The Current State of Multidrug‐Resistant Gram‐Negative Bacilli in North America

Although much of today's media focuses on multidrug‐resistant gram‐positive bacteria such as methicillin‐resistant Staphylococcus aureus and vancomycin‐resistant Enterococcus resistance within gram‐negative bacilli continues to rise, occasionally creating situations in which few or no antibiotics that retain activity are available. Extended‐spectrum β‐lactamase (ESBL)‐producing Escherichia coli and Klebsiella sp are emerging threats nationally. Although carbapenems are considered the antibiotic class of choice to treat ESBL‐producing Enterobacteriaceae, the ability of these organisms to produce carbapenemases has now become apparent in some regions throughout the United States. Although still rare, Klebsiella sp that produce KPC‐2 retain susceptibility only to tigecycline, polymyxins, and occasionally aminoglycosides. Multidrug resistance among Pseudomonas aeruginosa and Acinetobacter sp has always been apparent across many hospitals in the United States. Recent surveillance indicates increasing resistance to all currently available antibiotics, including carbapenems, cephalosporins, penicillins, fluoroquinolones, and aminoglycosides. Against many strains, only polymyxins retain activity; however, resistance has also been reported to these agents. Fortunately, resistance mechanisms such as metallo‐β‐lactamases are still rare in the United States. As no new antibiotics with novel mechanisms against many of these gram‐negative bacilli are expected to be developed in the foreseeable future, careful and conservative use of agents combined with good infection control practices is required.

[1]  M. Falagas,et al.  Pandrug-resistant Gram-negative bacteria: the dawn of the post-antibiotic era? , 2007, International journal of antimicrobial agents.

[2]  N. Ledeboer,et al.  Tigecycline for Treatment of Pneumonia and Empyema Caused by Carbapenemase‐Producing Klebsiella pneumoniae , 2007, Pharmacotherapy.

[3]  R. MacLaren,et al.  National Surveillance of Antimicrobial Resistance in Pseudomonas aeruginosa Isolates Obtained from Intensive Care Unit Patients from 1993 to 2002 , 2004, Antimicrobial Agents and Chemotherapy.

[4]  D. Livermore,et al.  Doripenem versus Pseudomonas aeruginosa In Vitro: Activity against Characterized Isolates, Mutants, and Transconjugants and Resistance Selection Potential , 2004, Antimicrobial Agents and Chemotherapy.

[5]  D. Nathwani Tigecycline: clinical evidence and formulary positioning. , 2005, International journal of antimicrobial agents.

[6]  R. Jones,et al.  blaVIM-2 and blaVIM-7 Carbapenemase-Producing Pseudomonas aeruginosa Isolates Detected in a Tertiary Care Medical Center in the United States: Report from the MYSTIC Program , 2006, Journal of Clinical Microbiology.

[7]  S. Sinto,et al.  In vitro synergy test of meropenem and sulbactam against clinical isolates of Acinetobacter baumannii. , 2005, Diagnostic microbiology and infectious disease.

[8]  Zhaoxia Li,et al.  In vitro activity of cefepime combined with sulbactam against clinical isolates of carbapenem-resistant Acinetobacter spp. , 2006, International journal of antimicrobial agents.

[9]  D. Nicolau,et al.  Questioning the paradigm: monotherapy vs combination antimicrobial therapy for treatment of Pseudomonas aeruginosa. , 2005, Connecticut medicine.

[10]  T. Fabian,et al.  Comparison of ampicillin-sulbactam and imipenem-cilastatin for the treatment of acinetobacter ventilator-associated pneumonia. , 2002, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[11]  Ronald N. Jones,et al.  Geographic variations in activity of broad-spectrum beta-lactams against Pseudomonas aeruginosa: summary of the worldwide SENTRY Antimicrobial Surveillance Program (1997-2000). , 2002, Diagnostic microbiology and infectious disease.

[12]  D. Landman,et al.  Carbapenemase-producing Klebsiella pneumoniae in Brooklyn, NY: molecular epidemiology and in vitro activity of polymyxin B and other agents. , 2005, The Journal of antimicrobial chemotherapy.

[13]  G. Reid,et al.  Rapid Development of Acinetobacter baumannii Resistance to Tigecycline , 2007, Pharmacotherapy.

