In vitro activity of zidebactam/cefepime (WCK 5222), a ß-lactam enhancer/ ß-lactam combination against carbapenem- and colistin-resistant Klebsiella pneumoniae isolates.

OBJECTIVES: In vitro activity of ß-lactam enhancer/ß-lactam combination zidebactam/cefepime was evaluated against carbapenem- and colistin-resistant Klebsiella pneumoniae isolates. METHODS: Non duplicate K. pneumoniae (n=185), resistant to colistin as well as non-susceptible to carbapenems were collected (2018-2019) at two large tertiary care hospitals in India. Colistin resistance-conferring genes mcr1 and mcr3 were screened among 123 of 185 randomly-selected isolates. These isolates were also subjected to multi-locus sequence typing (MLST). Additionally, alterations in mgrB were screened in 109 of these 123 isolates. All the study isolates were screened for presence of carbapenemases genes. MICs of zidebactam/cefepime, colistin, carbapenems, ceftazidime/avibactam, imipenem/relebactam, amikacin and piperacillin/tazobactam were determined by reference CLSI broth dilution method. RESULTS: Among the isolates, 65.4% (121/185) carried blaOXA-48-like gene and 27.6% isolates (51/185) carried dual carbapenemase genes; blaOXA-48-like and blaNDM. Of the remainder, 8 isolates carried blaNDM and 5 isolates lacked carbapenemases gene despite being carbapenem-resistant. None of the isolates showed presence of mcr1 and mcr3. Out of 109 isolates analysed for mgrB, 36 showed mutational changes. The MLST profile revealed at least 14 unique sequence types with ST231 being the dominant clone. All the isolates showed colistin MICs >2 mg/L and were non-susceptible to carbapenems. Zidebactam/cefepime demonstrated potent activity with MIC50 and MIC90 of 1 and 2 mg/L, respectively. MIC90s of amikacin, ceftazidime/avibactam and imipenem/relebactam were >32 mg/L. CONCLUSION: Zidebactam/cefepime combination was highly active against multi-clonal, carbapenem-non-susceptible and colistin-resistant K. pneumoniae isolates producing OXA-48-like (Ambler class D) or/and NDM (Ambler class B) carbapenemases, thus potentially offering a valuable treatment options for infections caused by such pan-drug resistant resistotypes. Though, zidebactam is not an inhibitor of class B and D ß-lactamases, potent activity of zidebactam/cefepime combination is attributable to ß-lactam enhancer mechanism.

A systematic review and meta-analysis to develop a landscape map of antibiotic resistance for six WHO priority pathogens in east and north-east India from 2011 to 2022.

BACKGROUND: Determining regional patterns of antimicrobial resistance in bacterial infections in the healthcare setting (AMR) identifies surveillance gaps and informs policies for mitigation. We estimated the prevalence of AMR for six WHO priority pathogens in diagnostic and surveillance samples in the twelve east and north-east Indian states from 2011 to 2022 (PROSPERO ID: CRD42021278961). METHODS: Studies were searched on Medline, Scopus, and Web of Science. Observational, descriptive, and cross-sectional studies, reporting AMR based on laboratory diagnostics, in individuals from east and north-east India from 2011 to 2022 were included. Four reviewers in pairs conducted abstract, full-text screening, and data extraction. We estimated the prevalence of resistance in fifty-four pathogen-antibiotic combinations, and six antibiotic resistance patterns. Pooled estimates of prevalence (Ɵ), heterogeneity (I2), and 95 % confidence intervals were calculated using the random effects model. RESULTS: Fifty-five studies were included. Information was available for nine states, none from Arunachal Pradesh, Mizoram, and Nagaland. E. coli was most frequently isolated (59.2 %, 95 % CI: 48.8-69.6 %), followed by S. aureus (36.2 %, 95 % CI: 20.2-52.2 %), Enterococcus (27.5 %, 95 % CI: 11.2-43.7 %), Klebsiella (25 %, 95 % CI: 15-35 %), Acinetobacter (15.7 %, 95 % CI: 2.3-29.1 %), and Pseudomonas aeruginosa (15.7 %, 95 % CI: 4.1-27.3 %). There was high prevalence of ESBL (45 %, 95 % CI: 35-55 %) and carbapenem resistance (30 %, 95 % CI: 22-38 %). AmpC (23 %, 95 % CI: 9-37 %) and colistin resistance was lower (10 %, 95 % CI: 0-22 %) but supporting data was limited. Overall prevalence of MRSA was 26 % (95 % CI: 14-39 %), and VRE was 9 % (95 % CI: 0-17 %). CONCLUSION: High prevalence of resistance was seen to all first-line antibiotics. Gram positive bacteria had high resistance to penicillins, and Gram negatives to third-generation cephalosporins, beta-lactam/beta-lactamase inhibitors, and carbapenems. Aminoglycoside, fluoroquinolone, and trimethoprim-sulphamethoxazole resistance was common across all genera. Critical regional AMR information gaps exist.

