Current review of antimicrobial treatment of nosocomial pneumonia caused by multidrug-resistant pathogens

Nosocomial pneumonia (including ventilator-associated pneumonia; VAP), a consistently difficult-to-treat entity, is frequently caused by multidrug-resistant (MDR) or pandrug-resistant (PDR) bacteria. Given the high mortality rates caused by drug-resistant bacteria and the difficulty of developing new potent antibiotics to target the problematic pathogens, combination regimens are under ardent evaluation as new strategies to overcome increasing drug resistance. Adjustment of the administration method of certain β-lactams (meropenem, or imipenem/cilastatin), or combination of tigecycline with some agents, may show promise with regard to successful management of MDR or PDR Acinetobacter baumannii pneumonia. Additionally, vancomycin plus rifampicin is an effective regimen against nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) responding poorly to vancomycin monotherapy. The clinical appropriateness of parenteral colistin against pneumonia caused by MDR A. baumannii has been established in a clinical trial. Facing the decline of clinical vancomycin efficacy after initial use, linezolid might be the drug of choice with regard to the treatment of MRSA-VAP. The role of tigecycline monotherapy for the management of nosocomial pneumonia caused by MRSA and extended-spectrum β-lactamase-producing Enterobacteriaceae needs to be cautiously evaluated.     

Potentially multidrug-resistant non-fermentative Gram-negative pathogens causing nosocomial pneumonia

Owing to its high morbidity and mortality, nosocomial pneumonia represents a particularly serious illness and one of the most frequent complications in ventilated patients admitted to the Intensive Care Unit. Gram-negative microorganisms, such as Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia, are the most relevant pathogens responsible for particularly difficult-to-treat nosocomial pneumonia. The intrinsic resistance of these bacteria to many antimicrobial agents and, in addition, the variety of their increasingly recognised acquired resistance mechanisms make their management in the hospital setting problematic. Antimicrobials that retain the best activity against P. aeruginosa include carbapenems, piperacillin, cefepime, ceftazidime, ciprofloxacin and certain aminoglycosides, whilst carbapenems and sulphamethoxazole/trimethoprim remain the most active agents against A. baumannii and S. maltophilia, respectively. However, the growing emergence among these microorganisms of multidrug-resistant (MDR) isolates and the severity of associated infections call for potential alternative drugs. Sulbactam alone or in combination with ampicillin may represent an acceptable option for MDR A. baumannii as well as colistin, which also covers MDR P. aeruginosa. Newer fluoroquinolones and some tetracyclines may be alternative drugs both for MDR S. maltophilia and A. baumannii. However, large-scale controlled clinical trials are needed to confirm these promising therapeutic options.     

Intravenous polymyxin B for the treatment of nosocomial pneumonia caused by multidrug-resistant Pseudomonas aeruginosa

Nosocomial pneumonia caused by multidrug-resistant (MDR) Pseudomonas aeruginosa is becoming increasingly prevalent throughout the world. The use of polymyxins to treat these infections has greatly increased. We analysed 74 patients with nosocomial pneumonia caused by MDR P. aeruginosa who were treated with polymyxin B. A favourable outcome was observed in 35 patients (47.3%). A case-control study was performed to assess the variables associated with an unfavourable outcome. The presence of acute respiratory distress syndrome (odds ratio (OR)=11.29, 95% confidence interval (CI) 2.64-48.22; P=0.001) and septic shock (OR=4.81, 95% CI 1.42-16.25; P=0.01) were independently associated with an unfavourable outcome in patients with nosocomial pneumonia due to MDR P. aeruginosa. Our study demonstrated that polymyxin B is a reliable antimicrobial drug, but only as salvage therapy, for nosocomial pneumonia caused by MDR P. aeruginosa.     