[14]  A. Prince,et al.  Antibiotic susceptibility of multiply resistant Pseudomonas aeruginosa isolated from patients with cystic fibrosis, including candidates for transplantation. , 1996, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[15]  D. Nicolau,et al.  Pharmacodynamic profiling of imipenem, meropenem and ertapenem against clinical isolates of extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella spp. from Brazil. , 2006, International journal of antimicrobial agents.

[16]  A. Antoniadou,et al.  In Vitro Activity of Tigecycline against Multiple-Drug-Resistant, Including Pan-Resistant, Gram-Negative and Gram-Positive Clinical Isolates from Greek Hospitals , 2006, Antimicrobial Agents and Chemotherapy.

[17]  B. Cunha,et al.  Extended spectrum beta-lactamase-producing Klebsiella pneumoniae chronic ambulatory peritoneal dialysis peritonitis treated successfully with polymyxin B. , 2005, Heart & lung : the journal of critical care.

[18]  P. Nordmann,et al.  Ambler Class A Extended-Spectrum β-Lactamases in Pseudomonas aeruginosa: Novel Developments and Clinical Impact , 2003, Antimicrobial Agents and Chemotherapy.

[19]  A. Evangelista,et al.  Stable antimicrobial susceptibility rates for clinical isolates of Pseudomonas aeruginosa from the 2001-2003 tracking resistance in the United States today surveillance studies. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[20]  J. Bartlett Nosocomial bloodstream infections in US hospitals: Analysis of 24,179 cases from a prospective nationwide surveillance study , 2004 .

[21]  J. Turnidge,et al.  In Vitro Pharmacodynamic Properties of Colistin and Colistin Methanesulfonate against Pseudomonas aeruginosaIsolates from Patients with Cystic Fibrosis , 2001, Antimicrobial Agents and Chemotherapy.

[22]  Ronald N. Jones,et al.  Activity of tigecycline tested against a global collection of Enterobacteriaceae, including tetracycline-resistant isolates. , 2005, Diagnostic microbiology and infectious disease.

[23]  G. Drusano,et al.  Piperacillin-tazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended-infusion dosing strategy. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[24]  R. Bonnet Growing Group of Extended-Spectrum β-Lactamases: the CTX-M Enzymes , 2004, Antimicrobial Agents and Chemotherapy.

[25]  J. Vila,et al.  In vitro antimicrobial production of beta-lactamases, aminoglycoside-modifying enzymes, and chloramphenicol acetyltransferase by and susceptibility of clinical isolates of Acinetobacter baumannii , 1993, Antimicrobial Agents and Chemotherapy.

[26]  P. Kiratisin,et al.  Efficacy and safety of colistin (colistimethate sodium) for therapy of infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii in Siriraj Hospital, Bangkok, Thailand. , 2007, International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases.

[27]  S. Segal-Maurer,et al.  Successful treatment of ceftazidime-resistant Klebsiella pneumoniae ventriculitis with intravenous meropenem and intraventricular polymyxin B: case report and review. , 1999, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[28]  Russell E. Lewis,et al.  Pharmacodynamics of Polymyxin B against Pseudomonas aeruginosa , 2005, Antimicrobial Agents and Chemotherapy.

[29]  D. Landman,et al.  Molecular epidemiology and mechanisms of carbapenem resistance in Acinetobacter baumannii endemic in New York City. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[30]  J. Mcgowan Resistance in nonfermenting gram-negative bacteria: multidrug resistance to the maximum. , 2006, The American journal of medicine.

[31]  N. Caroff,et al.  AmpC cephalosporinase hyperproduction in Acinetobacter baumannii clinical strains. , 2003, The Journal of antimicrobial chemotherapy.

[32]  G. Royo,et al.  Cepas de Escherichia coli productoras de betalactamasas de espectro extendido: origen, características e incidencia en el sur de la provincia de Alicante en el período 1999-2003 , 2005 .

[33]  J. Wu,et al.  Comparison of the double-disk, combined disk, and Etest methods for detecting metallo-beta-lactamases in gram-negative bacilli. , 2004, Diagnostic microbiology and infectious disease.