Understanding the rationale and clinical impact of the revised CLSI 2024 minocycline susceptibility breakpoints against Stenotrophomonas maltophilia.

Stenotrophomonas maltophilia is challenging to treat due to the presence of multiple intrinsic and acquired resistance mechanisms. TMP-SMZ is the standard care of therapy for treating S. maltophilia infections; levofloxavin and minocycline are the preferred potential alternatives. Recently, in 2024, CLSI has lowered the susceptibility breakpoints for minocycline against S. maltophilia. Applying the revised minocycline's susceptibility breakpoint of ≤ 1 mg/L, susceptibility to minocycline dropped significantly from 77% (previous breakpoint, ≤ 4 mg/L) to 35% (revised breakpoint of ≤ 1 mg/L). In the wake of this change, minocycline's dependency has been questioned for treating S. maltophilia infections.

Current trend of biapenem susceptibility and disc diffusion breakpoints in Enterobacterales and Pseudomonas aeruginosa.

INTRODUCTION: Biapenem has been recently approved by the Drug Controller General of India for the treatment of complicated urinary tract infections (cUTI). However, there are no assessment studies that evaluate the in-vitro activity of biapenem against contemporary ESBL-producing Indian Enterobacterales isolates. To determine the activity of biapenem against contemporary ESBLs and/or OXA-1/ampC producing Enterobacterales and Pseudomonas aeruginosa isolates. METHODOLOGY: Isolates were tested for susceptibility to biapenem and its comparators using the broth microdilution method. Presence of ESBLs (SHV, TEM, CTX-M) genes, OXA-1, and ampC genes (ACC, ACT, DHA, CIT/CMY, FOX) using multiplex PCR. RESULTS: Against ESBL with OXA-1 and/or ampC-producing E. coli, ESBL-K. pneumoniae, and cephalosporin-resistant P. aeruginosa, biapenem showed in-vitro activity similar to that of meropenem. Overall, a biapenem disc concentration of 10 µg provided no error rates for testing E. coli, K. pneumoniae, and P. aeruginosa isolates. CONCLUSION: It is more accurate to test biapenem at a 10 µg disc concentration and apply more stringent disc diffusion breakpoints for interpretation.

Surveillance of ventilator associated pneumonia in a network of indian hospitals using modified definitions: a pilot study.

Background: Ventilator-associated pneumonia (VAP) is a major cause of morbidity and mortality in patients receiving mechanical ventilation in India. Surveillance of VAP is essential to implement data-based preventive measures. Implementation of ventilator-associated events (VAE) criteria for surveillance has major constraints for low resource settings, which can lead to significant underreporting. Surveillance of VAP using common protocols in a large network of hospitals would give meaningful estimates of the burden of VAP in low resource settings. This study leverages a previously established healthcare-associated infections (HAI) surveillance network to develop and test a modified VAP definition adjusted for Indian settings. Methods: In this observational pilot study, thirteen hospitals from the existing HAI surveillance network were selected for developing and testing a modified VAP definition between February 2021 and April 2023. The criteria used for diagnosing VAP were adapted from the CDC's Pediatric VAP definition and modified to cater to the needs of Indian hospitals. Designated nurses recorded each VAP event in a case report form (CRF) and also collected denominator data. The data was entered into an indigenously developed database for validation and analysis. At the time of data analysis, a questionnaire was sent to sites to get feedback on the performance of the modified VAP definitions. Findings: Out of 133,445 patient days and 40,533 ventilator days, 261 VAP events were recorded, with an overall VAP rate of 6.4 per 1000 ventilator days and a device utilization ratio (DUR) of 0.3. A total of 344 organisms were reported from the VAP events. Of these, Acinetobacter spp (29.6%, 102) was the most frequent, followed by Klebsiella spp (26.7%, 92). Isolates of Acinetobacter spp (98%) and Enterobacterales (85.5%) showed very high resistance against Carbapenem. Colistin resistance was observed in 6% of Enterobacterales and 3.2% of Acinetobacter spp. Interpretation: Data from this pilot study needs to validated in the larger Indian HAI surveillance network so that it can help in wider implementation of this protocol in order to assess its applicability p VAP across India. Funding: This work was supported by a grant received from the Indian Council of Medical Research (code I-1203).

