Lessons learned from an external quality assurance program in applying CLSI interpretive criteria for reporting piperacillin/tazobactam susceptibility.

We evaluated the performance of automated susceptibility testing for piperacillin/tazobactam (PTZ) MICs against the reference microbroth dilution method. The Minimum Inhibitory Concentration of PTZ against a clinical isolate of Klebsiella pneumoniae was determined by reference broth micro-dilution method in 10 replicates which yielded a modal MIC of 16 mg/L (susceptible dose-dependent). Out of 434 laboratories who obtained MIC of 16 mg/L correctly, only 301 interpreted the result as susceptible dose dependent as per 2022 revised CLSI criteria. Educating the clinical laboratories in validating AST methods as per latest CLSI guidelines is of utmost important.

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.

Transcending the challenge of evolving resistance mechanisms in Pseudomonas aeruginosa through ß-lactam-enhancer-mechanism-based cefepime/zidebactam.

Multi-drug resistant (MDR) Pseudomonas aeruginosa harbor a complex array of ß-lactamases and non-enzymatic resistance mechanisms. In this study, the activity of a ß-lactam/ß-lactam-enhancer, cefepime/zidebactam, and novel ß-lactam/ß-lactamase inhibitor combinations was determined against an MDR phenotype-enriched, challenge panel of P. aeruginosa (n = 108). Isolates were multi-clonal as they belonged to at least 29 distinct sequence types (STs) and harbored metallo-ß-lactamases, serine ß-lactamases, penicillin binding protein (PBP) mutations, and other non-enzymatic resistance mechanisms. Ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/relebactam, and cefepime/taniborbactam demonstrated MIC90s of >128 mg/L, while cefepime/zidebactam MIC90 was 16 mg/L. In a neutropenic-murine lung infection model, a cefepime/zidebactam human epithelial-lining fluid-simulated regimen achieved or exceeded a translational end point of 1-log10 kill for the isolates with elevated cefepime/zidebactam MICs (16-32 mg/L), harboring VIM-2 or KPC-2 and alterations in PBP2 and PBP3. In the same model, to assess the impact of zidebactam on the pharmacodynamic (PD) requirement of cefepime, dose-fractionation studies were undertaken employing cefepime-susceptible P. aeruginosa isolates. Administered alone, cefepime required 47%-68% fT >MIC for stasis to ~1 log10 kill effect, while cefepime in the presence of zidebactam required just 8%-16% for >2 log10 kill effect, thus, providing the pharmacokinetic/PD basis for in vivo efficacy of cefepime/zidebactam against isolates with MICs up to 32 mg/L. Unlike ß-lactam/ß-lactamase inhibitors, ß-lactam enhancer mechanism-based cefepime/zidebactam shows a potential to transcend the challenge of ever-evolving resistance mechanisms by targeting multiple PBPs and overcoming diverse ß-lactamases including carbapenemases in P. aeruginosa.IMPORTANCECompared to other genera of Gram-negative pathogens, Pseudomonas is adept in acquiring complex non-enzymatic and enzymatic resistance mechanisms thus remaining a challenge to even novel antibiotics including recently developed ß-lactam and ß-lactamase inhibitor combinations. This study shows that the novel ß-lactam enhancer approach enables cefepime/zidebactam to overcome both non-enzymatic and enzymatic resistance mechanisms associated with a challenging panel of P. aeruginosa. This study highlights that the ß-lactam enhancer mechanism is a promising alternative to the conventional ß-lactam/ß-lactamase inhibitor approach in combating ever-evolving MDR P. aeruginosa.

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.

Compassionate use of a novel ß-lactam enhancer-based investigational antibiotic cefepime/zidebactam (WCK 5222) for the treatment of extensively-drug-resistant NDM-expressing Pseudomonas aeruginosa infection in an intra-abdominal infection-induced sepsis patient: a case report.