[34]  G. Drusano,et al.  Application of Antimicrobial Pharmacodynamic Concepts into Clinical Practice: Focus on β‐Lactam Antibiotics , 2006 .

[35]  Y. Carmeli,et al.  Plasmid-Mediated Imipenem-Hydrolyzing Enzyme KPC-2 among Multiple Carbapenem-Resistant Escherichia coli Clones in Israel , 2006, Antimicrobial Agents and Chemotherapy.

[36]  P. Bradford,et al.  Molecular epidemiology of a citywide outbreak of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae infection. , 2002, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[37]  A. Hsiung,et al.  In vitro activity of tigecycline against 3989 Gram-negative and Gram-positive clinical isolates from the United States Tigecycline Evaluation and Surveillance Trial (TEST Program; 2004). , 2005, Diagnostic microbiology and infectious disease.

[38]  G. Drusano,et al.  Application of antimicrobial pharmacodynamic concepts into clinical practice: focus on beta-lactam antibiotics: insights from the Society of Infectious Diseases Pharmacists. , 2006, Pharmacotherapy.

[39]  K. Bush,et al.  Novel Carbapenem-Hydrolyzing β-Lactamase, KPC-1, from a Carbapenem-Resistant Strain of Klebsiella pneumoniae , 2001, Antimicrobial Agents and Chemotherapy.

[40]  J. Quinn,et al.  Prevalence of extended spectrum beta-lactamase producing Escherichia coli and Klebsiella isolates in a large community teaching hospital in Connecticut. , 2004, Diagnostic microbiology and infectious disease.

[41]  L. Danziger,et al.  Multidrug-Resistant Acinetobacter Infections: An Emerging Challenge to Clinicians , 2004, The Annals of pharmacotherapy.

[42]  D. Landman,et al.  Citywide clonal outbreak of multiresistant Acinetobacter baumannii and Pseudomonas aeruginosa in Brooklyn, NY: the preantibiotic era has returned. , 2002, Archives of internal medicine.

[43]  Yehuda Carmeli,et al.  Clinical and Economic Impact of Bacteremia with Extended- Spectrum-β-Lactamase-Producing Enterobacteriaceae , 2006, Antimicrobial Agents and Chemotherapy.

[44]  D. Livermore,et al.  Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: our worst nightmare? , 2002, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[45]  R. Gaynes,et al.  Nosocomial infections in medical intensive care units in the United States. National Nosocomial Infections Surveillance System. , 1999, Critical care medicine.

[46]  Y. Carmeli,et al.  High tigecycline resistance in multidrug-resistant Acinetobacter baumannii. , 2007, The Journal of antimicrobial chemotherapy.

[47]  A. Mitchell NEW EPIDEMIC STRAIN OF STAPHYLOCOCCUS AUREUS. EMERGENCE AND SPREAD IN A GENERAL HOSPITAL. , 1964, Lancet.

[48]  D. Livermore,et al.  Activity of Ertapenem (MK-0826) versusEnterobacteriaceae with Potent β-Lactamases , 2001, Antimicrobial Agents and Chemotherapy.

[49]  E. Abraham,et al.  An Enzyme from Bacteria able to Destroy Penicillin , 1940, Nature.

[50]  D. Landman,et al.  Detection and spread of Escherichia coli possessing the plasmid-borne carbapenemase KPC-2 in Brooklyn, New York. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[51]  D. Shlaes,et al.  The most frequent aminoglycoside resistance mechanisms--changes with time and geographic area: a reflection of aminoglycoside usage patterns? Aminoglycoside Resistance Study Groups. , 1997, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[52]  C. Frei,et al.  Pharmacodynamic modeling of carbapenems and fluoroquinolones against bacteria that produce extended-spectrum beta-lactamases. , 2004, Clinical therapeutics.

[53]  J. Vincent,et al.  Successful treatment of septic shock due to pan-resistant Acinetobacter baumannii using combined antimicrobial therapy including tigecycline , 2006, European Journal of Clinical Microbiology and Infectious Diseases.

[54]  A. Hossain,et al.  First Occurrence of a Pseudomonas aeruginosa Isolate in the United States Producing an IMP Metallo-β-Lactamase, IMP-18 , 2006, Antimicrobial Agents and Chemotherapy.

