Resurgence of colistin: a review of resistance, toxicity, pharmacodynamics, and dosing

Colistin is a polymyxin antibiotic that was discovered in the late 1940s for the treatment of gram-negative infections. After several years of clinical use, its popularity diminished because of reports of significant nephrotoxicity and neurotoxicity. Recently, the antibiotic has resurfaced as a last-line treatment option for multidrug-resistant organisms such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. The need for antibiotics with coverage of these gram-negative pathogens is critical because of their high morbidity and mortality, making colistin a very important treatment option. Unfortunately, however, resistance to colistin has been documented among all three of these organisms in case reports. Although the exact mechanism causing colistin resistance has not been defined, it is hypothesized that the PmrA-PmrB and PhoP-PhoQ genetic regulatory systems may play a role. Colistin dosages must be optimized, as colistin is a last-line treatment option; in addition, suboptimal doses have been linked to the development of resistance. The lack of pharmacokinetic and pharmacodynamic studies and no universal harmonization of dose units, however, have made it difficult to derive optimal dosing regimens and specific dosing guidelines for colistin. In critically ill patients who may have multiorgan failure, renal insufficiency may alter colistin pharmacokinetics. Therefore, dosage alterations in this patient population are imperative to achieve maximal efficacy and minimal toxicity. With regard to colistin toxicity, most studies show that nephrotoxicity is reversible and less frequent than once thought, and neurotoxicity is rare. Further research is needed to fully understand the impact that the two regulatory systems have on resistance, as well as the dosages of colistin needed to inhibit and overcome these developing patterns.     

多黏菌素E耐药基因mcr-1在我国养殖场的流行及其传播扩散

多黏菌素E是临床上用来治疗多重耐药革兰阴性菌的重要药物之一，特别是用于治疗产超广谱β-内酰胺酶或碳青霉烯酶的多重耐药菌。多黏菌素耐药基因mcr-1的出现，使得细菌对多黏菌素E的耐药性有了水平传播的可能。养殖场被认为是MCR-1阳性菌株传播的源头。食物链和环境是mcr-1基因传播的主要途径。本篇综述重点阐述了mcr-1在我国养殖场的流行情况以及其可能的传播扩散途径，并提出了当下需要解决的一些问题，以期能为今后同行的相关研究提供参考。     

多粘菌素用法及药代动力学研究进展

多粘菌素是一种阳离子多肽类抗生素,在1950年代首次用于临床,但在1970年代由于肾毒性和神经毒性而被基本弃用.最近,多重耐药革兰阴性病原体的流行,迫使多粘菌素再次成为临床治疗多重耐药革兰阴性菌的最后一线药物手段.临床证据表明,多粘菌素B由于以其活性形式给药,其药代动力学变异较小,主要通过非肾脏途径消除,因此肾功能损害患者无需调整用药剂量.而CMS可通过肾小球滤过和肾小管排泄迅速清除,20％～25％自发水解为粘菌素.但是不同患者具有其特殊的病理生理状态,药代动力学参数与健康志愿者间存在较大差异,按照健康人体的药代动力学参数指导用药,可能会导致药物剂量不足或剂量过大而增加毒副作用.     

Use of colistin in the treatment of multiple-drug-resistant gram-negative infections.

PURPOSE: The use of colistin for the treatment of infections caused by multiple-drug-resistant (MDR) gram-negative microorganisms was studied. METHODS: The efficacy of colistin for treating infections caused by MDR gram-negative microorganisms and the development of renal toxicity were studied in hospitalized adult patients in Spain. Patients treated between January 2001 and October 2001 were included. RESULTS: Over the study period, 71 courses of inhaled colistin, 12 courses of i.v. or intramuscular (i.m.) colistin, and 2 courses of intrathecal colistin were administered to 80 patients. All were infected by MDR organisms: 69 (86%) by Acinetobacter baumannii and 11 (14%) by Pseudomonas aeruginosa. In 41 patients (51%), the episodes were caused by A. baumannii strains susceptible exclusively to colistin. The causative organisms were cleared in 92% of the patients from whom posttreatment repeat specimens were obtained. The in-hospital mortality rate was 18% (14 patients). There were no significant changes in mean serum urea or creatinine concentrations in patients receiving i.v. or i.m. therapy. CONCLUSION: Colistin was used in 80 patients infected with A. baumannii or P. aeruginosa and appeared to be efficacious and safe.     