Infections in critically-ill patients caused by extensively-drug-resistant (XDR)-Pseudomonas aeruginosa are challenging to manage due to paucity of effective treatment options. Cefepime/zidebactam, which is currently in global Phase 3 clinical development (Clinical Trials Identifier: NCT04979806, registered on July 28, 2021) is a novel mechanism of action based ß-lactam/ ß-lactam-enhancer combination with a promising activity against a broad-range of Gram-negative pathogens including XDR P. aeruginosa. We present a case report of an intra-abdominal infection-induced sepsis patient infected with XDR P. aeruginosa and successfully treated with cefepime/zidebactam under compassionate use. The 50 year old female patient with past-history of bariatric surgery and recent elective abdominoplasty and liposuction developed secondary pneumonia and failed a prolonged course of polymyxins. The organism repeatedly isolated from the patient was a New-Delhi metallo ß-lactamase-producing XDR P. aeruginosa resistant to ceftazidime/avibactam, imipenem/relebactam and ceftolozane/tazobactam, susceptible only to cefepime/zidebactam. As polymyxins failed to rescue the patient, cefepime/zidebactam was administered under compassionate grounds leading to discharge of patient in stable condition. The present case highlights the prevailing precarious scenario of antimicrobial resistance and the need for novel antibiotics to tackle infections caused by XDR phenotype pathogens.

ß-Lactam Resistance in ESKAPE Pathogens Mediated Through Modifications in Penicillin-Binding Proteins: An Overview.

Bacteria acquire ß-lactam resistance through a multitude of mechanisms among which production of ß-lactamases (enzymes that hydrolyze ß-lactams) is the most common, especially in Gram-negatives. Structural changes in the high-molecular-weight, essential penicillin-binding proteins (PBPs) are widespread in Gram-positives and increasingly reported in Gram-negatives. PBP-mediated resistance is largely achieved by accumulation of mutation(s) resulting in reduced binding affinities of ß-lactams. Herein, we discuss PBP-mediated resistance among ESKAPE pathogens that cause diverse hospital- and community-acquired infections globally.

Can fosfomycin be an alternative therapy for infections caused by E. coli harbouring dual resistance: NDM and four-amino acid insertion in PBP3?

NDM-expressing Escherichia coli infections are challenging to treat, due to limited treatment options. E. coli with four-amino acid inserts (YRIN/YRIK) are also common in India and it has been reported to reduce the susceptibility to aztreonam/avibactam and the clinically used triple combination ceftazidime/avibactam with aztreonam. Thus, there is a severe dearth of antibiotics to treat infections of NDM + PBP3 insert E. coli. In this study, we determined the susceptibility of E. coli with NDM and PBP3 insert to fosfomycin as an alternative option to treat serious infections. Non-duplicate well-characterized NDM-expressing (without or with co-expression of OXA-48-like) E. coli isolates (n = 213) subsequently carrying four-amino acid inserts in PBP3 were included in this study. MICs of fosfomycin were determined by the agar dilution method with glucose-6-phosphate supplementation, while for other comparators the broth microdilution method was used. Collectively, 98% of NDM-expressing E. coli isolates with PBP3 insert were susceptible to fosfomycin at the MIC of ≤32 mg/L. Resistance to aztreonam was noticed in 38% of the tested isolates. Putting together fosfomycin's in vitro activity, clinical efficacy and safety in randomized controlled trials, we conclude that fosfomycin could be considered as an alternative option to treat infections caused by E. coli harbouring NDM and PBP3 insert resistance mechanisms.

Enhanced bacterial killing with a combination of sulbactam/minocycline against dual carbapenemase-producing Acinetobacter baumannii.