Doripenem: an expected arrival in the treatment of infections caused by multidrug-resistant Gram-negative pathogens

Background: Potent new drugs against multidrug-resistant Gram-negative bacteria, namely Pseudomonas aeruginosa and Acinetobacter spp. and pan-drug-resistant Klebsiella pneumoniae, which constitute an increasing medical threat, are almost absent from the future pharmaceutical pipeline. Objective: This drug evaluation focuses on the position of doripenem, a novel forthcoming carbapenem. Mechanisms of resistance and new drugs with anti-Gram-negative activity are also briefly reviewed. Methods: Literature search was performed for new carbapenems, new antibiotics, doripenem, metallo-β-lactamase inhibitors, multidrug-resistant pathogens, antipseudomonal antibiotics and multidrug-resistant epidemiology. Results: Doripenem possesses a broad spectrum of activity against Gram-negative bacteria, similar to that of meropenem, while retaining the spectrum of imipenem against Gram-positive pathogens. Against P. aeruginosa, doripenem exhibits rapid bactericidal activity with 2 – 4-fold lower MIC values, compared to meropenem. Exploitation of pharmacokinetic/pharmacodynamic applications could offer a treatment opportunity against strains exhibiting borderline resistance to doripenem. Stability against numerous β-lactamases, low adverse event potential and more potent in vitro antibacterial activity against P. aeruginosa and A. baumanni compared to the existing carbapenems, are its principal features.     

Levofloxacin for the treatment of pneumonia caused by Streptococcus pneumoniae including multidrug-resistant strains: pooled analysis

ABSTRACT

Objective: To determine the clinical and microbiologic efficacy of levofloxacin for the treatment of subjects with pneumonia caused by multidrug-resistant (MDR) Streptococcus pneumoniae (MDRSP) and non-MDRSP strains.

Research design and methods: A pooled analysis was conducted using data from ten clinical studies in pneumonia: five comparative studies and five noncomparative studies conducted from 1992 to 2002. This analysis included data from levofloxacin-treated subjects with S.?pneumoniae isolated at study entry. Susceptibility of S.?pneumoniae isolated from subjects at study entry was determined against representative agents from five antimicrobial classes: tetracyclines, sulfonamides, second-generation cephalosporins, penicillins, and macrolides. Isolates were classified as MDRSP (based on resistance to two or more antimicrobial classes) or non-MDRSP (intermediate resistance or susceptible to all classes or resistant to 1 antimicrobial class). Clinical and microbiologic efficacy of levofloxacin (i.v., p.o., or i.v./p.o. for 5 to 14 days) in the microbiologically evaluable population was determined at post-therapy; a test for homogeneity of the odds ratio of the difference in clinical success for comparative versus noncomparative studies was performed.

Main outcome measures and results: The main outcome measures were clinical success rates and microbiologic eradication rates of 419 microbiologically evaluable levofloxacin-treated subjects with MDRSP or non-MDRSP. Clinical success rates were 96.3% (52/54) and 95.1% (347/365), respectively (difference ?1.2; 95% confidence interval [CI]: ?6.7, 4.3). Similarly, per pathogen microbiologic eradication rates for MDRSP and non-MDRSP were 96.3% (52/54) and 95.6% (350/366), respectively (difference ?0.7; 95%?CI: ?6.1, 4.8). Study limitations include the use of data from comparative and noncomparative studies. A test for homogeneity of the odds ratios for clinical success in comparative versus noncomparative studies showed no significant difference (p?=?0.27).

Conclusions: These data support the use of levofloxacin for patients with community-acquired pneumonia caused by S.?pneumoniae, including MDR strains.     

Intrapulmonary pharmacokinetics of antibiotics used to treat nosocomial pneumonia caused by Gram-negative bacilli: A systematic review

Background

Knowledge of antibiotic concentrations achievable in the epithelial lining fluid (ELF) will help guide antibiotic dosing for treating patients with Gram-negative bacillary ventilator-associated pneumonia (VAP).

Colistin as a salvage therapy for nosocomial infections caused by multidrug-resistant bacteria in the ICU

The objective of this study was to determine the efficacy of systemic colistin therapy in the treatment of nosocomial infections caused by multidrug-resistant Acinetobacter baumannii or Pseudomonas aeruginosa and to study related adverse events. We prospectively studied 78 infections caused by multidrug-resistant A. baumannii or P. aeruginosa that were treated with colistin. The sites of infection were pulmonary infection (78.2%), urinary tract infection (7.7%), primary bloodstream infection (11.5%) and meningitis (2.6%). The mean daily dose of colistin was 5.5+/-1.1 MU/day (range 2-9 MU/day) and the mean duration of colistin therapy was 9.3+/-3.8 days (range 5-21 days). A favourable clinical response to colistin occurred in 60 cases (76.9%). Renal failure occurred in only seven cases. We conclude that colistin can be a safe and effective salvage therapeutic option for nosocomial infections caused by multidrug-resistant A. baumannii or P. aeruginosa.     

