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.

Efficacy and Safety of Oral and IV Levonadifloxacin Therapy in Management of Bacterial Infections: Findings of a Prospective, Observational, Multi-center, Post-marketing Surveillance Study.

Background Antimicrobial resistance by bacteria poses a substantial threat to morbidity and mortality worldwide, and treatment of resistant infections is a challenge for the treating clinician. Levonadifloxacin is a novel broad-spectrum agent belonging to the benzoquinolizine subclass of quinolone, which can be used by both oral and intravenous administration for the treatment of infections caused by gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA). Patients and methods This prescription event monitoring study captured data from 1266 patients receiving levonadifloxacin (oral and/or IV) in a real-world setting to assess the safety and efficacy in the treatment of various bacterial infections. The duration of the study was 18 months. Study outcomes were clinical success and microbial success at the end of therapy. Global assessments were done for safety and efficacy at the end of therapy using a 5-point Likert scale (excellent, very good, good, satisfactory, and poor). Results The mean (median) duration of therapy was 7.2 (7.0) days, with a median time to clinical improvement of four days. Oral therapy was administered to 224 patients; 940 received IV, and 102 received IV followed by oral therapy. Patients were prescribed levonadifloxacin for gram-positive infections, skin and soft tissue infections, diabetic foot infections, septicemia, catheter-related blood-stream infections, bone and joint infections, febrile neutropenia, and respiratory infections, including COVID-19 pneumonia. The clinical cure on the eighth day was 95.7%, whereas the microbial success on the eighth day was 93.3% (n=60). For different types of infections, the clinical success rates ranged from 85.2% to 100%. There were only 30 treatment-emergent adverse events reported in 29 patients. Overall, about 95.6% of patients rated the efficacy as good to excellent, whereas only 3.8% of patients rated it satisfactory; for safety, 95.7% of patients rated it as good to excellent, with only 3.9% of patients rated it as satisfactory. Conclusions The excellent safety and efficacy profile of levonadifloxacin, when administered as an oral or intravenous therapy, makes it a desirable treatment modality for the management of various bacterial infections, including those caused by resistant pathogens such as MRSA and quinolone-resistant Staphylococcus aureus (QRSA). Features of levonadifloxacin, such as availability in both IV and oral form, minimal drug-drug interactions, lack of the need to adjust dosages in renal and hepatically impaired patients along with a broad spectrum of coverage, make it a suitable agent that meets several unmet clinical needs of physicians.

Treatment challenges in the management of difficult-to-treat gram-positive infections: A consensus view apropos therapeutic role of novel anti-MRSA antibiotics, levonadifloxacin (IV) and alalevonadifloxacin (oral).

PURPOSE: Treatment of antibiotic-resistant Gram-positive infections (GPIs), including methicillin-resistant Staphylococcus aureus (MRSA) is becoming increasingly difficult, particularly in patients with multiple co-morbidities who require antibiotics with greater safety and a consistent pharmacokinetic/pharmacodynamic (PK/PD) profile. Such difficult-to-treat GPIs are often associated with poor outcomes, extended hospital stay and increased expenditure. This can be partly attributed to the limited safety and aberrant PK/PD profile of existing anti-MRSA antibiotics. In this context, intravenous levonadifloxacin and its oral prodrug alalevonadifloxacin are novel anti-MRSA antibiotics that have significant advantages over conventional anti-Gram-positive antibiotics. The purpose of this paper was to generate a consensus on the optimal use of levonadifloxacin and alalevonadifloxacin for tackling resistant Gram-positive infections in patients with multiple co-morbidities. METHOD: Using a modified Delphi approach that combines critical appraisal of evidence and expert opinion, therapeutic use of levonadifloxacin and alalevonadifloxacin in various clinical scenarios and specific unmet conditions was deliberated. Fifteen expert members from medicine, critical-care, emergency, microbiology, and intensive-care disciplines participated and voted on 11 pre-conceived statements. When there was at least 70 % agreement, a consensus was reached. RESULTS: Following the voting, agreements were reached on 10 out of the 11 statements. Broadly, a consensus was reached in defining the therapeutic role of levonadifloxacin and alalevonadifloxacin in the treatment of various clinical indications involving resistant Gram-positive pathogens, including MRSA, in patients with co-morbidities, such as co-existing or increased risk for kidney dysfunction or hepatic disease and/or immunosuppression; also, in therapeutically challenging conditions caused by Gram-positive bacteria such as bacteraemia, bone and joint infection, diabetic foot infection, febrile neutropenia, and hospital-acquired pneumonia. CONCLUSIONS: This consensus supports the therapeutic use of levonadifloxacin and alalevonadifloxacin in the treatment of antibiotic-resistant GPIs, including those caused by MRSA and certain polymicrobial infections, in patients with multiple co-morbidities requiring drug with adequate safety and consistent efficacy.