Carbapenem-resistant Acinetobacter baumannii (CRAB) is often difficult to treat. Considering the current circumstances, there is an unquestionable need for new therapeutic options to treat CRAB infections. In the present study, the synergistic activity of sulbactam-based combination was determined against genetically characterized CRAB isolates. Non-duplicate CRAB isolates (n = 150) recovered from blood culture and endotracheal aspirates were included in this study. The minimum inhibitory concentrations (MICs) of tetracyclines (minocycline, tigecycline, eravacycline) and their comparators (meropenem, sulbactam, cefoperazone/sulbactam, ceftazidime/avibactam, and colistin) were determined using the microbroth dilution method. Six isolates were tested for the synergistic activity of various sulbactam-based combinations using time-kill experiments. Tigecycline and minocycline showed a wide spread of MICs with most isolates in the range of 1 to 16 mg/L. The MIC90 of eravacycline (0.5 mg/L) was four dilutions lower than that of tigecycline (8 mg/L). Minocycline with sulbactam was the most active dual combination against OXA-23 like (n = 2) and NDM with OXA-23 like producers (n = 1), which resulted in ≥ 2 log10 kill. The combination of ceftazidime-avibactam with sulbactam showed ≥ 3 log10 kill against all the three tested OXA-23 like producing CRAB isolates, but showed no activity against dual carbapenemase producers. Sulbactam with meropenem showed ≥ 2 log10 kill against one OXA-23 like producing CRAB isolate. The findings suggest that sulbactam-based combination may confer therapeutic benefits against CRAB infections.

In Vitro Activity of Two Cefepime-Based Novel Combinations, Cefepime/Taniborbactam and Cefepime/Zidebactam, against Carbapenemase-Expressing Enterobacterales Collected in India.

In recent times, discovery efforts for novel antibiotics have mostly targeted carbapenemase-producing Gram-negative organisms. Two different combination approaches are pertinent: ß-lactam-ß-lactamase inhibitor (BL/BLI) or ß-lactam-ß-lactam enhancer (BL/BLE). Cefepime combined with a BLI, taniborbactam, or with a BLE, zidebactam, has been shown to be promising. In this study, we determined the in vitro activity of both these agents along with comparators against multicentric carbapenemase-producing Enterobacterales (CPE). Nonduplicate CPE isolates of Escherichia coli (n = 270) and Klebsiella pneumoniae (n = 300), collected from nine different tertiary-care hospitals across India during 2019 to 2021, were included in the study. Carbapenemases in these isolates were detected by PCR. E. coli isolates were also screened for the presence of the 4-amino-acid insert in penicillin binding protein 3 (PBP3). MICs were determined by reference broth microdilution. Higher MICs of cefepime/taniborbactam (>8 mg/L) were linked to NDM, both in K. pneumoniae and in E. coli. In particular, such higher MICs were observed in 88 to 90% of E. coli isolates producing NDM and OXA-48-like or NDM alone. On the other hand, OXA-48-like-producing E. coli or K. pneumoniae isolates were nearly 100% susceptible to cefepime/taniborbactam. Regardless of the carbapenemase types and the pathogens, cefepime/zidebactam showed potent activity (>99% inhibited at ≤8 mg/L). It seems that the 4-amino-acid insert in PBP3 (present universally in the study E. coli isolates) along with NDM adversely impact the activity of cefepime/taniborbactam. Thus, the limitations of the BL/BLI approach in tackling the complex interplay of enzymatic and nonenzymatic resistance mechanisms were better revealed in whole-cell studies where the activity observed was a net effect of ß-lactamase inhibition, cellular uptake, and target affinity of the combination. IMPORTANCE The study revealed the differential ability of cefepime/taniborbactam and cefepime/zidebactam in tackling carbapenemase-producing Indian clinical isolates that also harbored additional mechanisms of resistance. NDM-expressing E. coli with 4-amino-acid insert in PBP3 are predominately resistant to cefepime/taniborbactam, while the ß-lactam enhancer mechanism-based cefepime/zidebactam showed consistent activity against single- or dual-carbapenemase-producing isolates including E. coli with PBP3 inserts.

Genomics and structural insight into the masking of gentamicin-resistance in clinical Burkholderia pseudomallei strain VB29710 from India.

The present study reported a rare gentamicin-susceptible ß-lactamase (PenA, OXA-57) expressing clinical Burkholderia pseudomallei isolate VB29710 from India. Whole-genome sequencing and structural analyses revealed the insertion of R962 and L963 into AmrB, the transmembrane-protein of the AmrAB-OprA efflux-pump that affected aminoglycoside-efflux through local alterations in backbone conformation.

India-discovered levonadifloxacin & alalevonadifloxacin: A review on susceptibility testing methods, CLSI quality control and breakpoints along with a brief account of their emerging therapeutic profile as a novel standard-of-care.