Polymyxin antibiotics for gram-negative infections.

PURPOSE: The role of polymyxin antibiotics in the treatment of multidrug-resistant gram-negative infections is reviewed. SUMMARY: Antimicrobial resistance is an increasing problem across hospitals worldwide, especially in intensive care settings, where nosocomial infections are 5-10 times more likely to occur than on the general wards. The polymyxins, a group of basic polypeptide antibiotics, were first isolated from Bacillus species in the late 1940s and appear to have a surface detergent effect, making them active against most gram-negative organisms. Early clinical reports suggested a high rate of toxicity associated with the polymyxins, specifically nephrotoxicity (20%) and neurotoxicity (7%); thus the polymyxins had largely fallen out of favor. However, recent studies have suggested that the toxicities associated with the polymyxins may be less severe and less frequent than earlier reports. The emergence of multidrug-resistant gram-negative organisms has led to a reemergence in the use of this antibiotic class. Various clinical trials that evaluated the polymyxins for the treatment of multidrug-resistant gram-negative organisms found that these antibiotics have acceptable effectiveness and may be used if necessary. CONCLUSION: The polymyxins have become a last resort for the treatment of infections caused by multidrug-resistant gram-negative organisms. Recent studies have suggested that the frequency of polymyxin-associated nephrotoxicity and neurotoxicity may not be as high as was once thought. The polymyxins seem to be effective in treating various infections caused by multidrug-resistant gram-negative organisms but should not be used as first-line therapy until more is known about this class of antibiotics.     

Multidrug-resistant Gram-negative bacteria: how to treat and for how long

The emergence of multidrug-resistant (MDR) Gram-negative bacilli creates a big problem for the treatment of nosocomial infections. As the pharmaceutical pipeline wanes, the only therapeutic options are two revived antibacterials (colistin and fosfomycin), a newer one (tigecycline) and an early-phase neoglycoside (ACHN-490). Polymyxins, known since 1947, are mostly represented by polymyxin E (colistin), which has recently gained a principal position in the management of the most difficult-to-treat MDR Gram-negative pathogens -Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. However, despite promising therapeutic results in 59-75% of cases, the reported studies share common drawbacks, i.e. the absence of a control group, their retrospective nature, variable dosing and duration of therapy, simultaneous administration of other antibiotics in >70% and a lack of resistance development monitoring. The necessity for well-designed prospective clinical trials is therefore urgent. Fosfomycin is active in vitro against MDR Enterobacteriaceae, including a high proportion of P. aeruginosa; however, clinical experience is lacking with the parenteral formulation in MDR infection and on the best combinations to prevent resistance development. Tigecycline, which is active against MDR Enterobacteriaceae and A. baumannii, has shown satisfactory clinical experience. However, dosage adjustment is required because of low blood levels. ACHN-490, which has promising in vitro activity against MDR K. pneumoniae, is still in early phase II trials in urinary tract infections. Meanwhile, the strict application of infection control measures is the cornerstone of nosocomial infection prevention, and antibiotic stewardship, exemplified by appropriate duration of therapy and de-escalation policies, should not be overlooked.     

