Pandrug-resistant Gram-negative bacteria: the dawn of the post-antibiotic era?

doi:10.1016/j.ijantimicag.2006.12.012

International Journal of Antimicrobial Agents

Volume 29, Issue 6, June 2007, Pages 630-636

https://doi.org/10.1016/j.ijantimicag.2006.12.012 Get rights and content

Abstract

The evolving problem of antimicrobial resistance in Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae has led to the emergence of clinical isolates susceptible to only one class of antimicrobial agents and eventually to pandrug-resistant (PDR) isolates, i.e. resistant to all available antibiotics. We reviewed the available evidence from laboratory and clinical studies that reported on polymyxin-resistant and/or PDR P. aeruginosa, A. baumannii or K. pneumoniae clinical isolates. Eleven laboratory studies reported on isolates with resistance to polymyxins, three of which (including two surveillance studies) also included data regarding PDR isolates. In addition, two clinical studies (from Central and Southern Europe) reported on the clinical characteristics and outcomes of patients infected with PDR isolates. These data suggest that polymyxin-resistant or PDR P. aeruginosa, A. baumannii and K. pneumoniae clinical isolates are currently relatively rare. However, they have important global public health implications because of the therapeutic problems they pose. The fears for the dawn of a post-antibiotic era appear to be justified, at least for these three Gram-negative bacteria. We must increase our efforts to preserve the activity of available antibiotics, or at least expand as much as possible the period of their use, whilst intense research efforts should be focused on the development and introduction into clinical practice of new antimicrobial agents.

Introduction

Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae are among the bacteria that readily develop multiple resistance mechanisms to various classes of antibiotics [1], [2], [3], [4], [5]. In addition, they are important nosocomial pathogens affecting both immunocompetent and immunocompromised patients and are responsible for a considerable proportion of infections in patients in Intensive Care Units (ICUs) worldwide. Thus, infections by multidrug-resistant (MDR) P. aeruginosa, A. baumannii and K. pneumoniae strains have become common in healthcare institutions.

The continuously evolving resistance to antibiotics of P. aeruginosa, A. baumannii and K. pneumoniae has led to the emergence of clinical isolates susceptible to only one class of antimicrobial agents and eventually to pandrug-resistant (PDR) isolates, i.e. resistant to all available antibiotics [6], [7], [8]. Polymyxins, an old class of polypeptide cationic antibiotic that was abandoned during the 1980s and 1990s in most parts of the world, have been used as the last class of available antibiotics to which some of these bacterial isolates were susceptible in vitro. Several recent clinical studies have reported on the therapeutic use of polymyxins in patients with infections by organisms with such a phenotype (i.e. susceptible only to polymyxins) [9], [10], [11], [12]. In addition, there have been some recent clinical studies that reported on infections with isolates of P. aeruginosa, A. baumannii and K. pneumoniae that were characterised as PDR. However, in some of these studies either the isolates were not tested in vitro against polymyxins or they were tested and found to be susceptible to them [6], [7], [13].

PDR infections due to the aforementioned Gram-negative bacteria represent a fearful clinical situation with tremendous public health implications in which the clinician is left with practically no rational choice of antibiotic treatment. Thus, data regarding the frequency of PDR clinical isolates, the morbidity and mortality related to infections by these isolates and the therapeutic options, if any, are of great clinical and public health importance. Therefore, we sought to review systematically the available laboratory and clinical evidence regarding the frequency, therapy and clinical outcomes of infections by polymyxin-resistant and/or PDR clinical isolates of P. aeruginosa, A. baumannii and K. pneumoniae. The aim of this review is to attract the attention of clinicians, researchers, health policy-makers and the relevant industry to this growing problem that has obvious global public health implications.

Section snippets

Data sources and search strategy

Searches for relevant studies were performed in PubMed and the Institute for Scientific Information (ISI) Web of Science database during May and June 2006. The search terms ‘pandrug-resistant’, ‘pandrug resistance’, ‘PDR’, ‘resistant to all’, ‘highly resistant’, ‘colistin-resistant’, ‘resistance to colistin’, ‘resistant to colistin’, ‘polymyxin-resistant’, ‘polymyxin B-resistant’, ‘resistance to polymyxin’, ‘resistant to polymyxin’, ‘sulbactam-resistant’, ‘resistance to sulbactam’ and

Study selection

We reviewed laboratory and clinical studies that reported on polymyxin-resistant and/or PDR P. aeruginosa, A. baumannii or K. pneumoniae clinical isolates. Studies written in English, German, French, Italian, Spanish, Portuguese or Greek were eligible for detailed review and data extraction.

Definitions

An isolate should have a documented resistance to representative antibiotics of specific classes of antimicrobial agents to be characterised as PDR. Thus, a P. aeruginosa or K. pneumoniae isolate was defined as PDR only if it was resistant to agents from all seven available antipseudomonal classes of antimicrobial agents, i.e. antipseudomonal penicillins, cephalosporins, carbapenems, monobactams, quinolones, aminoglycosides and polymyxins. Similarly, A. baumannii was considered PDR if it was

Laboratory studies

In Table 1, we present data from laboratory studies that examined polymyxin-resistant and/or PDR isolates. As shown, 11 studies reported on isolates with resistance to polymyxins, three of which (including two surveillance studies) also included data regarding the percentage of isolates that were PDR [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]. Whenever possible, the actual proportion of isolates with decreased in vitro susceptibility to polymyxins was recalculated