BACKGROUND: Levonadifloxacin (intravenous) and alalevonadifloxacin (oral prodrug) are novel antibiotics based on benzoquinolizine subclass of fluoroquinolone, licensed for clinical use in India in 2019. The active moiety, levonadifloxacin, is a broad-spectrum antibiotic with a high potency against methicillin-resistant Staphylococcus. aureus, multi-drug resistant pneumococci and anaerobes. OBJECTIVE: This review, for the first time, critically analyses the antimicrobial susceptibility testing methods, Clinical Laboratory & Standards Institute (CLSI)-quality control of susceptibility testing and breakpoints of levonadifloxacin. Further, the genesis, discovery and developmental aspects as well as therapeutic profile of levonadifloxacin and alalevonadifloxacin are briefly described. CONTENTS: In order to aid the scientific and clinician communities with a single comprehensive overview on all the key aspects of levonadifloxacin and alalevonadifloxacin, the present article covers the reference MIC and disk diffusion methods for levonadifloxacin susceptibility testing that were approved by CLSI and the reference ranges for quality control strains published in the CLSI M100 document. The breakpoints of levonadifloxacin were derived in concordance to US FDA, European Committee on Antibiotic Susceptibility Testing (EUCAST) and CLSI approaches. Further, the article provides a brief account of challenges encountered during the discovery stages of levonadifloxacin and alalevonadifloxacin, activity spectrum and safety benefits accruing from structural novelty-linked mechanism of action. Further, the review also covers in vitro and in vivo activities, registrational clinical studies and patient-friendly features of levonadifloxacin/alalevonadifloxacin. Cumulatively, levonadifloxacin has a potential to offer a long awaited new standard-of-care treatment for the resistant Gram-positive bacterial infections.

Lack of Association of Helicobacter pylori in Laryngeal Pathologies.

To study the association of Helicobacter pylori (H. pylori) in patients with laryngeal pathologies. Study design: prospective observational study. Tertiary care teaching hospital. One hundred consecutive patients with laryngeal lesions scheduled for microlaryngoscopy were enrolled in the study. Laryngopharyngeal reflux was assessed using the reflux symptom index and reflux finding score. Tissue samples from the laryngeal lesions were taken under general anaesthesia and were screened for the presence of H. pylori using real time polymerase chain reaction (PCR) for ureA genes and histopathological examination. Of the 100 patients, 14 had a significant reflux symptom index score and 35 had significant reflux finding score. The lesions in the study subjects included both benign and malignant laryngeal pathologies. Vocal cord polyps formed more than half of the laryngeal pathology (57%) studied. Our study could not detect H. pylori in any laryngeal lesions by PCR analysis and histopathological examination. H. pylori may not be associated with laryngeal pathologies.

Skin Colonizers and Catheter Associated Blood Stream Infections in Incident Indian Dialysis Patients.

Introduction: Skin colonization is a risk factor for multi-drug resistant (MDR) catheter-associated bloodstream infections (CABSI). This study aimed to determine the prevalence and spectrum of skin colonizing MDR organisms in incident HD patients and their correlation with CABSI. Methods: This single-center prospective cohort study included consecutive adult incident HD patients who underwent tunneled or non-tunneled internal jugular vein HD catheter insertion between June 1, 2017 and October 31, 2017. Nasal, axillary, and exit site swabs were obtained prior to catheter insertion, at 14-21 days, and 28-35 days after catheter insertion. Results: Forty-three patients (69.7% male, 32.5% diabetic) were included and provided baseline swabs, while 29 and 10 patients respectively were available for follow-up swabs. MDR bacterial colonization, MRSA colonization, and MDR gram-negative colonization on the baseline set of swabs were seen in 76.7%, 69.7%, and 9.3% patients respectively. Of the 29 patients with at least two consecutive sets of swabs, 79.3% showed persistent colonization by MDR gram-positive organisms, most commonly by MRSA. Six patients developed a CABSI during the follow-up period (incidence rate 3.7 per 1000 patient days), 83.4% were gram negative, and in only one instance (16.6%) was the bacterial strain identical to that which had previously colonized the skin. Conclusions: Three-fourths of HD patients were colonized by MDR bacteria prior to HD initiation. Despite the majority being persistently colonized by MDR gram-positive organisms, CABSIs were predominantly gram negative.