A case series of melioidosis: An underdiagnosed infection.

Melioidosis is an infection caused by Burkholderia pseudomallei. It is a non notifiable disease and is not included in Integrated Disease Surveillance Program by National Center of Disease Control. India is predicted to have highest burden of disease with an estimated mortality of 32,000 per year. Melioidosis presents with a wide range of clinical manifestations like pneumonia, liver and splenic abscess, septicemia etc. This wide spectrum of presentation and mimicry with other infections leads to its misdiagnosis or underdiagnosis. The only source of disease burden in India is few case reports and the true burden and distribution of disease still needs to be assessed. We, hereby, report a case series of four cases aged 28 years, 53 years, 33 years and 22 years. All cases had different clinical presentation ranging from abdominal wall abscess to septicemia and neurological manifestations making the diagnosis challenging. Three of the four cases were discharged after complete recovery while one case went leave against medical advice. To our knowledge this is the first series describing complete recovery of three out of four cases. This case series will help the physicians to raise their index of clinical suspicion of melioidosis in high risk patients presenting with various findings thus improving the chances of correct diagnosis and treatment.

Predictors and microbiology of ventilator-associated pneumonia among patients with exacerbation of chronic obstructive pulmonary disease.

BACKGROUND: Understanding the risk factors and microbiology of ventilator-associated pneumonia (VAP) among patients with chronic obstructive pulmonary disease (COPD) is important for the application of preventive and therapeutic interventions. Therefore, this study was planned to assess the clinical predictors and microbiological features of VAP among COPD patients. MATERIALS AND METHODS: This prospective study involved patients with exacerbation of COPD who required mechanical ventilation and admitted in respiratory intensive care unit at a tertiary care teaching hospital. Various baseline demographic and clinical features were compared between patients with VAP and without VAP. Univariate and multivariable analyses were done to assess the impact of demographic and clinical features on the development of VAP. RESULTS: The study included 100 intubated patients with age (mean ± standard deviation [SD]) of 62.45 ± 8.32 years, duration (median) of COPD of 6 years, and Acute Physiology, Age, and Chronic Health Evaluation score (mean ± SD) of 18.60 ± 4.30. In this cohort, 17 patients developed VAP. Multivariable analysis showed that Sequential Organ Failure Assessment (SOFA) score at admission, re-intubation, and history of previous hospitalization were independent predictors of VAP with odds ratio (95% confidence interval) of 2.70 (1.24, 5.63; P = 0.012), 66.96 (4.86, 922.72; P = 0.002), and 35.92 (2.84, 454.63; P = 0.006), respectively. Acinetobacter baumannii was the most frequent organism (n = 8; 47%), followed by Klebsiella pneumoniae (n = 5; 29%), Pseudomonas aeruginosa (n = 1; 6%), and Enterobacter spp. (n = 1; 6%). All organisms were multidrug resistant (MDR). CONCLUSIONS: SOFA score at admission, re-intubation, and history of previous hospitalization were independent predictors of VAP. Antimicrobial therapy for VAP should cover MDR Gram-negative organisms.

Guidelines for diagnostic flexible bronchoscopy in adults: Joint Indian Chest Society/National College of chest physicians (I)/Indian association for bronchology recommendations.

Flexible bronchoscopy (FB) is commonly performed by respiratory physicians for diagnostic as well as therapeutic purposes. However, bronchoscopy practices vary widely across India and worldwide. The three major respiratory organizations of the country supported a national-level expert group that formulated a comprehensive guideline document for FB based on a detailed appraisal of available evidence. These guidelines are an attempt to provide the bronchoscopist with the most scientifically sound as well as practical approach of bronchoscopy. It involved framing appropriate questions, review and critical appraisal of the relevant literature and reaching a recommendation by the expert groups. The guidelines cover major areas in basic bronchoscopy including (but not limited to), indications for procedure, patient preparation, various sampling procedures, bronchoscopy in the ICU setting, equipment care, and training issues. The target audience is respiratory physicians working in India and well as other parts of the world. It is hoped that this document would serve as a complete reference guide for all pulmonary physicians performing or desiring to learn the technique of flexible bronchoscopy.