Therapeutic options for Acinetobacter baumannii infections: an update

Introduction: Although the clinical importance of Acinetobacter pittii and Acinetobacter nosocomialis has increased in the nosocomial setting in the last decade, infections caused by Acinetobacter baumannii still have the highest clinical relevance. The most important features of this latter species are the ability to persist in the hospital environment and the multi-drug, extended-drug or pandrug resistance they may present which compromises the treatment of infections caused by this microorganism.

Areas covered: In the present review, the authors describe the molecular bases of the acquisition of resistant mechanisms as well as different current and potential future strategies to treat infections caused by multi-drug resistant A. baumannii.

Expert opinion: With the increase in resistance to carbapenems, colistin has been extensively used, however some data suggest that the doses recommended are insufficient before a steady state is reached, suggesting that the administration of a loading dose on initiation of treatment may be beneficial. Combinations of antibacterial agents such as impenem plus sulbactam or imipenem plus colistin have been successfully used to treat VAP. Nonetheless, future alternatives for treating A. baumannii infections should be explored.     

Therapeutic options for infections due to vancomycin-resistant enterococci

Background: Vancomycin-resistant enterococci (VRE) are an important cause of nosocomial infection occurring in critical care or immunocompromised patients. Objectives: To provide updated information about therapeutic options for VRE infection. Methods: MEDLINE, EMBASE, and the Cochrane Library were searched to identify in vitro susceptibility data of VRE isolates, randomized and non-randomized controlled trials, case series, and cohort studies of VRE therapy published before 31 July 2008. Results/conclusion: The updated in vitro susceptibility data for VRE show high resistance to ampicillin and aminoglycosides. Quinupristin-dalfopristin is limited by its lack of activity against vancomycin-resistant Enterococcus faealis and its musculoskeletal side effects. Emerging linezolid resistance has been reported to cause hospital spread and may be related to prolonged linezolid use. Quinupristin-dalfopristin resistance is usually linked to agricultural use of streptogramin. Nitrofurantoin and fosfomycin are alternatives in uncomplicated VRE urinary tract infection. Daptomycin and tigecycline have shown excellent potential for treating VRE infection.     

鲍曼不动杆菌的临床分离及其耐药性分析

目的 分析鲍曼不动杆菌（Ab）对抗菌药物的耐药性,以指导临床医师合理用药. 方法 应用法国生物-梅里埃ATB Expression型全自动鉴定等系统分析我院2009年1月1日至2010年2月28日住院患者分离出的56株Ab,对其分离率,耐药性进行分析. 结果 总分离率分别为：2009年1～4月1.25%（9/720）;2009年5～10月2.07%（15/726）;2009年11月至2010年2月4.34%（32/738）.其中重症监护室在各病区占的比例较高,百分比为53.6%,该菌在临床各种标本中的分布情况以百分比计其中痰标本高达87.5%. 结论 Ab目前对多黏菌素E无耐药,对亚胺培南、美罗培南敏感,对其他抗菌药物已高度耐药;重视细菌培养、合理使用抗菌药物有利于控制耐药菌的产生.     

Multidrug-resistant Acinetobacter baumannii infections: Current evidence on treatment options and the role of pharmacokinetics/pharmacodynamics in dose optimisation

Acinetobacter baumannii remains a difficult-to-treat pathogen that poses a significant challenge to clinicians and costs to the healthcare system. There is a lack of clinical efficacy data to aid in the selection of optimal treatment for multidrug-resistant (MDR) A. baumannii infections. This paper aimed to review recent literature on the treatment of MDR A. baumannii infections and novel agents in the pipeline and to discuss the clinical data supporting their use. Colistin has been widely studied as monotherapy or as part of combination therapy, but its use is limited due to nephrotoxicity. The clinical benefit of combination therapy, whether empirical or targeted, has yet to be demonstrated owing to a lack of definitive evidence from randomised controlled trials (RCTs). Most available clinical studies are retrospective and lack control groups, which offers low-grade evidence. Novel agents such as cefiderocol, plazomicin, eravacycline and sulbactam/ETX2514 combination are promising options for the treatment of different infectious pathologies caused by MDR A. baumannii, but these have yet to be evaluated in RCTs. A better understanding of the pharmacokinetics/pharmacodynamics of the ‘old’ antibiotics is required to optimise their dosing regimens in order to maximise bacterial killing, minimise toxicities and improve clinical outcomes.     

