiological features suggestive of bronchopneumonia like radiological pattern which was very unusual for typical COVID-19 radiology. His laboratory parameters have shown abnormally raised inflammatory markers like CRP, Ferritin, LDH, D-Dimer and IL-6. Importantly, his random blood sugars were raised with abnormally raised HbA1c levels to label as diabetes mellitus. He was diagnosed with diabetes mellitus this time with COVID-19 illness without use of steroids. He was treated with standardized COVID-19 management institutional protocol with combination of low molecular weight heparin, methylprednisolone, remdesivir, meropenem and teicoplanin. Patient required BIPAP support with higher oxygen requirement with nasals canula for one week due to advanced radiological disease with more anatomical involvement. We have documented successful treatment outcome with use of rational treatment in timely by predicting disease severity with use of composite analysis of clinical, laboratory and radiological markers of illness. Transient hyperglycemia is known to occur and reported after COVID-19 illness due to virus induced inflammatory response and pancreatopathy with beta cell dysfunction. Transient hyperglycemia can be easily managed with insulin during hospitalization and oral anti-diabetic agents after discharge for few weeks. Dietary and lifestyle modification will help in majority with complete reversal of abnormally high sugar levels with restoration of normal HbA1c levels to non-diabetic range.