Clinical studies

Our search retrieved only two clinical studies reporting the clinical characteristics and outcomes of patients infected with PDR isolates of P. aeruginosa, A. baumannii or K. pneumoniae[27], [28]. The main characteristics of these infections and their outcome, as reported in the studies, are presented in Table 2. In addition, a case report was identified documenting the isolation of a polymyxin B-resistant strain of A. baumannii from a patient who was given polymyxin B for treatment of a MDR,

Evaluation of the presented data

The main conclusion of this review is that reports of polymyxin-resistant or PDR P. aeruginosa, A. baumannii and K. pneumoniae clinical isolates are relatively rare at present, however they represent an issue with important public health implications because they pose serious therapeutic problems [27], [28]. Another interesting finding from the review of the relevant studies is that reduced susceptibility to polymyxins does not necessarily translate to pandrug resistance, at least regarding

References (40)

M.S. Helfand et al.
Current challenges in antimicrobial chemotherapy: the impact of extended-spectrum beta-lactamases and metallo-beta-lactamases on the treatment of resistant Gram-negative pathogens
Curr Opin Pharmacol
(2005)
J.E. McGowan
Resistance in nonfermenting gram-negative bacteria: multidrug resistance to the maximum
Am J Med
(2006)
G.M. Rossolini et al.
Treatment and control of severe infections caused by multiresistant Pseudomonas aeruginosa
Clin Microbiol Infect
(2005)
E. Marais et al.
Interhospital transfer of pan-resistant Acinetobacter strains in Johannesburg, South Africa
Am J Infect Control
(2004)
A.S. Michalopoulos et al.
Colistin treatment in patients with ICU-acquired infections caused by multiresistant Gram-negative bacteria: the renaissance of an old antibiotic
Clin Microbiol Infect
(2005)
C.Y. Wang et al.
Pandrug-resistant Pseudomonas aeruginosa among hospitalised patients: clinical features, risk-factors and outcomes
Clin Microbiol Infect
(2006)
A.C. Gales et al.
Global assessment of the antimicrobial activity of polymyxin B against 54 731 clinical isolates of Gram-negative bacilli: report from the SENTRY antimicrobial surveillance programme (2001–2004)
Clin Microbiol Infect
(2006)
P. Beno et al.
Bacteraemia in cancer patients caused by colistin-resistant Gram-negative bacilli after previous exposure to ciprofloxacin and/or colistin
Clin Microbiol Infect
(2006)
S. Motaouakkil et al.
Colistin and rifampicin in the treatment of nosocomial infections from multiresistant Acinetobacter baumannii
J Infect
(2006)
F.M. MacKenzie et al.
Report of the Consensus Conference on Antibiotic Resistance; Prevention and Control (ARPAC)
Clin Microbiol Infect
(2005)

H. Grundmann et al.

Report of working group 1: public health challenges

Clin Microbiol Infect

(2005)

G.W. Hanlon

The emergence of multidrug resistant Acinetobacter species: a major concern in the hospital setting

Lett Appl Microbiol

(2005)

R. Ramphal et al.

Extended-spectrum beta-lactamases and clinical outcomes: current data

Clin Infect Dis

(2006)

L.C. Kuo et al.

Dissemination of a clone of unusual phenotype of pandrug-resistant Acinetobacter baumannii at a university hospital in Taiwan

J Clin Microbiol

(2004)

J. Yoon et al.

In vitro double and triple synergistic activities of polymyxin B, imipenem, and rifampin against multidrug-resistant Acinetobacter baumannii

Antimicrob Agents Chemother

(2004)

J. Garnacho-Montero et al.

Treatment of multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia (VAP) with intravenous colistin: a comparison with imipenem-susceptible VAP

Clin Infect Dis

(2003)

M.E. Falagas et al.

Effectiveness and nephrotoxicity of intravenous colistin for the treatment of patients with infections due to polymyxin-only-susceptible (POS) Gram-negative bacteria

Eur J Clin Microbiol Infect Dis

(2006)

A.S. Levin et al.

Intravenous colistin as therapy for nosocomial infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii

Clin Infect Dis

(1999)

National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial susceptibility testing....

National Committee for Clinical Laboratory Standards. Methods for dilution antimicrobial susceptibility test for...

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ReviewPandrug-resistant Gram-negative bacteria: the dawn of the post-antibiotic era?

Abstract

Introduction

Section snippets

Data sources and search strategy

Study selection

Definitions

Laboratory studies

Clinical studies

Evaluation of the presented data

Curr Opin Pharmacol

Am J Med

Clin Microbiol Infect

Am J Infect Control

Clin Microbiol Infect

Clin Microbiol Infect

Clin Microbiol Infect

Clin Microbiol Infect

J Infect

Clin Microbiol Infect

Clin Microbiol Infect

The emergence of multidrug resistant Acinetobacter species: a major concern in the hospital setting

Lett Appl Microbiol

Extended-spectrum beta-lactamases and clinical outcomes: current data

Clin Infect Dis

Dissemination of a clone of unusual phenotype of pandrug-resistant Acinetobacter baumannii at a university hospital in Taiwan

J Clin Microbiol

In vitro double and triple synergistic activities of polymyxin B, imipenem, and rifampin against multidrug-resistant Acinetobacter baumannii

Antimicrob Agents Chemother

Treatment of multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia (VAP) with intravenous colistin: a comparison with imipenem-susceptible VAP

Clin Infect Dis

Effectiveness and nephrotoxicity of intravenous colistin for the treatment of patients with infections due to polymyxin-only-susceptible (POS) Gram-negative bacteria

Eur J Clin Microbiol Infect Dis

Intravenous colistin as therapy for nosocomial infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii

Clin Infect Dis

Review
Pandrug-resistant Gram-negative bacteria: the dawn of the post-antibiotic era?