Knowledge, attitudes and practices of antimicrobial resistance awareness among healthcare workers in India: a systematic review.

Objectives: The study was conducted to identify and compile gaps in the Knowledge, Attitudes, and Practices (KAP) regarding Antimicrobial Resistance (AMR) among healthcare workers in India. Methods: A systematic review of published literature from PubMed, Google Scholar, and Scopus databases was conducted in compliance with the PRISMA guidelines. The inclusion criteria focused on studies evaluating KAP toward AMR among various healthcare workers in India without restricting context to specific diseases. We included articles published from inception to December 2023. Results: Following the inclusion criterion, 19 studies were selected for the review. The study has a cumulative sample size of 4,544 healthcare providers across India. We found that doctors and medical students have significant knowledge about AMR, followed by nurses and pharmacists. However, the attitudes toward AMR were higher among informal providers, followed by doctors and medical students. The study also observed a gap between theoretical knowledge and practical application of AMR principles among healthcare providers in India. Conclusion: The study highlights the need for targeted training and policy interventions to bridge the gap between KAP regarding AMR. Healthcare providers can significantly contribute to mitigating AMR threat by improving KAP related to AMR. This systematic review provides a foundation for developing and implementing effective evidence-based strategies to enhance AMR containment in India.

Development and validation of a pentaplex PCR assay for rapid detection of blaCTX-M, blaOXA-1, blaCMY, blaNDM and the PBP3 insert in Enterobacterales.

BACKGROUND: There is a high diversity of beta-lactamases in gram negative pathogens, making them difficult to treat. In the presence of OXA-1 and ampC, PTZ is no longer clinically relevant when treating Enterobacterales expressing ESBLs. Further, MBL infections are often treated with the combination of ceftazidime/avibactam with aztreonam. . It has recently been reported that NDM-expressing E. coli isolates co-harboring PBP3 insert develops resistance to this triple combination. METHODS: A pentaplex PCR is developed and validated to simultaneously detect blaCTX-M, blaOXA-1, blaCMY, blaNDM, and the PBP3 insert in whole genome sequenced E. coli and K. pneumoniae isolates. In addition, the isolates chosen for pentaplex PCR evaluation were tested for their minimum inhibitory concentrations (MICs) against piperacillin/tazobactam, cefoperazone/sulbactam (C/S), ertapenem, imipenem, meropenem, ceftazidime/avibactam, aztreonam/avibactam, cefepime/taniborbactam, and cefiderocol. RESULTS: The developed pentaplex PCR showed 100 % reproducibility with the antimicrobial resistance profile generated from whole genome sequenced data. PTZ and C/S are not effective against ESBL and/or OXA-1 expressing E. coli and K. pneumoniae isolates and do not offer any activity against CMY co-producers. Further, the combined effect of CMY, NDM and PBP3 inserts impacts aztreonam/avibactam activity and reduces the susceptibility to 40 % in E. coli isolates. While, aztreonam/avibactam showed potent activity against NDM-expressing K. pneumoniae isolates. Importantly, cefepime/taniborbactam and cefiderocol showed limited activity against NDM-expressing E. coli and K. pneumoniae isolates. CONCLUSION: The pentaplex PCR was effective in detecting four beta-lactamases (blaCTX-M, blaOXA-1, blaCMY, blaNDM) as well as PBP3 inserts. It is expected that using pentaplex PCR as a diagnostic test for resistance detection in clinical practice will improve patient outcomes by providing prompt and targeted treatment.

Prolonged treatment of dermatophytosis caused by Trichophyton indotinea with terbinafine or itraconazole impacts better outcomes irrespective of mutation in the squalene epoxidase gene.