Plazomicin: A Next-Generation Aminoglycoside

Plazomicin is a novel aminoglycoside antibiotic that binds to the bacterial 30S ribosomal subunit, thus inhibiting protein synthesis in a concentration-dependent manner. Plazomicin displays a broad spectrum of activity against aerobic gram-negative bacteria including extended-spectrum β-lactamase–producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and organisms with aminoglycoside-modifying enzymes. In a large phase III clinical trial, plazomicin was shown to be noninferior to meropenem in the treatment of complicated urinary tract infections (cUTIs) with respect to the coprimary efficacy end points of the microbiologically modified intent-to-treat composite cure rate at day 5 (plazomicin 88% [168/191 subjects] vs meropenem 91.4% [180/197]) and at the test-of-cure visit (plazomicin 81.7% [156/191] vs meropenem 70.1% [138/197]). In a small phase III clinical trial, plazomicin was shown to be effective in the treatment of infections caused by carbapenem-resistant Enterobacteriaceae. It was associated with a lower all-cause mortality or significant disease-related complication rate (23.5% [4/17]) compared with colistin (50% [10/20]). The most common adverse reactions associated with plazomicin are decreased renal function, diarrhea, hypertension, headache, nausea, vomiting, and hypotension. As with other aminoglycosides, plazomicin may cause neuromuscular blockade, ototoxicity, and fetal harm in pregnant women. Due to limited efficacy and safety data, plazomicin is indicated for the treatment of cUTIs in adults with limited or no alternative treatment options, using a dosage regimen of 15 mg/kg intravenously every 24 hours for 4–7 days. Dosage reductions and therapeutic drug monitoring are warranted in patients with moderate or severe renal impairment. Plazomicin is not recommended in patients with severe renal impairment including those receiving renal replacement therapy. With the approval of plazomicin, clinicians now have an additional option for the treatment of adults with cUTIs, particularly those caused by multidrug-resistant gram-negative rods.     

多黏菌素类药物的肾毒性及其优化给药方案研究进展

多重耐药及泛耐药革兰阴性菌的流行给临床抗感染治疗带来了巨大挑战。由于新型抗菌药物研究开发缓慢,多黏菌素这类曾因严重的神经毒性和肾毒性而逐渐停止使用的抗生素又重回人们视野,并成为了治疗重症难治性革兰阴性菌感染的主要药物。然而,肾毒性仍严重影响此类药物的临床治疗效果。其肾毒性机制复杂,并且临床上存在着许多肾毒性危险因素,因此想要实现较为理想的治疗效果,必须在临床给药时慎重全面的考虑各影响因素,为患者选择适宜的给药方案。本文将对其肾毒性和给药方案的优化进行综述,以期为临床医生利用多黏菌素进行抗感染治疗提供一定的参考依据。     

Unlabeled uses of nebulized medications.

PURPOSE: The uses, dosing recommendations, benefits, and disadvantages of unlabeled drugs administered by nebulization are reviewed. SUMMARY: Nebulization is gaining popularity as a treatment alternative, and many drugs are used unlabeled in a nebulized form, including the opioids, lidocaine, magnesium sulfate, amphotericin B, and colistin. The opioids are frequently used to treat dyspnea in end-stage diseases. Common dosages include 1-2 mg every two hours as needed for hydromorphone and 25-50 microg every two hours for fentanyl citrate. Lidocaine can be used to relieve bronchoconstriction and cough symptoms as well as acting as a local anesthetic. It is typically given in a dose between 20 and 160 mg. Nebulized magnesium sulfate can be used in managing acute asthma and is given in dosages between 125 and 250 mg every 20 minutes, with no more than four consecutive doses. Nebulized amphotericin B can be used to prevent infections in immunocompromised patients. A typical amphotericin B regimen is 25 mg every 24 hours. Nebulized colistin is being studied in the prevention and treatment of gram-negative infections and in patients awaiting lung transplants. Colistin is often given as 75 mg every 12 hours to combat infections. CONCLUSION: Unlabeled nebulization of opioids, lidocaine, magnesium, amphotericin B, and colistin is an alternative method of treatment for patients with pulmonary problems or infections or for those undergoing bronchoscopy. More research is needed to develop guidelines for their use since nebulization may provide benefits to many patients who otherwise cannot be treated or would be at risk of systemic adverse effects of the drugs.     

