Pandrug-resistant Gram-negative bacteria

International Journal of Antimicrobial Agents29(2007)630–636ReviewPandrug-resistant Gram-negative bacteria:the dawn of the post-antibiotic era?Matthew E.Falagas a,b,∗,Ioannis A.Bliziotis aa Alfa Institute of Biomedical Sciences(AIBS),9Neapoleos Street,15123Marousi,Athens,Greeceb Department of Medicine,Tufts University School of Medicine,Boston,MA,USAReceived8December2006;accepted11December2006AbstractThe 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.©2007Elsevier B.V.and the International Society of Chemotherapy.All rights reserved.Keywords:Pandrug-resistant;Gram-negative bacteria1.IntroductionPseudomonas aeruginosa,Acinetobacter baumannii and Klebsiella pneumoniae are among the bacteria that readily develop multiple resistance mechanisms to various classes of antibiotics[1–5].In addition,they are important nosocomial pathogens affecting both immunocompetent and immuno-compromised 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 ∗Corresponding author.Tel.:+306946110000;fax:+302106839605.E-mail address:m.falagas@aibs.gr(M.E.Falagas).of antimicrobial agents and eventually to pandrug-resistant (PDR)isolates,i.e.resistant to all available antibiotics[6–8]. Polymyxins,an old class of polypeptide cationic antibiotic that was abandoned during the1980s and1990s in most parts of the world,have been used as the last class of available antibiotics to which some of these bacterial isolates were sus-ceptible in vitro.Several recent clinical studies have reported on the therapeutic use of polymyxins in patients with infec-tions by organisms with such a phenotype(i.e.susceptible only to polymyxins)[9–12].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 tremendous0924-8579/$–see front matter©2007Elsevier B.V.and the International Society of Chemotherapy.All rights reserved. doi:10.1016/j.ijantimicag.2006.12.012M.E.Falagas,I.A.Bliziotis/International Journal of Antimicrobial Agents29(2007)630–636631public 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 iso-lates 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 iso-lates 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.2.Data sources and search strategySearches for relevant studies were performed in PubMed and the Institute for Scientific Information(ISI)Web of Sci-ence database during May and June2006.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 sulbac-tam’and‘resistant to sulbactam’were combined with the terms‘Acinetobacter’,‘Klebsiella’and‘Pseudomonas’.Ref-erences from retrieved articles were also evaluated for relevance to our objectives.3.Study selectionWe reviewed laboratory and clinical studies that reported on polymyxin-resistant and/or PDR P.aeruginosa,A.bau-mannii or K.pneumoniae clinical isolates.Studies written in English,German,French,Italian,Spanish,Portuguese or Greek were eligible for detailed review and data extraction.4.DefinitionsAn 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 resistant to representative antibiotics from all of the above categories plus ampicillin/sulbactam and one tetracycline(minocycline or doxycycline).According to the latest suggestions by the Clinical and Laboratory Standards Institute(CLSI),isolates were considered to have decreased in vitro susceptibility to polymyxins when the minimum inhibitory concentration of polymyxins against them was≥2mg/L,evaluated by the broth microdilution method[14,15].boratory studiesIn Table1,we present data from laboratory studies that examined polymyxin-resistant and/or PDR isolates.As shown,11studies reported on isolates with resistance to polymyxins,three of which(including two surveillance stud-ies)also included data regarding the percentage of isolates that were PDR[16–26].Whenever possible,the actual pro-portion of isolates with decreased in vitro susceptibility to polymyxins was recalculated according to the current CLSI breakpoint of2mg/L(Table1)[19,21].The highest propor-tion of isolates with resistance to polymyxins reported in surveillance studies was13.1%[24],whereas in the rest of them it was≤5%.In all reviewed studies polymyxins were the most active agents based on the results of in vitro suscep-tibility testing of the isolates.In the study by Landman et al.[18],a statistically significant increase(P<0.001)in the number of polymyxin-resistant isolates of P.aeruginosa was noted in2003 compared with2001in the area of Brooklyn(Table1).In that study,the increase in the number of polymyxin-resistant isolates accompanied an increase in the use of polymyxin B during the5-year period1999–2003in the studied hos-pitals.However,no evaluation of other relevant factors that may have contributed to the emergence of polymyxin resis-tance was performed.Moreover,most of the polymyxin B-resistant P.aeruginosa isolates were susceptible to other antipseudomonal agents(5%of all isolates were resistant to polymyxin B but<1.9%were PDR;Table1).A similar finding was observed in the SENTRY surveillance study by Gales et al.