BACKGROUND: Over the past decades, the increasing incidence of recurrent dermatophytosis associated with terbinafine-resistant Trichophyton has posed a serious challenge in management of dermatophytosis. Independent reports of failure of treatment and high minimum inhibitory concentrations (MIC) of antifungals are available, but data correlating MIC and clinical outcomes is still sparse. Therefore, the present study was conducted to evaluate the outcomes of systemic treatment of dermatophytosis and its correlation with MIC of the etiological agents isolated from such patients. METHODS: Retrospective analysis of 587 consecutive patients with dermatophytosis was done from March 2017 to March 2019. Demographic and clinical details of the patients were noted, along with the results of direct microscopy and fungal culture. The isolates were identified by sequencing the internal transcribed spacer region of rDNA. Antifungal susceptibility testing was performed following the CLSI M38 protocol. Mutation in the squalene epoxidase (SE) gene was detected by DNA sequencing and ARMS-PCR. Based on the culture-positivity and prescribed systemic antifungal, patients were categorised into Group I culture-positive cases treated with systemic terbinafine and Group II culture-positive cases treated with systemic itraconazole, each for a total period of 12 weeks. RESULTS: In the present study, 477 (81.39%) were culture-positive; however, 12 weeks follow-up was available for 294 patients (Group I-157 and Group II-137) who were included for statistical analysis. In both groups [Group I-37/63 (51.4%) and Group II-14/54 (58.3%)], a better cure rate was observed if the initiation of therapy was performed within <6 months of illness. Treatment outcome revealed that if therapy was extended for 8-12 weeks, the odds of cure rate are significantly better (p < .001) with either itraconazole (Odd Ratio-15.5) or terbinafine (Odd Ratio-4.34). Higher MICs for terbinafine were noted in 41 cases (cured-18 and uncured-23) in Group I and 39 cases (cured-16 and uncured-23) in Group II. From cured (Group I-17/18; 94.4% and Group II-14/16; 87.5%) and uncured (Group I-20/23; 86.9% and Group II-21/23; 91.3%) cases had F397L mutation in the SE gene. No significant difference in cure rate was observed in patients with Trichophyton spp. having terbinafine MIC ≥ 1or <1 µg/mL (Group I-p = .712 and Group II-p = .69). CONCLUSION: This study revealed that prolonging terbinafine or itraconazole therapy for beyond 8 weeks rather than the standard 4 weeks significantly increases the cure rate. Moreover, no correlation has been observed between antifungal susceptibility and clinical outcomes. The MIC remains the primary parameter for defining antifungal activity and predicting the potency of antifungal agents against specific fungi. However, predicting therapeutic success based solely on the MIC of a fungal strain is not always reliable, as studies have shown a poor correlation between in vitro data and in vivo outcomes. To address this issue, further correlation of antifungal susceptibility testing (AFST) data with clinical outcomes and therapeutic drug monitoring is needed. It also highlights that initiation of the treatment within <6 months of illness increases cure rates and reduces recurrence. Extensive research is warranted to establish a better treatment regime for dermatophytosis.

Evolutionary transition of hypervirulent Klebsiella pneumoniae to multidrug-resistant hypervirulent Klebsiella pneumoniae: Indian experience.

An emerging pathotype of Klebsiella pneumoniae, initially identified in Southeast Asian countries, has now spread to multiple countries, including India. These convergent strains, carrying both resistance and virulence determinants, are classified as multidrug-resistant Hypervirulent Klebsiella pneumoniae (MDR-HvKp). Since the initial reports, there has been a concerning surge in infections caused by this pathotype globally. In this context, we aim to shed light on the evolutionary changes that have taken place in this relatively novel pathotype. Understanding these changes is crucial for devising diagnosis and targeted intervention strategies to mitigate the spread of MDR-HvKp infections.

Social and biological evaluation of antimicrobial resistance (SOBEAR) in rural India: a study protocol.