Efficacy of 750-mg, 5-day levofloxacin in the treatment of community-acquired pneumonia caused by atypical pathogens

BACKGROUND: Current recommended durations for treatment of atypical community-acquired pneumonia (CAP) range from 10 to 21 days. However, antibiotics such as the fluoroquinolones may allow for effective, short-course regimens. OBJECTIVE: This study evaluated the efficacy of 750 mg levofloxacin for 5 days compared to a 500-mg, 10-day levofloxacin regimen for the treatment of atypical CAP. METHODS: A randomized, active-controlled, double-blind, multicenter study was conducted within the United States. Of the 528 patients enrolled in the study, 149 were diagnosed with CAP due to Legionella pneumophila, Chlamydia pneumoniae, or Mycoplasma pneumoniae. Patients' baseline symptoms were re-evaluated on Day 3 of therapy. Clinical efficacy and resolution of CAP symptoms were evaluated at the posttherapy visit (7-14 days after the last dose of active drug). RESULTS: This report represents a subgroup analysis of a previous clinical study. Among the 123 clinically evaluable patients diagnosed with atypical CAP (26 patients were unevaluable), the clinical success rates were 95.5% (63 of 66 patients) for the 750-mg group and 96.5% (55 of 57 patients) for the 500-mg group (95% CI for success rate of the 500-mg group minus that of the 750-mg group, -6.8 to 8.8). At the poststudy evaluation (31-38 days after treatment began), relapse occurred in 相似文献   

The importance of tissue penetration in achieving successful antimicrobial treatment of nosocomial pneumonia and complicated skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus: vancomycin and linezolid

Abstract

Background:

The rising prevalence of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) and the recent emergence of community-associated MRSA are major clinical, public health, and economic challenges. MRSA is a leading cause of nosocomial pneumonia and complicated skin and soft-tissue infections (cSSTI). Vancomycin and linezolid are two commonly used antimicrobial agents with activity against Gram-positive pathogens, particularly MRSA, that are used to treat both nosocomial pneumonia and cSSTI. Recently, the therapeutic efficacy of vancomycin in the treatment of hospitalized patients with MRSA infections has been questioned due to the emergence of MRSA strains with reduced susceptibility to vancomycin together with concerns related to inadequate dosing and poor tissue penetration of the drug.     

Early experience with tigecycline for ventilator-associated pneumonia and bacteremia caused by multidrug-resistant Acinetobacter baumannii

Study Objective . To evaluate early experience with tigecycline alone or in combination with other antimicrobials for treatment of ventilator-associated pneumonia (VAP) and/or bacteremia caused by multidrug-resistant Acinetobacter baumannii. Design . Retrospective case series. Setting . University-affiliated medical center. Patients . Twenty-five patients with multidrug-resistant A. baumannii who received tigecycline for VAP (19 patients), bacteremia (3), or VAP plus bacteremia (3) between September 1, 2005, and May 31, 2006. Five patients were treated with tigecycline alone. Measurements and Main Results . Primary outcomes were resolution of clinical signs and symptoms of the infection and documented microbial eradication of A. baumannii with tigecycline. Overall, 21 (84%) of the 25 patients had clinical resolution. Four had clinical failure: three with VAP and one with VAP plus bacteremia that developed resistance to tigecycline during therapy. Microbial eradication was demonstrated in 12 (80%) of 15 patients in whom repeat cultures were obtained. Three patients with VAP had a recurrence of infection: one patient had two recurrences, and two patients had one recurrence each. All four recurrent episodes led to clinical resolution and microbial eradication. No patients discontinued tigecycline because of adverse events. Conclusion . Tigecycline was effective in most of these 25 patients when used alone or in combination with other antimicrobials for VAP and/or bacteremia caused by multidrug-resistant A. baumannii. The emergence of a resistant strain while one patient was receiving therapy, however, is concerning.     