Clinical characteristics and risk factors of colistin-induced nephrotoxicity

Since multidrug-resistant Gram-negative organisms have been increasing, polymyxin E (colistin) has been reintroduced despite its nephrotoxicity. A case–control study was performed to investigate the incidence, clinical characteristics and risk factors of colistin-induced nephrotoxicity. From August 2006 to June 2008, 47 cases receiving at least one defined daily dose (DDD) of intravenous colistin were included; 15 (31.9%) of the 47 cases developed nephrotoxicity with preserved urine output, 3 (20%) of whom underwent renal replacement therapy. The mean dosage of colistimethate sodium was 2.25 g (22.5 DDD; range 0.6–8.7 g) at the time of nephrotoxicity. Of 10 patients who were re-assessed for renal function after 1 month, 9 (90%) recovered their renal function. In the univariate analysis, site of infection, hypoalbuminaemia and cumulative dosage of the second-generation fluoroquinolones, aminoglycosides and non-steroidal anti-inflammatory drugs (NSAIDs) co-administered during colistin treatment as well as concomitant use of NSAIDs were risk factors for nephrotoxicity. However, in the logistic regression hypoalbuminaemia and the use of NSAIDs were significant risk factors for increased nephrotoxicity during colistin administration, suggesting that free colistin might cause renal toxicity. In conclusion, colistin-induced nephrotoxicity occurred at a high rate, and hypoalbuminaemia and concomitant use of NSAIDs were significant risk factors.     

Is colistin-associated acute kidney injury clinically important in adults? A systematic review and meta-analysis

Colistin is the last-resort antimicrobial agent against infections caused by multidrug-resistance Gram-negative bacteria (MDR-GNB). However, a differing risk of colistin-associated acute kidney injury (CA-AKI) has been demonstrated without affecting mortality, thus the association and its importance needs to be questioned. To assess the impact of this adverse effect, a meta-analysis comparing colistin with other antibiotics in treating MDR-GNB infections was conducted. The PubMed, Embase and Cochrane Library electronic databases were searched up to 31 December 2018 for cohort studies and randomised controlled trials with at least two arms with one arm containing colistin-based treatment. The primary endpoint was the incidence of AKI. The secondary endpoint was 30-day all-cause mortality. A total of 34 studies, including 26 regarding colistin-based therapy versus other antibiotics and 9 regarding colistin monotherapy versus combination therapy, were included. The incidence of CA-AKI was 32.3%. Colistin was associated with an 82% higher incidence of AKI than other antibiotics [odd ratio (OR) = 1.82, 95% confidence interval (CI) 1.13–2.92; P = 0.01]. Most CA-AKI events were mild and reversible without a higher rate of mortality or the requirement for renal replacement therapy (RRT). Only 1.0% of patients required RRT for > 4 weeks. Compared with colistin monotherapy, combination therapy was associated with a significantly lower incidence of AKI (OR = 1.46, 95% CI 1.10–1.94; P = 0.009), particularly in combination with a carbapenem (OR = 1.97, 95% CI 1.30–2.99; P = 0.001). In conclusion, CA-AKI might not be an important limitation of colistin in MDR-GNB therapy.     

Dosing of colistin-back to basic PK/PD

The increasing prevalence of multidrug-resistant Gram-negative bacteria worldwide has led to a re-evaluation of the previously discarded antibiotic, colistin. Despite its important role as salvage therapy for otherwise untreatable infections, dosage guidelines for the prodrug colistin methanesulfonate (CMS) are not scientifically based and have led to treatment failure and increased colistin resistance. In this review we summarise the recent progress made in the understanding of the pharmacokinetics of CMS and formed colistin with an emphasis on critically ill patients. The pharmacodynamics of colistin is also reviewed, with special attention given to the relationship between pharmacokinetics and pharmacodynamics and how the emerging data can be used to inform design of optimal dosage regimens. Recent data suggest the current dosage regimens of CMS are suboptimal in many critically ill patients.     