Background: Antimicrobial resistance (AMR) has been one of the biggest global health threats in recent years, mostly in low- and middle-income countries, which requires urgent research using a multidisciplinary research approach. The use of large quantities of antimicrobial drugs inappropriately for humans, poultry and agriculture has been recognized as a leading cause of antibiotic resistance and the predominance of drug-resistance pathogens in the environment. This protocol aims to describe the use/misuse of antibiotics (ABs) in the community and evaluate clinical samples from healthcare settings to detect genes associated with antimicrobial resistance. Methods: We will conduct a community-level survey in different villages of the Tigiria block to assess knowledge and awareness on ABs and AMR. We will conduct in-depth interviews (IDIs) with doctors, pharmacists, nurses and drug sellers, as well as focus group discussions (FGDs) with ASHA and ANM workers who are involved in antibiotic supplies to the community. Quantitative data from the community survey and qualitative data of IDIs and FGDs will be linked and analyzed using statistical modeling and iterative thematic content analysis. Specimens (stool, urine, blood and wound/pus) will be collected from clinically diagnosed patients of different healthcare centers of Tigiria block. The samples will be cultured for bacterial isolation and antibiotic sensitivity testing. Genomic DNA will be isolated from positive bacterial cultures and sequenced using PCR to evaluate high-threat multi-drug resistance organisms (MDROs), screening of plasmid-mediated quinolone resistance (PMQR) genes, antimicrobial genes responsible for MDR and quinolone resistance-determining regions (QRDRs). Conclusion: This is the community-based protocol to evaluate the knowledge, attitudes, awareness and practices regarding ABs and AMR. The study protocol establishes a foundation for evaluating population-based prevalence and risk factors for AMR and MDROs in rural areas of the Odisha state, India.

Genomic investigation unveils colistin resistance mechanism in carbapenem-resistant Acinetobacter baumannii clinical isolates.

Colistin resistance in Acinetobacter baumannii is mediated by multiple mechanisms. Recently, mutations within pmrABC two-component system and overexpression of eptA gene due to upstream insertion of ISAba1 have been shown to play a major role. Thus, the aim of our study is to characterize colistin resistance mechanisms among the clinical isolates of A. baumannii in India. A total of 207 clinical isolates of A. baumannii collected from 2016 to 2019 were included in this study. Mutations within lipid A biosynthesis and pmrABC genes were characterized by whole-genome shotgun sequencing. Twenty-eight complete genomes were further characterized by hybrid assembly approach to study insertional inactivation of lpx genes and the association of ISAba1-eptA. Several single point mutations (SNPs), like M12I in pmrA, A138T and A444V in pmrB, and E117K in lpxD, were identified. We are the first to report two novel SNPs (T7I and V383I) in the pmrC gene. Among the five colistin-resistant A. baumannii isolates where complete genome was available, the analysis showed that three of the five isolates had ISAba1 insertion upstream of eptA. No mcr genes were identified among the isolates. We mapped the SNPs on the respective protein structures to understand the effect on the protein activity. We found that majority of the SNPs had little effect on the putative protein function; however, some SNPs might destabilize the local structure. Our study highlights the diversity of colistin resistance mechanisms occurring in A. baumannii, and ISAba1-driven eptA overexpression is responsible for colistin resistance among the Indian isolates.IMPORTANCEAcinetobacter baumannii is a Gram-negative, emerging and opportunistic bacterial pathogen that is often associated with a wide range of nosocomial infections. The treatment of these infections is hindered by increase in the occurrence of A. baumannii strains that are resistant to most of the existing antibiotics. The current drug of choice to treat the infection caused by A. baumannii is colistin, but unfortunately, the bacteria started to show resistance to the last-resort antibiotic. The loss of lipopolysaccharides and mutations in lipid A biosynthesis genes are the main reasons for the colistin resistance. The present study characterized 207 A. baumannii clinical isolates and constructed complete genomes of 28 isolates to recognize the mechanisms of colistin resistance. We showed the mutations in the colistin-resistant variants within genes essential for lipid A biosynthesis and that cause these isolates to lose the ability to produce lipopolysaccharides.

Diagnostic validation study of rapid urinary tract infection diagnosis kit at peripheral health facilities of West Bengal, India.

