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Background: Safe and effective use of colistin requires robust pharmacokinetic (PK) and pharmacodynamic (PD) data to guide dosing., Aim: To evaluate the pharmacokinetics of colistimethate sodium and colistin in critically ill patients and correlate with clinical efficacy and renal function., Materials and Methods: Twenty critically ill adult patients with colistin-susceptible multidrug-resistant (MDR) infections and normal renal function treated with intravenous colistimethate sodium - at a 9 million units (270 mg CBA) loading dose followed by maintenance (MD) of 3 million units t.i.d, 24 hours later - were evaluated for clinical cure (CC) at the end of therapy. Patient characteristics and plasma colistin levels at 0, 0.5, 1, 2, 4, 8 and 12 hours after the loading dose and at 1, 2 and 8 hours after the eighth and ninth infusion of MD were evaluated. Colistimethate sodium and colistin levels were measured by high-performance liquid chromatography and tandem mass spectrometry (HPLC-MS/MS)., Results: Among the 20 patients who were evaluated, 60% had pneumonia. Predominant pathogens were Klebsiella pneumoniae and Acinetobacter spp. Clinical cure was 50% (10/20). Mean peak loading dose concentrations were 3 ± 1.1 mg/L (1.75-5.14) and 2.37 ± 1.2 mg/L (1.52-5.54) for 'cure' and 'failure' groups, respectively (p = 0.13), while mean steady-state (Cssavg) concentrations were 2.25 ± 1.3 mg/L and 1.78 ± 1.1 mg/L in 'cure' and 'failure' groups, respectively (p = 0.19). Nephrotoxicity was 5% on day 7 of therapy. However, bacteriological cure could not be correlated with PK/PD., Conclusions: Subtherapeutic Cssavg with clinical failure and lower efficacy without significant nephrotoxicity highlights the need for therapeutic drug monitoring to guide colistin dosing., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Sepsis is one of the major causes of neonatal deaths in India and worldwide. Pathogens encountered in neonatal sepsis vary worldwide; reports from developing countries more commonly show Gram negative organisms, most common being Acinetobacter spp., Klebsiella spp. and Escherichia coli. Recent studies show that the incidence of antimicrobial resistance, to third generation cephalosporins and carbapenems, has been on a rise. Because of widespread antimicrobial resistance, 'Higher' or 'Reserve' antibiotics are increasingly being used as first/second line antibiotics. In the past decade, there has been a resurgence in the use of colistin as a result of Extended-spectrum β-lactamase (ESBL)- producing Enterobacteriaceae and carbapenem resistant Enterobacteriaceae (CRE), which retain susceptibility only to colistin. The increasing burden of drug resistant Gram negative organisms, particularly Acinetobacter spp., Klebsiella spp., and E. coli might pose a formidable threat in coming years.

Background & Objectives: The growing incidence and the wide diversity of carbapenemase-producing bacterial strains is a major concern as only a few antimicrobial agents are active on carbapenem-resistant bacteria. This study was designed to study molecular epidemiology of carbapenem-resistant Gram-negative bacterial (GNB) isolates from the community and hospital settings., Methods: In this study, non-duplicate GNB were isolated from clinical specimens, and phenotypic test such as modified Hodge test, metallo β-lactamase E-strip test, etc. were performed on carbapenem-resistant bacteria. Multiplex PCR was performed to identify the presence of bla IMP , bla VIM , bla KPC , bla OXA48 , bla OXA23 , bla SPM , bla GIM , bla SIM and bla NDM . Minimum inhibitory concentration (MIC) of colistin, fosfomycin, minocycline, chloramphenicol and tigecycline was also determined., Results: Of the 3414 GNB studied, carbapenem resistance was 9.20 per cent and maximum resistance (11.2%) was present at tertiary care centre, followed by secondary care (4%) and primary centre (2.1%). Among the carbapenem-resistant bacteria, overall, the most common isolate was Pseudomonas aeruginosa (24%). On multiplex PCR 90.3 per cent carbapenem-resistant isolates were positive for carbapenemase gene. The bla NDM (63%) was the most prevalent gene followed by bla VIM (18.4%). MIC results showed that 88 per cent carbapenem-resistant Enterobacteriaceae were sensitive to fosfomycin, whereas 78 per cent of P. aeruginosa and 85 per cent Acinetobacter spp. were sensitive to colistin., Interpretation & Conclusions: Carbapenem resistance in GNB isolates from the community and hospital settings was found to be on the rise and should be closely monitored. In the absence of new antibiotics in pipeline and limited therapeutic options, prudent use of antibiotics and strict infection control practices should be followed in hospital to limit the emergence and spread of multidrug-resistant bacteria., Competing Interests: None

In this study, we retrospectively evaluated clinical outcomes of 75 patients with dual colistin- and carbapenem-resistant Klebsiella pneumoniae bloodstream infections over a 5-year period in a single tertiary care hospital in India. We observed a high in-hospital mortality rate of 69.3%. Our findings indicate the urgent need for new antibiotics to treat these infections., (Copyright © 2017 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Infection by bacteria carrying New Delhi metallo-β-lactamase 1 (NDM-1) is becoming a global health problem. We report a case of meningitis caused by NDM-1-producing Klebsiella pneumoniae, for which intrathecal administration of colistin was curative. A previously healthy 38-year-old Japanese man, who lived in Hyderabad, India, suddenly collapsed and was brought to a local hospital. He was diagnosed with subarachnoid hemorrhage and underwent emergency surgery which included partial skull removal. Approximately 1 month after surgery, he was repatriated to Japan and was admitted to our institution with information that he had been treated for multi-drug resistant Acinetobacter infection with colistin. A week after admission, he developed aspiration pneumonia due to NDM-1-producing K. pneumoniae, which was successfully treated by intravenous (IV) administration of colistin. Subsequently, he underwent a surgical procedure to repair his skull defect. He developed high-grade fever and altered mental status on postoperative day 2. NDM-1-producing K. pneumoniae was identified in the cerebrospinal fluid, establishing the diagnosis of meningitis. Although IV colistin was only partially effective, intrathecal colistin (10 mg daily by lumbar puncture for 14 days) successfully eradicated the meningitis. Because of economic globalization, NDM-1-producing bacteria may be brought to Japan by those who are repatriated after sustaining critical illnesses and being treated in foreign countries. This report may provide useful information on the treatment of central nervous system infection by NDM-1-producing bacteria., (Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