哌拉西林和阿米卡星联用治疗重度院内铜绿假单胞菌肺炎评价

对哌拉西林和阿米卡星联用以头孢他啶为对照治疗４３例重度院内铜绿假单胞菌肺炎的疗效、细菌清除、不良反应等方面进行了评价，结果表明：两药联用组（２１例）总有效率为７１．４％，细菌清除率为８２．４％，不良反应发生率为９．５％；与头孢他啶组（２２例）比较无显著性差异（Ｐ＞０．０５）。结果揭示：对肝、肾功能正常重度院内铜绿假单胞菌肺炎患者，哌拉西林和阿米卡星联用可作为临床重要治疗方案之一予以选用。     

Current antimicrobial management of community-acquired pneumonia in HIV-infected children

Introduction: Community-acquired pneumonia is a leading cause of morbidity and mortality amongst HIV-infected infants and children. Polymicrobial infection is common and, due to the difficulties in confirming the etiology of pneumonia, empiric broad-spectrum antimicrobial therapy is frequently used.

Areas covered: The author based this article on literature identified from PubMed. The author’s search terms included: pneumonia, community-acquired pneumonia, HIV, children. The articles reviewed included original studies, recent review articles and current guidelines on the management of pneumonia in HIV-infected children. The microbiological etiology and the empiric and pathogen-specific antimicrobial therapy of community-acquired pneumonia in HIV-infected and HIV-exposed infants and children are also discussed.

Expert opinion: There are many changing epidemiological factors impacting antimicrobial management of community-acquired pneumonia in the context of HIV infection in infants and children. These include vaccination strategies, antimicrobial prophylaxis, emerging drug-resistant pathogens, and recognition of the importance of viruses and tuberculosis in the etiology of community-acquired pneumonia. Further research is needed on optimal amtimicrobial management strategies in HIV-exposed uninfected children, and HIV-infected children receiving antiretroviral therapy.     

Current concepts in the antimicrobial therapy of community-acquired pneumonia

The majority of community-acquired pneumonias (CAPs) are caused by typical bacterial pathogens, i.e., S. pneumoniae, H. influenzae or M. catarrhalis. Atypical pneumonias, i.e., legionnaires' disease, C. pneumoniae pneumonia and M. pneumoniae pneumonia are less common in frequency than typical bacterial pathogens, but are of considerable public health and therapeutic importance. The newest therapeutic considerations in CAP are related to monotherapy versus combination therapy, parenteral versus oral therapy, minimizing the emergence of penicillin-resistant pneumococci and an appreciation that comorbid factors in antibiotic selection are unimportant. Monotherapy using a respiratory quinolone or doxycycline covers both typical and atypical causes of CAPs and is equally efficacious and less expensive than double drug therapy. Except in patients unable to take oral medications/those in CCUs, patients with CAP may be started on i.v. antibiotic therapy, but should be switched to oral therapy after 48 hours/clinical defervescence. The combination of 2 days of i.v. therapy plus 12 days of oral therapy has been shown to be as effective as 14 days of i.v. therapy. The use of doxycycline or respiratory quinolones may forestall or eliminate the emergence of highly penicillin-resistant pneumococci, and, for this reason, these agents probably should be used preferentially over beta-lactam antibiotics to treat CAPs. The status of the host's immune system, particularly intact splenic function, and the underlying condition of the cardiorespiratory system are the critical factors in predicting mortality, morbidity, complications and hospital stay. However, antibiotic selection is not affected by comorbidities, and antibiotics should not be changed or added to the usual therapy of CAP because of comorbid factors. Multiple drug therapy does not improve the outcome, which is a function of underlying host factors.     

Investigational drugs for the treatment of infections caused by multidrug-resistant Gram-negative bacteria

Introduction: Infections caused by multidrug-resistant Gram-negative bacteria (MDR-GNB) are associated with significant mortality and costs. New drugs in development to combat these difficult-to-treat infections primarily target carbapenem-resistant Enterobacteriaceae, MDR Pseudomonas aeruginosa, and MDR Acinetobacter baumannii.

Areas covered: The authors summarize in vitro and in vivo efficacy studies, as well as available clinical trial findings, for new agents in development for treatment of infection caused by MDR-GNB. Information regarding dosage regimens utilized in clinical trials and key pharmacokinetic and pharmacodynamic considerations are provided if available. A summary of recently approved agents, delafloxacin and meropenem/vaborbactam, is also included.

Expert opinion: The development of multiple novel agents to fight MDR-GNB is promising to help save the lives of patients who acquire infection, and judicious use of these agents is imperative once they come to market to prevent the development of resistance. The other component paramount to this field of research is implementation of effective infection control policies and carbapenem-resistant Enterobacteriaceae (CRE) carrier screening protocols to mitigate the worldwide spread of MDR-GNB. Further investigation of anti-infective synergistic combinations will also be important, as well as support for economic research to reveal the true cost-benefit of utilization of the new agents discussed herein.     