Patients reporting to the outpatient departments of peripheral health care settings in India with symptoms of urinary tract infection (UTI) receive one or the other antibiotic before culture confirmation and out of the total culture confirmed UTI cases, in less than one third cases the prescribed antibiotics matches to the antibiotic sensitivity test result. Hence, in this study, an indigenous point-of-care (POCT) rapid diagnostic kit (Rapidogram) for UTI was validated against conventional urine culture and sensitivity to understand its possible applicability at peripheral health care settings. This cross-sectional study was conducted during November 2021 to June 2022 in OPDs of two peripheral hospitals. A sample size of 300 was calculated using prevalence of urinary tract infection (UTI) as 33% for sensitivity and specificity using Buderer's formula. Urine specimens were collected following standard aseptic procedures from the recruited suspected UTI cases and transferred to laboratory maintaining the cold chain. The validation work up was done in two sections: lab validation and field validation. Out of 300 urine samples, 29 were found positive for the growth of UTI pathogen by both methods and 267 were found negative by both methods. Thus, the kit shows very high specificity (99.6%; 97.9-99.9%) and considerably high sensitivity (90.6%; 74.9-98.0%). We also observed higher PPV, NPV, test accuracy (> 96%). Diagnostic Odds Ratio and Youden index were respectively 2581 and 0.89. Clinical data showed that 44% of the suspected UTI cases were prescribed at least one antibiotic before urine test. Mostly they received Norfloxacin whereas the mostly identified organism E.coli was sensitive to Nitrofurantoin. In the context of absence of microbiology facility at peripheral setting and rampant empirical use of antibiotics in UTI, this highly specific and sensitive POCT for UTI may be used as it not only identifies the organism, also shows the antibiotic sensitivity pattern.

Antimicrobial resistance and the great divide: inequity in priorities and agendas between the Global North and the Global South threatens global mitigation of antimicrobial resistance.

To limit the catastrophic effects of the increasing bacterial resistance to antimicrobials on health, food, environmental, and geopolitical security, and ensure that no country or region is left behind, a coordinated global approach is required. In this Viewpoint, we argue that the diverging resource availabilities, needs, and priorities of the Global North and the Global South in terms of the actions required to mitigate the antimicrobial resistance pandemic are a direct threat to success. We argue that evidence suggests a need to prioritise and support infection prevention interventions (ie, clean water and safe sanitation, increased vaccine coverage, and enhanced infection prevention measures for food production in the Global South contrary to the focus on research and development of new antibiotics in the Global North) and to recalibrate global funding resources to address this need. We call on global leaders to redress the current response, which threatens mitigation of the antimicrobial resistance pandemic.

Evidence review and recommendations for the implementation of genomics for antimicrobial resistance surveillance: reports from an international expert group.

Nearly a century after the beginning of the antibiotic era, which has been associated with unparalleled improvements in human health and reductions in mortality associated with infection, the dwindling pipeline for new antibiotic classes coupled with the inevitable spread of antimicrobial resistance (AMR) poses a major global challenge. Historically, surveillance of bacteria with AMR typically relied on phenotypic analysis of isolates taken from infected individuals, which provides only a low-resolution view of the epidemiology behind an individual infection or wider outbreak. Recent years have seen increasing adoption of powerful new genomic technologies with the potential to revolutionise AMR surveillance by providing a high-resolution picture of the AMR profile of the bacteria causing infections and providing real-time actionable information for treating and preventing infection. However, many barriers remain to be overcome before genomic technologies can be adopted as a standard part of routine AMR surveillance around the world. Accordingly, the Surveillance and Epidemiology of Drug-resistant Infections Consortium convened an expert working group to assess the benefits and challenges of using genomics for AMR surveillance. In this Series, we detail these discussions and provide recommendations from the working group that can help to realise the massive potential benefits for genomics in surveillance of AMR.

Molecular mechanisms of colistin- and multidrug-resistance in bacteria among patients with hospital-acquired infections.

Aim: The increasing burden of resistance in Gram-negative bacteria (GNB) is becoming a major issue for hospital-acquired infections. Therefore, understanding the molecular mechanisms is important. Methodology: Resistance genes of phenotypically colistin-resistant GNB (n = 60) were determined using whole genome sequencing. Antimicrobial susceptibility patterns were detected by Vitek®2 & broth microdilution. Results: Of these phenotypically colistin-resistant isolates, 78% were also genetically resistant to colistin. Activation of efflux pumps, and point-mutations in pmrB, and MgrB genes conferred colistin resistance among GNB. Eight different strains of K. pneumoniae were identified and ST43 was the most prominent strain with capsular type-specific (cps) gene KL30. Discussion: These results, in combination with rapid diagnostic methods, will help us better advice appropriate antimicrobial regimens.