This study describes 3 different blaNDM-1 genetic platforms in 3 different species obtained from the same patient who was directly transferred to an institution in Calgary, Alberta, Canada, following a prolonged hospital stay in India. The blaNDM-1 in the Escherichia coli isolate was located on a 176-kb IncA/C plasmid contained within an ISCR1 region. The blaNDM-1 in the Providencia rettgeri isolate was located on a 117-kb IncT plasmid contained within Tn3000, while the blaNDM-1 in the Pseudomonas aeruginosa isolate was located on the chromosome within an ISCR3 region. This report highlights the plasticity of the genetic regions and environments associated with blaNDM-1. To the best of our knowledge, this is the first report of P. aeruginosa with blaNDM-1 identified in North America and the first report of blaOXA-181 in P. rettgeri. The P. aeruginosa isolate belonged to the international high-risk sequence type 654 clone and was nonsusceptible to colistin. This case emphasizes the need for the use of appropriate infection prevention and control measures and vigilant screening for carbapenem-resistant Gram-negative bacteria in patients with a history of travel to areas of endemicity, such as the Indian subcontinent., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Context: Infections caused by carbapenem-resistant bacteria constitute a major challenge for current medical practice., Objective: To describe treatment and outcome of carbapenem-resistant Gram-negative bacilli (GNB) blood-stream infection (BSI) caused by these organisms at a tertiary care hospital in Mumbai., Methods: Carbapenem-resistant isolates from blood cultures were collected from January 2013 to April 2013. Identification and antimicrobial susceptibility testing were performed using Vitek 2 analyzer (Biomerieux Ltd.). Carbapenemase production was detected by modified Hodge's test (MHT). Patient's medical history, treatment and co-morbid conditions were noted. Outcomes of BSIs were evaluated., Results: Forty-two isolates of carbapenem-resistant GNB isolated from BSIs were Enterobacteriaceae spp. (19), Acinetobacter baumannii (15), and Pseudomonas aeruginosa (8). Colistin had maximum in vitro activity with 97% against Enterobacteriaceae, 100% against Acinetobacter, and 100% activity against Pseudomonas aeruginosa isolates. Positivity of MHT was 92.9%. Outcome of colistin mono and combination therapy was comparable with 83% and 79%, respectively. Outcome of colistin and carbapenem combination therapy was found to be 100 percent., Conclusions: High incidences of bacteremia by carbapenem-resistant GNB including Enterobacteriaceae is a worrisome trend. Treatment options are compromised and only available option is colistin which has its own limitation. Colistin monotherapy may be non-inferior compared to combination therapy for treating BSIs caused by isolates with minimum inhibitory concentration (MIC) for colistin as ≤0.5 mg/l. Combined use of the colistin and carbapenem may provide good therapeutic options for BSI caused by carbapenem-resistant GNB and warrants further investigations.

A novel type of carbapenemase, New Delhi metallo beta-lactamase 1 (NDM 1), was first identified in 2008 in two Enterobacteriacea isolates, both recovered from a Swedish patient transferred from India. The emergence of NDM 1 is now reported from all continents, often in patients with a history of travel or hospitalization in the Indian subcontinent. The NDM 1 producing Gram-negative bacteria are mainly Enterobacteriaceae, which can cause colonization or fatal infections, with worrying antimicrobial susceptibility profiles: some isolates have developed resistance to practically all available antibiotics. Is the NDM-1 the super-bug? Are we in the post-antibiotic era? This review is a summary of currently available knowledge of NDM-1 that draws attention to future antimicrobial resistance scenarios.

Melioidosis has recently gained the status of an emerging disease in India. Multidrug-resistant (MDR) Gram-negative bacteria, however, are already responsible for treatment failure and mortality. In addition, pandrug-resistant (PDR) Gram-negative bacteria have emerged as a new threat to modern medicine. The treatment, clinical follow up, and outcome of 25 patients with melioidosis and 46 patients with MDR non-fermenters (Pseudomonas aeruginosa and Acinetobacter spp.) infection were documented during the period 2005 2007. Pandrug resistance status of the MDR strains was evaluated with the minimum inhibitory concentration breakpoint of colistin. Skin and soft-tissue involvement (16%), liver abscess (16%) and bone and joint involvement (16%) were the most common presentations of melioidosis in diabetic patients. The presence of septicaemia (44%) and major organ failure (48%) resulted in death. Relapse was seen in patients with inappropriate treatment. Clinical cure was observed in five cases infected with PDR strains; colistin was used in only one case. Comorbid conditions may have contributed to the high fatality (82.7%). More awareness among clinicians and laboratory staff, and environmental investigations of soil are required for accurate diagnosis and prompt treatment of melioidosis. For MDR strains, colistin is the 'last resort' and should be used with caution; resistance should be monitored both globally and locally.