Repurposing the anticancer drug mitomycin C for the treatment of persistent Acinetobacter baumannii infections

Acinetobacter baumannii is an emergent opportunistic bacterial pathogen responsible for recalcitrant infections owing to its high intrinsic tolerance to most antibiotics; therefore, suitable strategies to treat these infections are needed. One plausible approach is the repurposing of drugs that are already in use. Among them, anticancer drugs may be especially useful due their cytotoxic activities and ample similarities between bacterial infections and growing tumours. In this work, the effectiveness of four anticancer drugs on the growth of A.?baumannii ATTC BAA-747 was evaluated, including the antimetabolite 5-fluorouracil and three DNA crosslinkers, namely cisplatin, mitomycin C (MMC) and merphalan. MMC was the most effective drug, having a minimum inhibitory concentration for 50% of growth in Luria–Bertani medium at ca. 7?µg/mL and completely inhibiting growth at 25?µg/mL. Hence, MMC was tested against a panel of 21 clinical isolates, including 18 multidrug-resistant (MDR) isolates, 3 of which were sensitive only to colistin. The minimum inhibitory concentrations and minimum bactericidal concentrations of MMC in all tested strains were found to be similar to those of A.?baumannii ATCC BAA-747, and MMC also effectively killed stationary-phase, persister and biofilm cells. Moreover, MMC was able to increase survival of the insect larvae Galleria mellonella against an otherwise lethal A.?baumannii infection from 0% to ≥53% for the antibiotic-sensitive A.?baumannii ATCC BAA-747 strain and the MDR strains A560 and A578. Therefore, MMC is highly effective at killing the emergent opportunistic pathogen A.?baumannii.     

新型抗生素在耐药鲍曼不动杆菌感染治疗中的研究进展

近年来,鲍曼不动杆菌的耐药问题日趋显著。科学家通过改良现有抗生素结构或改变作用靶点的方法,针对耐药菌尝试设计新型抗生素。本文总结了新型抗生素氟环素类、铁载体头孢菌素、新型氨基糖苷类、二氮杂二环辛烷衍生物、多黏菌素B衍生物、基于联苯乙炔的LpxC抑制剂在耐药鲍曼不动杆菌感染治疗中的作用机制、抗菌活性以及安全性。     

血流感染的耐碳青霉烯类鲍曼不动杆菌的分子机制及临床研究

目的 探讨血流感染的耐碳青霉烯类鲍曼不动杆菌(CRAB)耐药机制,分析菌株同源性及患者的临床特征,为CRAB的感染控制提供实验依据。方法 采用Bact/Alert 3D全自动血培养系统进行血培养,细菌鉴定和药敏使用Vitek-2 Compact全自动微生物分析系统。对2010年6月-2016年5月临床血流感染患者分离到的27株碳青霉烯类药物(亚胺培南和/或美罗培南MIC≥16μg/mL)耐药的CRAB复苏菌株,重新采用Vitek-MS质谱分析仪鉴定,采用改良Hodge试验检测碳青霉烯酶,PCR法检测B类酶基因(blaNDM、blaIMP和blaVIM)和D类酶基因(blaOXA-23、blaOXA-24、blaOXA-51和blaOXA-58)并测序比对。采用MALDI-TOF分析菌株同源性,并分析患者的临床资料及感染相关信息。结果 血流感染的CRAB绝大多数对常用抗生素耐药。27株CRAB改良Hodge试验均阳性。所有CRAB均未检测到B类酶基因(blaNDM、blaIMP和blaVIM);25株CRAB同时检测到blaOXA-23和blaOXA-51;另2株CRAB则为blaOXA-58阳性。采用Vitek-MS进行同源性分析,细菌分成3大簇(Ⅰ型13株、Ⅱ型12株、Ⅲ型2株)。85.2%(25/27)患者来自重症监护病房或专科的监护病床,原发感染灶以肺部炎症最常见(11例)。所有的患者在血培养出CRAB前的30d内均有抗菌药物使用史,使用频率较高的抗菌药物有：碳青霉烯类、氟喹诺酮类、头霉素类。15例CRAB血流感染患者死亡。结论 厦门地区的CRAB以D类产碳青霉烯酶OXA-23和OXA-51最为多见。CRAB血流感染的原发感染多为肺部炎症。     

New molecules and adjuvants in the treatment of infections by Acinetobacter baumannii

Introduction: The current problems of the treatment of infections by Acinetobacter baumannii are linked with the increase of multidrug- and extensive-drug resistance and the lack of development of new antimicrobial drugs for Gram-negative bacilli. For these reasons, new alternatives for the treatment and control of severe infections by A. baumannii are necessary. Several studies have reported the effect of adjuvants to restore the efficacy of existing antimicrobial agents.