[55]  M. Falagas,et al.  Toxicity of polymyxins: a systematic review of the evidence from old and recent studies , 2006, Critical care.

[56]  E. Baker,et al.  Aminoglycoside antibiotic resistance by enzymatic deactivation. , 2002, Current drug targets. Infectious disorders.

[57]  B. Charra,et al.  Colistin and rifampicin in the treatment of nosocomial infections from multiresistant Acinetobacter baumannii. , 2006, The Journal of infection.

[58]  J. Woo,et al.  Prevalence, microbiology, and clinical characteristics of extended-spectrum β-lactamase-producing Enterobacter spp., Serratia marcescens, Citrobacter freundii, and Morganella morganii in Korea , 2007, European Journal of Clinical Microbiology and Infectious Diseases.

[59]  L. Rice Challenges in identifying new antimicrobial agents effective for treating infections with Acinetobacter baumannii and Pseudomonas aeruginosa. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[60]  F. Frantzeskaki,et al.  High-dose ampicillin-sulbactam as an alternative treatment of late-onset VAP from multidrug-resistant Acinetobacter baumannii , 2007, Scandinavian journal of infectious diseases.

[61]  D. Nicolau,et al.  Pharmacodynamics of antimicrobials: treatment optimisation , 2005, Expert opinion on drug metabolism & toxicology.

[62]  Y. Chuang,et al.  Clinical experiences of the infections caused by extended-spectrum beta-lactamase-producing Serratia marcescens at a medical center in Taiwan. , 2006, Japanese journal of infectious diseases.

[63]  D. Livermore Of Pseudomonas, porins, pumps and carbapenems. , 2001, The Journal of antimicrobial chemotherapy.

[64]  Ronald N. Jones,et al.  Contemporary activity of meropenem and comparator broad-spectrum agents: MYSTIC program report from the United States component (2005). , 2007, Diagnostic microbiology and infectious disease.

[65]  R. Wenzel,et al.  Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[66]  F. Baquero,et al.  In Vitro Activities of Ertapenem (MK-0826) against Recent Clinical Bacteria Collected in Europe and Australia , 2001, Antimicrobial Agents and Chemotherapy.

[67]  M. Falagas,et al.  Toxicity after prolonged (more than four weeks) administration of intravenous colistin , 2005, BMC infectious diseases.

[68]  A. Rodloff,et al.  Epidemiologic characterization of Pseudomonas aeruginosa in patients with cystic fibrosis. , 2000, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[69]  A. Karabinis,et al.  Colistin for Klebsiella pneumoniae-associated sepsis. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[70]  J. Quinn,et al.  First Detection of the Plasmid-Mediated Class A Carbapenemase KPC-2 in Clinical Isolates of Klebsiella pneumoniae from South America , 2006, Antimicrobial Agents and Chemotherapy.

[71]  P. Turner Meropenem and imipenem activity against Pseudomonas aeruginosa isolates from the MYSTIC Program. , 2006, Diagnostic microbiology and infectious disease.

[72]  K. Bush,et al.  Novel Carbapenem-Hydrolyzing β-Lactamase, KPC-1, from a Carbapenem-Resistant Strain of Klebsiella pneumoniae , 2008, Antimicrobial Agents and Chemotherapy.

[73]  D. Livermore Interplay of impermeability and chromosomal beta-lactamase activity in imipenem-resistant Pseudomonas aeruginosa , 1992, Antimicrobial Agents and Chemotherapy.

[74]  L. Rice,et al.  Identification of a New Allelic Variant of the Acinetobacter baumannii Cephalosporinase , ADC-7-Lactamase : Defining a Unique Family of Class C Enzymes ‡ , 2005 .

[75]  D. Paterson,et al.  Parenteral and inhaled colistin for treatment of ventilator-associated pneumonia. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[76]  John Quale,et al.  Emergence of KPC-Possessing Klebsiella pneumoniae in Brooklyn, New York: Epidemiology and Recommendations for Detection , 2005, Antimicrobial Agents and Chemotherapy.

[77]  J. Ariza,et al.  Efficacy of sulbactam alone and in combination with ampicillin in nosocomial infections caused by multiresistant Acinetobacter baumannii. , 1998, The Journal of antimicrobial chemotherapy.