Loss of exclusivity of ceftazidime/avibactam in low- and middle-income countries: a test for antibiotic stewardship practice.

Ceftazidime/avibactam is a last-line antibiotic, to be used as a targeted therapy for certain carbapenem-resistant Gram-negative infections and not to be used as an empirical therapy or as a carbapenem-sparing therapy. After a span of 5 years, the antibiotic recently lost its exclusivity and become a generic drug in India. It is assumed that generic players will aggressively market the drug, making it freely available even in pharmacies catering to primary- and secondary-care hospitals. We thus foresee certain potential adverse implications of introducing generic versions of ceftazidime/avibactam into the Indian market; as they will be a challenge to the antibiotic stewardship. In the real world scenario, the stewardship system in India is fragile, therefore, we may see empirical use of ceftazidime/avibactam even in primary and secondary-care hospitals. The existing widespread prevalence of MBL-producing isolates in India, will be further enhanced by the indiscriminate use of ceftazidime/avibactam.

Determination of potential combination of non-ß-lactam, ß-lactam, and ß-lactamase inhibitors/ß-lactam enhancer against class D oxacillinases producing Acinetobacter baumannii: Evidence from in-vitro, molecular docking and dynamics simulation.

Carbapenem-resistant Acinetobacter baumannii, a predominant nosocomial pathogen in hospitals of intensive care units, is associated with bacteremia and ventilator-associated pneumonia with a high-risk mortality rate. To increase the effectiveness of the ß-lactam (BL) antibiotics, the use of ß-lactamase inhibitors (BLI) acts as a booster when given in combination with BL antibiotics. To this aspect, we selected BL antibiotics of cefiderocol, cefepime, non-BL antibiotic eravacycline, BLI of durlobactam, avibactam, and a ß-lactam enhancer (BLE) of zidebactam. To prove our hypothesis, we determined the minimum inhibitory concentration (MIC) of various BL or non-BL/BLI or BLE combinations using broth microdilution method followed by in silico analysis of molecular docking, molecular dynamics (MD) simulation, and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) identifies the potential combination. In MIC testing, eravacycline, cefepime/zidebactam, cefiderocol/zidebactam, and eravacycline in combination with zidebactam or durlobactam were found to be effective against oxacillinases (OXAs) (OXA-23/24/58 like) expressing A. baumannii isolates. The docking results of the selected ligands toward OXA-23, OXA-24, and OXA-58 had an excellent binding score ranging from -5.8 to -9.3 kcal/mol. Further, the docked complexes were subjected and evaluated using gromacs for molecular dynamics simulation of 50 ns toward selected class D OXAs. The binding energies obtained from MM-PBSA shed light on the binding efficiencies of each non-BL, BL, and BLI/BLE, thereby helping us to propose the drug combinations. Based on the MD trajectories scoring acquired, we propose using eravacycline, cefepime/zidebactam, cefiderocol/zidebactam, and eravacycline in combination with durlobactam or zidebactam would be promising for treating OXA-23, OXA-24, and OXA-58 like expressing A. baumannii infections.

How can lessons from the COVID-19 pandemic enhance antimicrobial resistance surveillance and stewardship?

COVID-19 demanded urgent and immediate global attention, during which other public health crises such as antimicrobial resistance (AMR) increased silently, undermining patient safety and the life-saving ability of several antimicrobials. In 2019, WHO declared AMR a top ten global public health threat facing humanity, with misuse and overuse of antimicrobials as the main drivers in the development of antimicrobial-resistant pathogens. AMR is steadily on the rise, especially in low-income and middle-income countries across south Asia, South America, and Africa. Extraordinary circumstances often demand an extraordinary response as did the COVID-19 pandemic, underscoring the fragility of health systems across the world and forcing governments and global agencies to think creatively. The key strategies that helped to contain the increasing SARS-CoV-2 infections included a focus on centralised governance with localised implementation, evidence-based risk communication and community engagement, use of technological methods for tracking and accountability, extensive expansion of access to diagnostics, and a global adult vaccination programme. The extensive and indiscriminate use of antimicrobials to treat patients, particularly in the early phase of the pandemic, have adversely affected AMR stewardship practices. However, there were important lessons learnt during the pandemic, which can be leveraged to strengthen surveillance and stewardship, and revitalise efforts to address the AMR crisis.