Novel linear plasmids carrying vanA cluster drives the spread of vancomycin resistance in Enterococcus faecium in India.

OBJECTIVES: The genetic basis for the spread of vancomycin resistance in Enterococcus faecium is largely unexplored in India. The present study aimed to investigate the plasmid diversity and variation of Tn1546 associated with vanA harbouring VREfm isolates. METHODS: A total of 122 VREfm isolates collected from blood cultures were included in this study. MLST analysis was performed on all isolates, and they were also screened for the presence of vanA and vanB genes. Whole genome sequencing was performed for a subset of fifteen VREfm isolates belonging to ST1643. RESULTS: All of the 122 VREfm isolates carried the vanA gene. Twenty-four different sequence types were seen; of these, ST1643, ST80 and ST17 were predominant. Whole genome sequencing was performed on 15 VREfm isolates belonging to ST1643. For eight isolates the vanA gene was found on pRUM-like circular plasmids, and for the remaining seven isolates, the vanA gene was found on the linear plasmids. Novel Tn1546 variants carrying vanA were found on both circular and linear plasmids. Interestingly, co-presence of vanA and optrA were seen in the backbone of three linear plasmids. CONCLUSION: Multiple vanA-carrying plasmids and Tn1546-like elements were involved in the dissemination of vancomycin resistance in VREfm. The co-occurrence of Tn1546 carrying vanA and Tn554 family transposon carrying optrA on the backbone of plasmids is worrisome. The dissemination of such plasmids may pose treatment and infection control challenges.

In vitro activity of Ceftazidime-Avibactam and its comparators against Carbapenem resistant Enterobacterales collected across India: results from ATLAS surveillance 2018 to 2019.

ATLAS (Antimicrobial Testing Leadership and Surveillance) detects trends in multi-drug resistance longitudinally over time. In the present study, the in vitro activity of ceftazidime-avibactam and comparators was analyzed against Escherichia coli (n = 458) and Klebsiella pneumoniae (n = 455)  isolates obtained from 9 centers across India. The overall susceptibility to ceftazidime-avibactam was observed to be 72% among K. pneumoniae isolates and 87% among E. coli isolates. Among the tested carbapenem resistant isolates, 51% of CR-K. pneumoniae and 24% of CR-E. coli were susceptible to ceftazidime- avibactam. OXA-48 like was identified in 52% of the K. pneumoniae isolates followed by co-production of NDM with OXA-48 like in 27%. NDM was predominantly identified in 68% of the E. coli isolates followed by OXA-48 like in 24% isolates. The findings suggest that ceftazidime- avibactam is a reasonable alternative to standard therapy for management of carbapenem resistant Enterobacterales infections particularly with K. pneumoniae and E. coli with the OXA-48 like genotype.

Clinical efficacy of novel combinations of older beta-lactam and beta-lactamase inhibitors: Where are the evidences?

India is well known for the rampant growth of ESBLs that jeopardized the clinical utility of standalone beta-lactam. Pharmaceutical organizations fancied to rescue these beta-lactams by combining them with generic beta-lactamase inhibitors despite such combinations were never investigated in non-clinical or clinical studies. Lack of stringency in regulatory review practices allowed the market entry of these combinations. CSE 1034 (ceftriaxone, sulbactam and EDTA) and cefoperazone sulbactam are the most irrational antibiotics in clinical use. The effectiveness of such combinations relies on multiple factors such as relative beta-lactamase stability of the standalone beta-lactam, the inhibitory potency of the beta-lactamase inhibitor and more importantly the adequacy of the dose incorporated in the formulation. Unfortunately, none of the unconventional BL-BLI inhibitor combinations marketed in India has been subjected to such evaluations. Therefore, their therapeutic utility is uncertain. Besides questionable therapeutic utility, sub-optimal exposures would lead to the selection of resistant clones.