[78]  J. Bartlett,et al.  Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[79]  F. Tenover,et al.  Antimicrobial Susceptibility Testing of Acinetobacter spp. by NCCLS Broth Microdilution and Disk Diffusion Methods , 2004, Journal of Clinical Microbiology.

[80]  D. Hospenthal,et al.  Susceptibility of Acinetobacter Strains Isolated from Deployed U.S. Military Personnel , 2006, Antimicrobial Agents and Chemotherapy.

[81]  M. Dowzicky,et al.  Antimicrobial susceptibility among Acinetobacter calcoaceticus-baumannii complex and Enterobacteriaceae collected as part of the Tigecycline Evaluation and Surveillance Trial. , 2007, The Journal of infection.

[82]  R. Ambler,et al.  The structure of beta-lactamases. , 1980, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[83]  Ronald N. Jones,et al.  Resistance patterns among nosocomial pathogens: trends over the past few years. , 2001, Chest.

[84]  D. Livermore,et al.  Activity of ertapenem (MK-0826) versus Enterobacteriaceae with potent beta-lactamases. , 2001, Antimicrobial agents and chemotherapy.

[85]  R. Bonomo,et al.  Mechanisms of multidrug resistance in Acinetobacter species and Pseudomonas aeruginosa. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[86]  J. E. Eiros Bouza,et al.  Susceptibility of the Acinetobacter calcoaceticus-A. baumannii complex to imipenem, meropenem, sulbactam and colistin. , 2004, International journal of antimicrobial agents.

[87]  J. Turnidge,et al.  Evaluation of colistin as an agent against multi-resistant Gram-negative bacteria. , 2005, International journal of antimicrobial agents.

[88]  L. Saiman,et al.  Antimicrobial Susceptibility and Synergy Studies of Burkholderia cepacia Complex Isolated from Patients with Cystic Fibrosis , 2006, Antimicrobial Agents and Chemotherapy.

[89]  Ronald N. Jones,et al.  Molecular characterization of SPM-1, a novel metallo-beta-lactamase isolated in Latin America: report from the SENTRY antimicrobial surveillance programme. , 2002, The Journal of antimicrobial chemotherapy.

[90]  W. Bilker,et al.  Extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae: risk factors for infection and impact of resistance on outcomes. , 2001, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[91]  A. Bolmström,et al.  Evaluation of a New Etest for Detecting Metallo-β-Lactamases in Routine Clinical Testing , 2002, Journal of Clinical Microbiology.

[92]  C. van der Werken,et al.  The evolution of Pseudomonas aeruginosa during antibiotic rotation in a medical intensive care unit: the RADAR-trial. , 2004, International journal of antimicrobial agents.

[93]  D. Ecker,et al.  Analysis of Antibiotic Resistance Genes in Multidrug-Resistant Acinetobacter sp. Isolates from Military and Civilian Patients Treated at the Walter Reed Army Medical Center , 2006, Antimicrobial Agents and Chemotherapy.

[94]  D. Nicolau,et al.  Optimising antibiotic dosing regimens based on pharmacodynamic target attainment against Pseudomonas aeruginosa collected in Hungarian hospitals. , 2006, International journal of antimicrobial agents.

[95]  Ronald N. Jones,et al.  Evolution and dissemination of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae: epidemiology and molecular report from the SENTRY Antimicrobial Surveillance Program (1997-2003). , 2005, Diagnostic microbiology and infectious disease.

[96]  P. Bradford Extended-Spectrum β-Lactamases in the 21st Century: Characterization, Epidemiology, and Detection of This Important Resistance Threat , 2001, Clinical Microbiology Reviews.

[97]  Jonathan R Edwards,et al.  Overview of nosocomial infections caused by gram-negative bacilli. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[98]  M. Falagas,et al.  Outcome of infections due to pandrug-resistant (PDR) Gram-negative bacteria , 2005, BMC infectious diseases.

[99]  Robert A. Bonomo,et al.  Extended-Spectrum (cid:2) -Lactamases: a Clinical Update , 2005 .

[100]  G. Jacoby,et al.  A functional classification scheme for beta-lactamases and its correlation with molecular structure , 1995, Antimicrobial agents and chemotherapy.