(Table1)[20],in which only a small proportion of polymyxin B-resistant isolates of P.aeruginosa and A. baumannii were PDR.Four studies[17–19,25]evaluated in vitro the activ-ity of polymyxins in combination with other antibiotics against highly resistant Gram-negative bacterial isolates. Giamarellos-Bourboulis et al.[19]reported that the com-bination of colistin with rifampicin was synergistic against 42%of17genetically diverse PDR P.aeruginosa isolates. In addition,Landman et al.[18]examined a subset of10 P.aeruginosa isolates resistant to polymyxin B with con-comitant resistance to imipenem and at least one additional antibiotic class.They reported that the combination of polymyxin B with rifampicin or imipenem was bactericidal (synergistic)in9/10and8/10strains,respectively.In addi-tion,they found that the triple combination of polymyxin B with rifampicin and imipenem was bactericidal for all10 strains.Manikal et al.[25]reported that against24,mainly polymyxin-susceptible,isolates of A.baumannii the combi-nation of polymyxin B with azithromycin or rifampicin was634M.E.Falagas,I.A.Bliziotis/International Journal of Antimicrobial Agents29(2007)630–636synergistic against20and12isolates,respectively.Finally, Bratu et al.[17]reported that the combination of polymyxin B with rifampicin or imipenem was synergistic against 15/16and10/16carbapenem-resistant K.pneumoniae isolates(some of which were susceptible to polymyxin B),respectively.However,the addition of imipenem to the combination of polymyxin B with rifampicin had no effect.6.Clinical studiesOur 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.pneu-moniae[27,28].The main characteristics of these infections and their outcome,as reported in the studies,are presented in Table2.In addition,a case report was identified documenting the isolation of a polymyxin B-resistant strain of A.bauman-nii from a patient who was given polymyxin B for treatment of a MDR,polymyxin-susceptible strain of A.baumannii[29]. However,that case report focused on in vitro characteristics of the isolate without reporting relevant clinical data.Both clinical studies reviewed in Table2were case series published after2005and originated in Central and Southern Europe,respectively[27,28].The study population in one study was patients with cancer and bacteraemia hospitalised in the ICU[27],whereas in the second study patients were from two tertiary hospitals,most of whom(6/7)were also in the ICU[28].Altogether,16patients(15of them infected with PDR isolates)were included in the studies.No evalua-tion of risk factors leading to the isolation of these organisms was performed in the studies.Nevertheless,in both studies the patients suffered from another serious co-morbidity and,at the time of isolation of the highly resistant organism,in most cases they were either already hospitalised for a relatively long period of time or they had been recently re-hospitalised.The study by Beno et al.[27]did not discuss the exact therapy that was administered to patients infected with PDR organisms.In our study[28],combination of colistin with other antibiotics(mainly imipenem)was the main therapeutic modality,used infive of seven patients.As shown in Table2, the overall mortality was relatively high both in the study by Beno et al.(44%)and our study(29%);however,in the first study the death of one patient could be attributed to the progress of the underlying malignancy(which would trans-late to an infection-related mortality of38%(3/8patients)in that case series).7.Evaluation of the presented dataThe 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 interestingfinding from the review of the relevant studies is that reduced susceptibility to polymyxins does not necessarily translate to pandrug resistance,at least regarding isolates from surveillance studies[18,20].However,there has been a large number of case series describing the use of polymyxins as salvage therapy for patients with a variety of infections caused by strains of the above bacteria for which polymyxins were the last class that remained active in vitro[9–12].In addition,the limited evi-dence from the two clinical studies included in our review suggests that isolation of a PDR organism is often preceded by isolation of an organism susceptible only to polymyxins [27,28].Moreover,in a surveillance study reviewed in this article,Landman et al.[18]attributed the increase in the inci-dence of P.aeruginosa isolates resistant to polymyxins to the increased use of polymyxin B for the treatment of patients with A.baumannii infections susceptible only to polymyxins, indicating transferable resistance as the most possible mecha-nism in the cases of polymyxin-resistant isolates that are not PDR.Furthermore,in all of the reviewed laboratory stud-ies,polymyxins were the antibiotics that retained the highest activity against the three examined species of Gram-negative bacteria.Thus,all the above observations suggest that when polymyxin resistance occurs in a clinical isolate,there is often no other available antimicrobial agent to be used by clinicians.It should be mentioned that in most of the laboratory stud-ies reviewed,there were classes of antibiotics that were not tested against the studied P.aeruginosa,A.baumannii and