Areas covered: In the present review, the authors describe the main results in the development of adjuvant drugs as well as new data on antimicrobial peptides, in monotherapy or in combination therapy with existing antimicrobial agents, which have shown promising preclinical results in vitro and in vivo.

Expert opinion: The preclinical evaluation of adjuvants and antimicrobial peptides, in monotherapy or in combination therapy, for A. baumannii infections has shown promising results. However, caution is needed and further extensive in vivo studies and clinical trials have to be performed to confirm the potential use of these adjuvants as true therapeutic alternatives.     

Severe nosocomial infections with imipenem-resistant Acinetobacter baumannii treated with ampicillin/sulbactam

Forty consecutive patients with nosomial infections caused by multidrug-resistant Acinetobacter baumannii were treated with intravenous ampicillin/sulbactam. The infections were primary bloodstream (32.5%), pneumonia (30%), urinary tract (15%), peritonitis (7.5%), surgical site (7.5%), meningitis (5%) and sinusitis (2.5%). Most were severe infections with underlying conditions (median APACHE II score: 14.5) and 72.5% occurred in the ICU. Twenty-seven (67.5%) were improved/cured, seven (17.5%) were failures and six (15%) were considered to have an indeterminate outcome because patients died within the first 48 h of treatment. Two cases of meningitis were treated and did not respond. The median daily dose of ampicillin/sulbactam was 6 g/3 g and six patients received 12 g/6 g. No adverse effects were observed. This study indicates that ampicillin/sulbactam may be a good and safe therapeutic option to treat severe nosocomial infections caused by multi-drug resistant A. baumannii.     

Rifabutin for infusion (BV100) for the treatment of severe carbapenem-resistant Acinetobacter baumannii infections

Rifamycin antibiotics were discovered during the 1950s, and their main representative, rifampicin, remains a cornerstone treatment for TB. The clinical use of rifamycin is restricted to mycobacteria and Gram-positive infections because of its poor ability to penetrate the Gram-negative outer membrane. Rifabutin, a rifamycin antibiotic approved for the prevention of Mycobacterium avium complex disease, makes an exception to this rule by hijacking the iron uptake system of Acinetobacter baumannii, resulting in potent activity against this important Gram-negative pathogen. Here, we describe recent findings on the specific activity of rifabutin and provide evidence of the need for the development of an intravenous formulation of rifabutin (BV100) for the treatment of difficult-to-treat carbapenem-resistant A. baumannii infections.     

Antimicrobial treatment and clinical outcome for infections with carbapenem- and multiply-resistant Acinetobacter baumannii around London

Carbapenem- and multiply-resistant Acinetobacter baumannii (C-MRAB) are challenging pathogens, often susceptible only to polymyxins and tigecycline. We reviewed clinical outcomes in relation to antibiotic treatment for 166 consecutive patients infected or colonised with these organisms at 18 hospitals around London, UK. Clinical data were obtained along with the isolates, which were typed by pulsed-field gel electrophoresis (PFGE). Outcomes were compared for colonised and infected patients and in relation to treatment, with associations examined by logistic regression. Most subjects (103/166; 62%) were in Intensive Care Units (ICUs) or high dependency units; 84 (50.6%) were judged to be infected and 73 (44.0%) were colonised, with 9 indeterminate. Among the 166 C-MRAB isolates, 141 belonged to OXA-23 clone 1, a European clone II lineage. Survival rates among infected and colonised patients were 68% and 67%, respectively (P > 0.05), indicating little attributable mortality. Univariate and multivariate analyses indicated poorer outcomes among ICU-infected patients and those with pulmonary infection or bacteraemia, whereas trauma patients had significantly better outcomes than the generality. Outcomes varied with hospital, even in multivariate analysis, reflecting either differences in management or case mix. There was little association between outcome and therapy with colistin and/or tigecycline except that, among patients with respiratory infection, 12/15 treated with intravenous colistin alone had poor outcome compared with 1/8 whose therapy include nebulised colistin. This difference was significant (P = 0.003), although the patients receiving nebulised drug were mostly younger, included trauma cases and were at a hospital with good outcomes.     