Community-acquired pneumonia: new management strategies for evolving pathogens and antimicrobial susceptibilities

Community-acquired pneumonia (CAP) is still one of the leading causes of mortality and morbidity. The most common bacterial cause of CAP is Streptococcus pneumoniae. The increase in antimicrobial resistance has raised concerns about the efficacy of available therapies, and a call for the reassessment of both existing and newer therapeutic agents. Although microbiological breakpoints are useful for monitoring the emergence of resistance, the current National Committee for Clinical Laboratory Standards (NCCLS) guidelines make no distinction between clinical and microbiological breakpoints. Recent changes in NCCLS breakpoints for extended spectrum cephalosporins have provided a more meaningful approach to susceptibility testing and to consideration of the site of infection. Further controversy surrounds the clinical guidelines relating to CAP in terms of which antimicrobial agents should be given empirically to which types of patients. Within this review, the role of monotherapy versus the need for combination antimicrobial therapy, which often includes a macrolide and an extended spectrum cephalosporin such as ceftriaxone, is discussed. This review also discusses the various aspects of antimicrobial susceptibilities of S. pneumoniae, the drivers and influences of increasing resistance, the clinical relevance of this resistance and possible therapeutic options in the face of changing susceptibilities and mixed bacterial aetiologies. New guidelines from the IDSA attempt to embrace these changes.     

Perspectives on synthetic pharmacotherapy for the treatment of nosocomial pneumonia

ABSTRACT

Introduction: Nosocomial pneumonia is the second most common infection in hospital settings, resulting in substantial increases in morbidity, mortality, and length of hospital stay. The rapid increase in resistance of nosocomial pathogens to many antibiotics and the high dissemination of resistance genes highlight the need for innovative approaches to combat difficult-to-treat nosocomial respiratory infections.

Areas covered: This review summarizes the synthetic antimicrobials that are currently in development for the treatment of nosocomial pneumonia, focusing on antibiotics in the final phases of clinical development and on the strategies employed by novel synthetic antimicrobial peptides.

Expert opinion: Several novel synthetic antimicrobials are currently in the pipeline, and it appears that new antimicrobial peptides or mimetics will soon be made available, expanding the opportunities to treat nosocomial pneumonia. However, the approval process for use in the treatment of nosocomial pneumonia is arduous. Given that significant investments by pharmaceutical companies have ended in failure to obtain the approval of regulatory agencies, novel platforms for antimicrobial discovery are needed. The identification of new and fully synthetic chemical structures with activity against nosocomial pathogens needs to be followed by preclinical studies in large animals and by pharmacokinetic and pharmacodynamic studies in specific critically ill populations to assess lung penetration.     

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。     

Linezolid for the treatment of infections caused by Gram-positive pathogens in China

In this randomised, double-blind, comparator-controlled, multicentre study conducted in China, 142 hospitalised patients aged 18-75 years with pneumonia (n=80) or complicated skin and soft-tissue infection (cSSTI) (n=62) due to suspected or known Gram-positive pathogens were randomised (1:1) to receive either linezolid 600mg (n=71) or vancomycin 1g in patients aged 60 years (n=71) intravenously every 12h. The duration of treatment was 10-21 days for patients with pneumonia and 7-21 days for patients with cSSTI. Clinical outcomes were assessed at end-of-treatment (EOT) visit and follow-up (FU) visit 7-28 days post therapy. Staphylococcus aureus was the most common pathogen at baseline and most of these isolates were resistant to meticillin. All isolates were susceptible to linezolid and vancomycin. For the evaluable patients, the effective treatment rate for linezolid was higher than that for vancomycin at EOT (86.9% (53/61) vs. 61.7% (37/60)) and at FU (83.1% (49/59) vs. 64.9% (37/57)). Pathogen eradication rates for the microbiologically evaluable patients at FU were 79.2% (42/53) for linezolid and 61.5% (32/52) for vancomycin. The incidence of drug-related adverse events (AEs) was 25.4% (18/71) for linezolid and 16.9% (12/71) for vancomycin. Four (5.6%) linezolid-treated and eight (11.3%) vancomycin-treated patients discontinued the study drug because of an AE. Linezolid was well tolerated and effective for the treatment of infections caused by Gram-positive pathogens, including meticillin-resistant S. aureus.