85例注射用硫酸多黏菌素B用药合理性评价与分析

摘要：目的 分析我院使用多黏菌素B患者的病例特点和用药情况，以期为优化多黏菌素B给药方案提供参考。方法 回 顾性分析2018年1月1日—2020年7月10日我院使用注射用硫酸多黏菌素B的所有住院患者的病例资料，共计85例，记录患者人 群特征、感染分布、微生物检查结果、用药情况、疗效及不良反应，对多黏菌素B的用药合理性进行评价及分析。结果 多黏 菌素B临床用于多重耐药革兰阴性菌的感染，主要为肺部感染、血流感染和皮肤软组织感染。检出病原菌前三位是铜绿假单胞 菌、鲍曼不动感染、肺炎克雷伯菌。其给药存在首剂未加倍、维持剂量偏低、疗程过短、给药途径及联合用药不适宜等不合理 现象。多黏菌素B相关不良反应8例，发生率为9.41%。结论 多黏菌素B在重症感染患者中的应用还有待进一步的规范和探讨， 临床用药过程中应密切关注不良反应的发生，进一步加强药学监护。     

Aerosolized antibiotics: the past,present and future,with a special emphasis on inhaled colistin

Inhaled antibiotics, such as TOBI (a tobramycin solution), gentamicin, colistin and aztreonam lysine (Cayston) have been effectively administered with safety and efficacy in patients with cystic fibrosis and bronchiectasis. In addition, inhaled antibiotics have been administered with safety and efficacy for the prevention and treatment of patients with ventilator-associated tracheobronchitis or pneumonia due to multidrug-resistant Gram-negative bacteria (mainly Pseudomonas aeruginosa or Acinetobacter baumannii). Original studies showed that inhaled colistin resulted in treatment success of nosocomial pneumonia or ventilator-associated pneumonia (VAP) due to multidrug-resistant Gram-negative bacteria. However, although aerosolized colistin seems to be safe and effective for the eradication of P. aeruginosa and the management of pneumonia in cystic fibrosis patients, hospital-acquired pneumonia and VAP due to multidrug-resistant Gram-negative bacteria, it is still unclear if it provides additional benefit in all-cause hospital mortality, or VAP-related mortality rates. For this reason, randomized controlled trials (RCTs) are necessary to validate the efficacy and safety of aerosolized colistin, mainly in patients with nosocomial pneumonia or VAP. In addition, RCTs are necessary to determine the appropriate inhaled colistin dose and the optimal delivery device.     

耐多黏菌素肺炎克雷伯菌的研究进展

碳青霉烯类耐药肺炎克雷伯菌导致的感染逐年攀升,使抗菌药物的选择陷入窘境。多黏菌素在临床上被重新启用治疗多重耐药革兰阴性杆菌引发的严重感染。但随其在畜牧业等领域的广泛应用和不合理使用,耐多黏菌素菌株报道逐年增多,耐药相关问题不断涌现。本文将多黏菌素耐药的主要机制和治疗中联合用药组合方式作一综述,以期为临床治疗提供指导。     