K.pneumoniae isolates,most notably monobactams.In addi-tion,there are several clinical and laboratory studies of MDR infections in which polymyxins were not tested against the responsible isolates;these studies were not reviewed in this article[30–32].It is noteworthy that there are considerable differences in the types of antibiotics tested against the afore-mentioned isolates worldwide,which are mainly attributed to local differences in the in vitro susceptibility of isolates as well as to disparities in the commercial availability of the various antimicrobial agents worldwide[13].However, with the increasing emergence of resistance of these Gram-negative bacteria to drugs of all or almost all available classes of antibiotics,it becomes necessary to increase the number of antibacterial agents used in the in vitro susceptibility tests in settings with a high incidence of MDR infections[33]. Apart from the obvious benefits that the implementation of such a strategy will have(i.e.identification of appropriate antibiotic therapy for patients with infections that would oth-erwise be mistakenly considered PDR),it would allow for a more conservative,alternating use of‘salvage’therapies such as polymyxins or sulbactam and newer agents such as tigecycline.There is no therapy that has been proven to be effec-tive for patients with PDR infections on clinical grounds and the limited clinical data reviewed here cannot offer suf-ficient evidence.However,based on in vitro studies,the use of combinations of colistin with rifampicin[8,18,19,34]M.E.Falagas,I.A.Bliziotis/International Journal of Antimicrobial Agents29(2007)630–636635or imipenem[8,17,18]or both of these agents[8,18]may represent a reasonable approach for the treatment of such infections.Thus,the need for a systematic clinical evalua-tion of such combinations is evident[34].In addition,we should not overlook the introduction into clinical practice of tigecycline,a new agent that may represent a good therapeu-tic option for A.baumannii and K.pneumoniae but not for P. aeruginosa infections[17,21].Of note,a report has recently been published of successful use of this agent in a patient with septic shock due to a polymyxin-resistant A.baumannii refractory to other administered antibiotic regimens,includ-ing colistin[35].Also,the role of antimicrobial peptides such as cecropin A–melittin against MDR and polymyxin-resistant A.baumannii infections is being explored in microbiological studies[36,37].The fears for the dawn of a post-antibiotic era,at least for the three Gram-negative isolates evaluated in this review, appear to be justified.Many relevant societies,including the Infectious Diseases Society of America(IDSA)and the European Society of Clinical Microbiology and Infectious Diseases(ESCMID),have expressed their concerns regard-ing the increase in the incidence of highly resistant isolates [38,39]and have also implemented various programmes to reduce the spread of antimicrobial resistance[39,40].The laboratory and clinical data reviewed here show that further prompt action should be taken to explore new therapeutic strategies that will overcome the problem of evolving pan-drug resistance of specific Gram-negative isolates.We must preserve the activity of the available antibiotics,or at least expand as much as possible the period of their use,whilst intense efforts should be focused on the development of new antimicrobial agents.References[1]Hanlon GW.The emergence of multidrug resistant Acinetobacterspecies:a major concern in the hospital setting.Lett Appl Microbiol 2005;41:375–8.[2]Helfand MS,Bonomo RA.Current challenges in antimicrobialchemotherapy:the impact of extended-spectrum beta-lactamases and metallo-beta-lactamases on the treatment of resistant Gram-negative pathogens.Curr Opin Pharmacol2005;5:452–8.[3]McGowan Jr JE.Resistance in nonfermenting gram-negative bacteria:multidrug resistance to the maximum.Am J Med2006;119(6Suppl.1):S29–36.[4]Ramphal R,Ambrose PG.Extended-spectrum beta-lactamases andclinical outcomes:current data.Clin Infect Dis2006;42(Suppl.4):S164–72.[5]Rossolini GM,Mantengoli E.Treatment and control of severeinfections caused by multiresistant Pseudomonas aeruginosa.Clin Microbiol Infect2005;11(Suppl.4):17–32.[6]Kuo LC,Teng LJ,Yu CJ,Ho SW,Hsueh PR.Dissemination of a cloneof unusual phenotype of pandrug-resistant Acinetobacter baumannii ata university hospital in Taiwan.J Clin Microbiol2004;42:1759–63.[7]Marais E,de Jong G,Ferraz V,Maloba B,Duse AG.Interhospitaltransfer of pan-resistant Acinetobacter strains in Johannesburg,South Africa.Am J Infect Control2004;32:278–81.[8]Yoon J,Urban C,Terzian C,Mariano N,Rahal JJ.In vitro dou-ble and triple synergistic activities of polymyxin B,imipenem,andrifampin against multidrug-resistant Acinetobacter baumannii.Antimi-crob Agents Chemother2004;48:753–7.[9]Garnacho-Montero J,Ortiz-Leyba C,Jimenez-Jimenez FJ,et al.Treatment of multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia(V AP)with intravenous colistin:a comparison with imipenem-susceptible V AP.Clin Infect Dis2003;36:1111–8. 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