Treatment options for multidrug-resistant Acinetobacter species

Multidrug-resistant Acinetobacter spp. are emerging nosocomial pathogens and have become a leading cause of Gram-negative infections in many parts of the world. Acinetobacter spp. are commonly implicated in bloodstream infection, hospital-acquired pneumonia, and wound and other surgical-site infections. They are difficult to treat, thus often leading to adverse patient outcome. Group II carbapenems (imipenem/cilastatin and meropenem) are the agents of choice for the treatment of severe infections caused by Acinetobacter spp. isolates susceptible to this antimicrobial group, but infection with carbapenem-resistant strains is increasingly encountered. Therapy of such infections necessitates the use of old drugs (e.g. colistin), unusual drugs (e.g. sulbactam) or drugs with which there is presently little clinical experience (e.g. tigecycline). Case reports, case series and small comparative observational studies suggest that these regimens are efficacious and demonstrate lower-than-expected toxicity, but there is substantial variation between these reports. Combination antimicrobial therapy is often used to treat infections caused by such multidrug-resistant strains. This article summarizes the cumulative experience with and the evidence for treating infections caused by multidrug-resistant Acinetobacter spp. infections. Special emphasis is placed on the use of 'non-traditional' antimicrobial agents, various aspects of combination therapy, alternative routes of drug administration, and discrete entities such as ventilator-associated pneumonia and postsurgical meningitis.     

某院鲍曼不动杆菌血流感染治疗方案的制定

目的：制定某院鲍曼不动杆菌血流感染的治疗方案。方法：收集某院2015-2016年血标本培养出的鲍曼不动杆菌39株,测定对氨苄西林舒巴坦,替加环素,亚胺培南,美罗培南的最低抑菌浓度。运用蒙特卡洛方法计算不同方案的达标概率（PTA）和累积反应分数（CFR）。结果：氨苄西林舒巴坦3 g q6h对鲍曼不动杆菌的CFR为66.05%,替加环素50 mg q12h,100 mg q12h的CFR分别为95.75%和99.77%,亚胺培南1 g q8h,q6h和美罗培南1 g q8h,q6h的CFR分别是67.74%,96.56%和74.19%,88.8%。结论：某院鲍曼不动杆菌血流感染时,经验选择可用替加环素50 mg q12h,100 mg q12h和亚胺培南1 g q6h方案。目标治疗应根据最低抑菌浓度（MIC）情况选择方案。     

Emergence of resistance to carbapenems in Acinetobacter baumannii in Europe: clinical impact and therapeutic options

Despite having a reputation of low virulence, Acinetobacter baumannii is an emerging multidrug-resistant (MDR) pathogen responsible for community- and hospital-acquired infections that are difficult to control and treat. Interest in this pathogen emerged about one decade ago because of its natural MDR phenotype, its capability of acquiring new mechanisms of resistance and the existence of nosocomial outbreaks. Recent advances in molecular biology, including full genome sequencing of several A. baumannii isolates, has led to the discovery of the extraordinary plasticity of their genomes, which is linked to their great propensity to adapt to any environment, including hospitals. In this context, as well as the increasing antimicrobial resistance amongst A. baumannii isolates to the last-line antibiotics carbapenems and colistin, therapeutic options are very limited or absent in some cases of infections with pandrug-resistant bacteria. However, a large proportion of patients may be colonised by such MDR bacteria without any sign of infection, leading to a recurrent question for clinicians as to whether antibiotic treatment should be given and will be effective in the presence of resistance mechanisms. The worldwide emergence of A. baumannii strains resistant to colistin is worrying and the increasing use of colistin to treat infections caused by MDR bacteria will inevitably increase the recovery rate of colistin-resistant isolates in the future. Current knowledge about A. baumannii, including biological and epidemiological aspects as well as resistance to antibiotics and antibiotic therapy, are reviewed in this article, in addition to therapeutic recommendations.     