Inhaled colistin for lower respiratory tract infections

INTRODUCTION: Lower respiratory tract infections, due to Pseudomonas aeruginosa or Acinetobacter baumannii, are frequently encountered in patients with cystic fibrosis (CF) or in patients developing nosocomial pneumonias. Both of these conditions bear a high mortality risk and aggressive antibiotic therapy is necessary. Inhaled antibiotics might represent an effective therapeutic approach for these diseases as it has demonstrated good bactericidal efficacy and safety in both preclinical and clinical studies. This colistin formulation might be useful particularly in patients with respiratory tract infections due to multidrug-resistant Gram-negative bacteria. Its main advantages are a better safety profile with a minimal or absent risk of nephrotoxicity. AREAS COVERED: This paper discusses the available systemic formulations of colistin, with pharmacokinetic and safety profiles, followed by an overview of inhaled antibiotics in lower respiratory tract infections. EXPERT OPINION: Inhaled colistin should be used selectively as monotherapy in chronic infections with P. aeruginosa in CF patients, whereas in patients with hospital/ventilator-acquired pneumonia (HAP/VAP), it should be used in a combined regimen with systemic antibiotics.     

Klebsiella pneumoniae carbapenemases in Enterobacteriaceae: history, evolution, and microbiology concerns

Since the discovery of penicillin 80 years ago, gram-negative bacteria have become proficient at evading the lethal activity of β-lactam antibiotics, principally through the production of β-lactamases. The rapid emergence of penicillinases in both gram-positive and gram-negative bacteria led to the development of cephalosporin β-lactam antibiotics, but production of plasmid-mediated extended-spectrum cephalosporinases (or extended-spectrum β-lactamases) and AmpC enzymes resulted in resistance to this drug class. Because carbapenems were the only β-lactam agents active against such extended-spectrum β-lactamase-producing strains, appropriate and inappropriate use soon resulted in Enterobacteriaceae resistance. As a result, two distinct types of carbapenemases-the metallo-β-lactamases and Klebsiella pneumoniae carbapenemases (KPCs)-were soon identified. The KPCs comprise 10 variants that differ from one another by one to three amino acid substitutions (KPC-2 to KPC-11). The KPC-producing Enterobacteriaceae are not only multidrug resistant but are also difficult to detect routinely in the clinical microbiology laboratory. Tigecycline, polymyxins (colistin and polymyxin B), and aminoglycosides are possible candidate therapies for infections caused by KPC-producing organisms, although well-conducted clinical trials are required to fully define their roles in patient management. The shortage of new antimicrobial agents on the immediate horizon suggests that enhanced adherence with infection prevention procedures and antimicrobial stewardship programs are needed to curb patient-to-patient transmission and to reduce the selection of multidrug-resistant bacteria.     

Imipenem-cilastatin sodium, a broad-spectrum carbapenem antibiotic combination

The chemistry, antimicrobial spectrum, mechanism of action, pharmacology and pharmacokinetics, clinical use, adverse effects, dosage and administration, place in therapy, cost-effectiveness, and formulary considerations of imipenem-cilastatin sodium are reviewed. Imipenem is the first carbapenem antibiotic of the thienamycin class to be used clinically. Imipenem has the widest spectrum of antimicrobial activity of currently available beta-lactam agents and, in contrast to other beta-lactam antibiotics, lacks cross resistance with recently introduced extended-spectrum penicillins and third-generation cephalosporins. Against gram-positive and gram-negative aerobic and anaerobic organisms, imipenem demonstrates excellent activity. Pseudomonas maltophilia, some strains of Pseudomonas cepacia, and Streptococcus faecium are resistant. Strains of methicillin-resistant staphylococci should also be considered resistant to imipenem. For clinical use imipenem is coadministered in equal parts with cilastatin. Cilastatin is a renal dehydropeptidase inhibitor that inhibits the metabolism of imipenem by renal brush-border enzymes, thus increasing imipenem concentrations in urine. Imipenem-cilastatin is administered by the intravenous route only. The adverse reaction profile of imipenem-cilastatin is similar to t that of other beta-lactam antibiotics. Recommended dosage reductions appropriate for renal impairment should be guided by periodic assessments of renal function, with close adherence to recommended dosage schedules, particularly among patients who are predisposed to seizures or receiving anticonvulsant medication. Imipenem-cilastatin performed well in both comparative and noncomparative trials of clinical efficacy and safety. For infections with multiple organisms (e.g., pelvic, intra-abdominal, or soft-tissue infections), imipenem-cilastatin may be a cost-effective and less toxic single-agent alternative to "standard" combination (e.g., aminoglycoside-penicillin plus an antianaerobic agent) therapy. However, in patients with serious pseudomonal infections (e.g., pneumonia), isolates may rapidly acquire resistance to imipenem or be replaced by resistant strains of Ps. aeruginosa when imipenem is used alone. Therefore, when the recovery of Ps. aeruginosa is anticipated or documented, treatment with imipenem-cilastatin should include an aminoglycoside to reduce the likelihood of the emergency of resistant organisms during therapy.     