Susceptibility testing for aztreonam plus ceftazidime/avibactam combination: A general guidance for clinical microbiology laboratories in India.

Metallo beta-lactamases-producing Gram-negative infection is often challenging and there is no defined treatment option. In recent years, the combination of aztreonam with ceftazidime-avibactam has gained much clinical attention mainly for MBL-producing Enterobacterales, while MBL-producing P. aeruginosa and A. baumannii are likely to be resistant. A consensus susceptibility testing method for this triple combination has yet to be recommended. Various methods such as broth disk elution, disk stacking, gradient strip stacking, and strip crossing have been proposed for testing this combination. Among them, broth disk elution and strip based testing methods showed good correlation with the broth micro-dilution method.

In-Vitro Selection of Ceftazidime/Avibactam Resistance in OXA-48-Like-Expressing Klebsiella pneumoniae: In-Vitro and In-Vivo Fitness, Genetic Basis and Activities of ß-Lactam Plus Novel ß-Lactamase Inhibitor or ß-Lactam Enhancer Combinations.

Ceftazidime/avibactam uniquely demonstrates activity against both KPC and OXA-48-like carbapenemase-expressing Enterobacterales. Clinical resistance to ceftazidime/avibactam in KPC-producers was foreseen in in-vitro resistance studies. Herein, we assessed the resistance selection propensity of ceftazidime/avibactam in K. pneumoniae expressing OXA-48-like ß-lactamases (n = 10), employing serial transfer approach. Ceftazidime/avibactam MICs (0.25-4 mg/L) increased to 16-256 mg/L after 15 daily-sequential transfers. The whole genome sequence analysis of terminal mutants showed modifications in proteins linked to efflux (AcrB/AcrD/EmrA/Mdt), outer membrane permeability (OmpK36) and/or stress response pathways (CpxA/EnvZ/RpoE). In-vitro growth properties of all the ceftazidime/avibactam-selected mutants were comparable to their respective parents and they retained the ability to cause pulmonary infection in neutropenic mice. Against these mutants, we explored the activities of various combinations of ß-lactams (ceftazidime or cefepime) with structurally diverse ß-lactamase inhibitors or a ß-lactam enhancer, zidebactam. Zidebactam, in combination with either cefepime or ceftazidime, overcame ceftazidime/avibactam resistance (MIC range 0.5-8 mg/L), while cefepime/avibactam was the second best (MIC: 0.5-16 mg/L) in yielding lower MICs. The present work revealed the possibility of ceftazidime/avibactam resistance in OXA-48-like K. pneumoniae through mutations in proteins involved in efflux and/or porins without concomitant fitness cost mandating astute monitoring of ceftazidime/avibactam resistance among OXA-48 genotypes.

Oral Antibiotics in Clinical Development for Community-Acquired Urinary Tract Infections.

The treatment of urinary tract infections (UTIs) has been complicated by the emergence of multidrug-resistant, ß-lactamase-expressing pathogens. As a result of the limited treatment options, patients often require hospitalization and intravenous therapy. In essence, a strong unmet need for oral antibiotics, active against extended-spectrum ß-lactamase (ESBL) uropathogens has emerged. Oral carbapenems (tebipenem and sulopenem) and oral cephalosporin/ß-lactamase inhibitor combinations are in various stages of clinical development for the treatment of uncomplicated and complicated UTI. Tebipenem, if approved, will be the first oral treatment for complicated UTI while sulopenem will be for uncomplicated UTI. The ß-lactamase inhibitors ETX0282, VNRX7145, ARX1796, and QPX7728 are combined with cefpodoxime proxetil or ceftibuten that achieve favorable exposures in urine compared to other uropathogen-active oral cephalosporins. The combination ceftibuten-QPX7728 has potential broad-spectrum coverage against carbapenemase producers including metallo ß-lactamase producers. Other novel combinations, namely cefpodoxime/ETX0282, ceftibuten/VNRX-7145, and ceftibuten/ARX1796, have also demonstrated excellent activity against Klebsiella pneumoniae carbapanemase (KPC) and OXA-48-like producers. All these agents, upon their arrival for commercial use, would strengthen the outpatient therapy.