Colistin-based treatment for extensively drug-resistant Acinetobacter baumannii pneumonia

Data for treatment and outcomes of extensively drug-resistant Acinetobacter baumannii (XDR-AB) pneumonia are limited. A retrospective cohort study of 236 adult patients with XDR-AB pneumonia was conducted between January 2009 and December 2012. The median age of subjects was 70 years (range 17–95 years), 53% were male, 55% had ventilator-associated pneumonia and 42% had been admitted to the intensive care unit. All XDR-AB isolates were susceptible only to tigecycline and colistin; 52 (22%) of the 236 subjects did not receive an agent active against XDR-AB, with an associated 28-day survival of 0%. Colistin-based two-drug combination treatment was prescribed to 166 subjects (70%); regimens included (i) colistin and high-dose sulbactam (n = 93); (ii) colistin and tigecycline (n = 43); and (iii) colistin and high-dose prolonged infusion of a carbapenem (n = 30). The 28-day survival rate and mean length of hospital stay were not statistically different between these three regimens (65%, 53% and 60% and 39, 39 and 38 days, respectively). Predictors of mortality included Acute Physiology and Chronic Health Evaluation (APACHE) II score [adjusted odds ratio (aOR) = 1.11; P < 0.001 for each point increase], duration from infection onset to receipt of active regimen (aOR = 1.01; P = 0.002 for each hour delay), underlying malignancy (aOR = 3.46; P = 0.01) and chronic kidney disease (aOR = 2.85; P = 0.03). These findings suggest that the three colistin-based two-drug combination regimens may be treatment options for XDR-AB pneumonia.     

临床药师参与治疗鲍曼不动杆菌颅内感染患儿的药学实践

目的为临床救治重症难治性鲍曼不动杆菌颅内感染患儿提供用药参考。方法通过分析临床药师参与救治我院1例鲍曼不动杆菌颅内感染患儿提供的药学服务,根据患者的病情变化,临床药师结合药物的药理药化知识,查阅相关文献资料,与临床医师共同协商,制定出最优的药物治疗方案。结果通过临床医师及临床药师的共同努力,最终成功救治该患儿。结论临床药师的参与可以协助医师制订安全、有效的治疗方案。     

替加环素治疗多重耐药鲍曼不动杆菌感染的疗效观察

目的回顾性分析替加环素治疗多重耐药鲍曼不动杆菌(MDRAB)的微生物学清除率及临床治疗效果。方法我院重症医学科2011年9月至2013年5月,26例确诊为MDRAB感染的患者。使用替加环素治疗,替加环素首剂100 mg,随后每12 h 50 mg静脉滴注,疗程≥5 d,收集其临床及微生物学相关资料。结果26例鲍曼不动杆菌感染患者应用替加环素治疗后17例(17/26,65.4%)临床治疗有效,22例(22/26,84.6%)微生物清除。14 d死亡率15.4%。4例(15.4%)因临床和细菌学反应差而在2周内死亡。其中血流感染9例中微生物学清除8例,临床治疗有效5例;肺部感染16例中微生物清除13例,临床治疗有效11例;1例血流感染合并肺部感染微生物和临床反应均成功。结论替加环素治疗MDRAB感染具有良好疗效。     

鲍曼不动杆菌的临床调查

目的　了解鲍曼不动杆菌在医院的分布 ,动态观察其耐药性发展情况 ,为临床合理应用抗生素提供依据。方法　用法国生物梅里埃公司的API及VITEK2鉴定系统对临床分离菌株进行鉴定 ,用K- B纸片扩散法进行药敏试验 ,用WHONET5软件对药敏结果进行统计学分析。结果　鲍曼不动杆菌对所监测的 11种抗生素均有不同程度的耐药 ,动态观察其耐药率有逐渐增高的趋势 ,尤以 2 0 0 3年增高最为明显 ,重症监护室 (ICU)的耐药率明显高于非ICU。结论　多重耐药的鲍曼不动杆菌感染在临床上呈上升趋势 ,尤其在ICU ,使临床医生对鲍曼不动杆菌感染的治疗越来越棘手 ,因此对鲍曼不动杆菌进行规范的连续的耐药监测 ,及时发现耐药菌株 ,对临床调整治疗方案、预防医院感染的发生是十分重要的。