[101]  D. Nicolau,et al.  Empiric Treatment of Multidrug‐Resistant Burkholderia cepacia Lung Exacerbation in a Patient with Cystic Fibrosis: Application of Pharmacodynamic Concepts to Meropenem Therapy , 2004, Pharmacotherapy.

[102]  G. Bodey,et al.  Colistin Is Effective in Treatment of Infections Caused by Multidrug-Resistant Pseudomonas aeruginosa in Cancer Patients , 2007, Antimicrobial Agents and Chemotherapy.

[103]  J. Govan,et al.  Microbiology of lung infection in cystic fibrosis. , 1992, British medical bulletin.

[104]  H. Kallel,et al.  Colistin as a salvage therapy for nosocomial infections caused by multidrug-resistant bacteria in the ICU. , 2006, International journal of antimicrobial agents.

[105]  D. Paterson,et al.  Acinetobacter baumannii bloodstream infection while receiving tigecycline: a cautionary report. , 2006, The Journal of antimicrobial chemotherapy.

[106]  M. Yasuda,et al.  Detection of mutations in the gyrA and parC genes in quinolone-resistant clinical isolates of Enterobacter cloacae. , 1997, The Journal of antimicrobial chemotherapy.

[107]  D. Livermore Tigecycline: what is it, and where should it be used? , 2005, The Journal of antimicrobial chemotherapy.

[108]  F. Baquero,et al.  Antibiotic Coresistance in Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae and In Vitro Activity of Tigecycline , 2006, Antimicrobial Agents and Chemotherapy.

[109]  J. Bartlett International prospective study of klebsiella pneumoniae bacteremia: Implications of extended-spectrum β-lactamase production in nosocomial infections , 2004 .

[110]  Ronald N. Jones,et al.  Tigecycline activity tested against 26,474 bloodstream infection isolates: a collection from 6 continents. , 2005, Diagnostic microbiology and infectious disease.

[111]  J. Quinn,et al.  First Nosocomial Outbreak of Pseudomonas aeruginosa Producing an Integron-Borne Metallo-β-Lactamase (VIM-2) in the United States , 2005, Antimicrobial Agents and Chemotherapy.

[112]  P. Nordmann,et al.  Emerging carbapenemases in Gram-negative aerobes. , 2002, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[113]  Ronald N. Jones,et al.  bla VIM-7, an Evolutionarily Distinct Metallo-β-Lactamase Gene in a Pseudomonas aeruginosa Isolate from the United States , 2004, Antimicrobial Agents and Chemotherapy.

[114]  J. Aeschlimann The Role of Multidrug Efflux Pumps in the Antibiotic Resistance of Pseudomonas aeruginosa and Other Gram‐Negative Bacteria , 2003, Pharmacotherapy.

[115]  K S Meyer,et al.  Nosocomial Outbreak of Klebsiella Infection Resistant to Late-Generation Cephalosporins , 1993, Annals of Internal Medicine.

[116]  Ronald N. Jones,et al.  Italian metallo-beta-lactamases: a national problem? Report from the SENTRY Antimicrobial Surveillance Programme. , 2005, The Journal of antimicrobial chemotherapy.

[117]  M. Schaller,et al.  Cefepime versus Imipenem-Cilastatin for Treatment of Nosocomial Pneumonia in Intensive Care Unit Patients: a Multicenter, Evaluator-Blind, Prospective, Randomized Study , 2003, Antimicrobial Agents and Chemotherapy.

[118]  Neil Woodford,et al.  The β-lactamase threat in Enterobacteriaceae, Pseudomonas and Acinetobacter , 2006 .

[119]  E. Estenssoro,et al.  Safety and efficacy of colistin in Acinetobacter and Pseudomonas infections: a prospective cohort study , 2005, Intensive Care Medicine.

[120]  W. Bilker,et al.  Reemergence of gram-negative health care-associated bloodstream infections. , 2006, Archives of internal medicine.

[121]  J. Rello,et al.  Gram-negative bacterial pneumonia: aetiology and management , 2006, Current opinion in pulmonary medicine.

[122]  D. Paterson,et al.  Meropenem Administered as a Prolonged Infusion to Treat Serious Gram‐Negative Central Nervous System Infections , 2004, Pharmacotherapy.

