Pulmonary epithelial lining fluid (ELF) was commonly used for the pharmacokinetic study in lower respiratory tract infections. To characterize the intrapulmonary pharmacokinetic properties of polymyxin B following aerosol delivery, we developed and fully validated a liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for quantifying polymyxin B in human bronchoalveolar lavage fluid (BALF). The ELF concentrations were calculated by the BALF values of polymyxin B using urea as a volume normalizer. Chromatographic separation was achieved on a Phonomenex Kinetex XB-C18 column(100 mm × 2.1 mm I.D., 2.6 μm)in acetonitrile and water both containing 0.2 % formic acid. The flow rate was set as 0.4 mL/min for a 3.5 min running time. Protein precipitation was used in preparing BALF samples with polymyxin E1 as an internal standard. Polymyxin B was detected under multiple reaction monitoring conditions using the electrospray ionization interface running in the positive ionization mode. The assay showed a good linear relationship over the tested concentration ranges of 0.0300/0.00306---10.0/1.02 mg/L for polymyxin B1/B2 in bronchoalveolar lavage fluid (R² > 0.99). The inter- and inter-day precisions (RSD, %) were < 12.2 %(15.2 % for LLOQ samples)and the accuracies (%) were within the range of 94.3 ∼ 110.4 %. This reliable LC-MS/MS method for detection of polymyxin B was successfully applied to conduct a pulmonary penetration study in patients following aerosol administration.

01 Oct 2024·The Journal of the Association of Physicians of India

Emerging Colistin Resistance: Experience from an Intensive Care Unit of a Tertiary Care Center in India.

Article

Author: Sharma, Mayank ; Poddar, Banani ; Gurjar, Mohan ; Sahu, Chinmoy ; Azim, Afzal

BACKGROUNDResistance to the currently available classes of antimicrobials has emerged as a major health concern, with a growing number of isolated organisms demonstrating resistance to available antimicrobials. With the escalation of carbapenem resistance, the use of polymyxin B/E (colistin) has increased over the years, which has, in turn, contributed to the worldwide emergence of colistin resistance. The available data on colistin resistance from Southeast Asian nations, including India, is limited, especially in intensive care unit (ICU) settings. The primary objective of our study was to analyze the clinical profile of patients with polymyxin B/E (colistin) resistant positive cultures and to study their outcome in terms of length of ICU stay and outcome at discharge.MATERIALS AND METHODSThis observational, single-center, prospective study was conducted in a 20-bed adult ICU serving both medical and surgical patients at a 1,600-bed tertiary care institute in northern India between Jan 2020 and Dec 2021. In this study, all adult patients, defined as individuals older than 18 years of age, admitted to our ICU with cultures detecting polymyxin B/E (colistin) resistant organisms were included as cases, and all adult ICU patients (age >18 years) with polymyxin B/E (colistin) sensitive cultures were taken as controls. Clinical, laboratory, and demographic parameters, along with ICU variables like severity of illness, length of ICU stay, mechanical ventilation, days of shock, renal replacement therapy (RRT), etc., and outcome at discharge were collected. Identification of resistance to colistin and minimal inhibitory concentration (MIC) of colistin is based on Clinical and Laboratory Standards Institute (CLSI) guidelines. For statistical analysis, Mann-Whitney U test, Fisher's exact test, and binary logistic regression were used.RESULTSTwenty-eight cases and 55 controls (n = 83) were included for analysis. Abdominal [gastrointestinal (GI)] sepsis was the most common diagnosis (41.8%) at admission to the ICU, and Klebsiella pneumoniae was the most common species isolated in both the cases (96.4%) and the controls (50.9%). The most common site of isolation of Gram-negative bacteria in both cases and controls was blood (71.4 vs 74.5%), followed by deep-seated pus (21.4 vs 23.64%). The most common class of drugs to which the cases were sensitive was tetracyclines in 60.7%, followed by ceftazidime-avibactam. Factors such as prior exposure to colistin, exposure to monobactams in the ICU, and ICU stay in days were identified as independent predictors for colistin resistance. Overall mortality was not statistically different between cases and controls (p -value 0.38).CONCLUSIONFactors like prolonged ICU stay, exposure to monobactams in the ICU, and a history of prior exposure to colistin in the previous 90 days are independent predictors of colistin resistance. The most common organism to develop colistin resistance identified was K. pneumoniae, and the most common site of isolation was blood. There was no difference in mortality between colistin-resistant and colistin-sensitive patients.

01 Jun 2012·Clinical Infectious Diseases

Unmet Medical Need in Infectious Diseases

Letter

Author: David N. Gilbert ; Susan E. Beekmann ; Adam L. Hersh ; Jason G. Newland ; Philip M. Polgreen

To the Editor—Multidrug-resistant (MDR) infections are rapidly increasing worldwide, and, unfortunately, few new antimicrobials capable of treating these infections are under development [1, 2]. The emergence of infections for which there are limited treatment options represents a critical unmet medical need. In October 2011, we electronically surveyed the 1356 members of the Emerging Infections Network (EIN) about 3 areas of unmet medical need in the treatment of antibiotic-resistant infections. Respondents ranked the severity of unmet medical need for different infections from 1 (least severe) to 5 (most severe). Respondents also ranked the importance of specific challenges related to the treatment of MDR infections from 1 (not important) to 5 (most important). Finally, they ranked 5 specific strategies designed to combat antibiotic-resistant infections in the order in which they felt would best aid in targeting these infections. Additional questions pertained to use of polymyxin B/E (colistin). We received 562 responses (41.6%). The severity of unmet medical need was viewed as greatest for MDR gram-negative bacilli (mean score, 4.6), higher than for methicillin-resistant Staphylococcus aureus (MRSA), MDR tuberculosis, aspergillosis, and MDR gonorrhea (Figure 1A). The greatest challenge in the treatment of MDR infections was noted to be the limited number of new antimicrobials under development (mean score, 4.7) (Figure 1B). Respondents believed that the development of new antibacterials (mean score, 3.4) and more aggressive antimicrobial stewardship programs were the most important strategies in combating MDR infections (Figure 1C). Sixty-four percent of respondents reported using colistin during the previous year, 63% reported caring for a patient with an infection resistant to all available antibacterials, and 56% believe that the number of these untreatable infections is increasing. Figure 1. A, Mean score for rating severity of unmet medical need, ranging from 1 (least severe) to 5 (most severe). B, Mean score for rating importance of challenges in the treatment of multidrug-resistant infections, ranging from 1 (least important) to 5 (most ... We found that management of infection due to MDR gram-negative bacteria represents the most severe unmet medical need in infectious diseases. In their practice, EIN members are experiencing an alarming increase in infections due to MDR gram-negative bacilli for which few and, in some cases, no effective therapies exist. In response, the Infectious Diseases Society of America has taken an active role in supporting national legislation that promotes control of antibiotic resistance and incentives for new drug development (the Generating Antibiotic Incentives Now Act). [3] Although MRSA and tuberculosis have drawn the attention of the public media, infectious diseases clinicians from the EIN believed that gram-negative bacilli represent a far greater unmet need. From the vantage of front-line physicians, the limited number of new antibacterials represents both the greatest limitation and the most important solution to combating this crisis.

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