Quantitative determination of colistin A/B and colistin methanesulfonate in biological samples using hydrophilic interaction chromatography tandem mass spectrometry

Colistin (polymyxin E) is a polycation antibiotic which is increasingly used (administered as colistin methanesulfonate, CMS) as a salvage therapy in critically ill patients with multidrug resistant Gram‐negative infections. Even though colistin has been used for more than 50 years, its metabolic fate is poorly understood. One of the current challenges for studying the pharmacokinetics (PK) is the precise and accurate determination of colistin in in vitro and in vivo studies. In the present study, we developed and validated a series of sensitive and robust liquid chromatography tandem mass spectrometry (LC–MS/MS) methods for analysing biological samples obtained from in vitro and in vivo disposition assays. After a zinc acetate‐mediated precipitation, hydrophilic–lipophilic‐balanced solid phase extraction (HLB‐SPE) was used for the extraction of colistin. The compounds were retained on a hydrophilic interaction liquid chromatography (HILIC) column and were detected by MS/MS. CMS was quantified by determining the produced amount of colistin during acidic hydrolysis. The developed methods are sensitive with lower limits of quantification varying between 0.009 μg/mL and 0.071 μg/mL for colistin A, and 0.002 μg/mL to 0.013 μg/mL for colistin B. The intra‐ and inter‐day precision and accuracy were within ±15%. Calibration curves of colistin were linear (0.063 μg/mL to 8.00 μg/mL) within clinically relevant concentration ranges. Zinc acetate‐mediated precipitation and the use of a HILIC column were found to be essential. The developed methods are sensitive, accurate, precise, highly efficient and allow monitoring colistin and CMS in biological samples without the need for an internal standard.     

Colistin offers prolonged survival in experimental infection by multidrug-resistant Acinetobacter baumannii: the significance of co-administration of rifampicin

The effect of colistin on bacterial eradication and survival was tested in experimental infection by multidrug-resistant Acinetobacter baumannii. The thigh infection model was applied in 86 neutropenic Wistar rats. Six rats were used for the induction of neutropenia and for the selection of the dose regimen of colistin; the remainder was equally divided into four groups: A, controls; B, rifampicin; C, colistin; and D, both agents. Therapy was administered 5 h after bacterial challenge; 5mg/kg of rifampicin was administered intravenously and 3mg/kg of colistin intramuscularly. Survival was recorded in 10 animals of each group. The remaining 10 rats per group were killed 4h after therapy; blood and tissue samples were sampled. Median survival of animals of groups A, B, C and D was 2.00, 2.50, 4.00 and 4.00 days, respectively (P=0.0048 between A and C and P=0.0012 between A and D. Mortality rates after 6 days of follow-up were 100, 100, 100 and 70%, respectively (P=0.018 between groups). Statistically significant decreases of bacteria were found in blood, liver, lung and spleen of group B compared with A; in lung of group C compared with A; and in blood and liver of group D compared with A. Colistin was effective in prolonging survival in an experimental thigh infection by multidrug-resistant A. baumannii in neutropenic rats. Its activity was enhanced after co-administration with rifampicin. These results mandate the application of colistin in the event of infections by multidrug-resistant pathogens and the need for its co-administration with rifampicin.