[123]  D. Landman,et al.  Endemic carbapenem-resistant Acinetobacter species in Brooklyn, New York: citywide prevalence, interinstitutional spread, and relation to antibiotic usage. , 2000, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[124]  Y. Carmeli,et al.  Emergence of Antibiotic-Resistant Pseudomonas aeruginosa: Comparison of Risks Associated with Different Antipseudomonal Agents , 1999, Antimicrobial Agents and Chemotherapy.

[125]  J. Turnidge,et al.  Defining the Dosage Units for Colistin Methanesulfonate: Urgent Need for International Harmonization , 2006, Antimicrobial Agents and Chemotherapy.

[126]  J. Schafer,et al.  Early Experience with Tigecycline for Ventilator‐Associated Pneumonia and Bacteremia Caused by Multidrug‐Resistant Acinetobacter baumannii , 2007, Pharmacotherapy.

[127]  S. Ünal,et al.  A surveillance study of antimicrobial resistance of gram-negative bacteria isolated from intensive care units in eight hospitals in Turkey. , 1999, The Journal of antimicrobial chemotherapy.

[128]  D. Hoban,et al.  In vitro activity of tigecycline against 6792 Gram-negative and Gram-positive clinical isolates from the global Tigecycline Evaluation and Surveillance Trial (TEST Program, 2004) , 2005 .

[129]  J. Quinn,et al.  Antibiotic resistance among gram-negative bacilli in US intensive care units: implications for fluoroquinolone use. , 2003, JAMA.

[130]  M. Ferraro Performance standards for antimicrobial susceptibility testing , 2001 .

[131]  P. Bradford,et al.  Emergence of carbapenem-resistant Klebsiella species possessing the class A carbapenem-hydrolyzing KPC-2 and inhibitor-resistant TEM-30 beta-lactamases in New York City. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[132]  W. Bilker,et al.  Epidemiological investigation of fluoroquinolone resistance in infections due to extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae. , 2001, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[133]  Y. Carmeli,et al.  Update on Pseudomonas aeruginosa and Acinetobacter baumannii infections in the healthcare setting , 2005, Current opinion in infectious diseases.

[134]  Fred C Tenover,et al.  Mechanisms of antimicrobial resistance in bacteria. , 2006, The American journal of medicine.

[135]  J. Ariza,et al.  Nosocomial Outbreak Due to Extended-Spectrum-Beta-Lactamase- Producing Enterobacter cloacae in a Cardiothoracic Intensive Care Unit , 2007, Journal of Clinical Microbiology.

[136]  Robert A Bonomo,et al.  What's new in antibiotic resistance? Focus on beta-lactamases. , 2006, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[137]  M. Falagas,et al.  Use of International Units When Dosing Colistin Will Help Decrease Confusion Related to Various Formulations of the Drug around the World , 2006, Antimicrobial Agents and Chemotherapy.

[138]  J. Karlowsky,et al.  Surveillance for Antimicrobial Susceptibility among Clinical Isolates of Pseudomonas aeruginosa and Acinetobacter baumannii from Hospitalized Patients in the United States, 1998 to 2001 , 2003, Antimicrobial Agents and Chemotherapy.

[139]  J. Verhoef,et al.  Emerging importance of multidrug-resistant Acinetobacter species and Stenotrophomonas maltophilia as pathogens in seriously ill patients: geographic patterns, epidemiological features, and trends in the SENTRY Antimicrobial Surveillance Program (1997-1999). , 2001, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[140]  M. Kaufmann,et al.  Outbreak of Carbapenem-Resistant Pseudomonas aeruginosa Producing VIM-8, a Novel Metallo-β-Lactamase, in a Tertiary Care Center in Cali, Colombia , 2004, Journal of Clinical Microbiology.

[141]  G. Bou,et al.  Characterization of a Nosocomial Outbreak Caused by a Multiresistant Acinetobacter baumannii Strain with a Carbapenem-Hydrolyzing Enzyme: High-Level Carbapenem Resistance inA. baumannii Is Not Due Solely to the Presence of β-Lactamases , 2000, Journal of Clinical Microbiology.

[142]  G. Rossolini,et al.  Simple Microdilution Test for Detection of Metallo-β-Lactamase Production in Pseudomonas aeruginosa , 2002, Journal of Clinical Microbiology.