New Treatment Options for Infections Caused by Multiresistant Strains of Pseudomonas aeruginosa and Other Nonfermenting Gram-Negative Bacilli

ABSTRACT

Hospital-acquired infections are one of the most important challenges to patient safety, especially in critical care units. The use of broad-spectrum antibiotics results frequently in multidrug-resistant pathogens. Therefore, we are attending to increased rates of multidrug-resistant microorganisms, especially gram-negative bacilli, that have been associated with prolonged hospital stays, higher costs, and increased mortality. The most important multidrug-resistant pathogens are Pseudomonas aeruginosa and Acinetobacter baumannii. There has been an important but as yet unsuccessful effort to develop new drugs to treat these pathogens. Nevertheless, old, very well known drugs, such as polymyxins, administered intravenously and aerosolized, have been revisited. Future options include immunotherapy or the continuous infusion of antibiotics. It is also important to emphasize the rational use of antibiotics to diminish the appearance of multiresistant pathogens.

KEYWORDS

Multiresistant nonfermenting bacilli - Pseudomonas aeruginosa - Acinetobacter baumannii - health-associated infections - cystic fibrosis - pneumonia

REFERENCES

• 1 Klevens R M, Edwards J R, Richards Jr C L et al.. Estimating health care-associated infections and deaths in U.S. hospitals, 2002.  Public Health Rep. 2007;  122 (2) 160-166
• 2 Chopra I, Schofield C, Everett M et al.. Treatment of health-care-associated infections caused by gram-negative bacteria: a consensus statement.  Lancet Infect Dis. 2008;  8 (2) 133-139
• 3 Peleg A Y, Hooper D C. Hospital-acquired infections due to gram-negative bacteria.  N Engl J Med. 2010;  362 (19) 1804-1813
• 4 Diaz E, Muñoz E, Agbaht K, Rello J. Management of ventilator-associated pneumonia caused by multiresistant bacteria.  Curr Opin Crit Care. 2007;  13 (1) 45-50
• 5 Rello J, Sa-Borges M, Correa H, Leal S R, Baraibar J. Variations in etiology of ventilator-associated pneumonia across four treatment sites: implications for antimicrobial prescribing practices.  Am J Respir Crit Care Med. 1999;  160 (2) 608-613
• 6 Spellberg B, Guidos R, Gilbert D Infectious Diseases Society of America et al. The epidemic of antibiotic-resistant infections: a call to action for the medical community from the Infectious Diseases Society of America.  Clin Infect Dis. 2008;  46 (2) 155-164
• 7 Boucher H W, Talbot G H, Bradley J S et al.. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America.  Clin Infect Dis. 2009;  48 (1) 1-12
• 8 Rice L B. The clinical consequences of antimicrobial resistance.  Curr Opin Microbiol. 2009;  12 (5) 476-481
• 9 Schulert G S, Feltman H, Rabin S DP et al.. Secretion of the toxin ExoU is a marker for highly virulent Pseudomonas aeruginosa isolates obtained from patients with hospital-acquired pneumonia.  J Infect Dis. 2003;  188 (11) 1695-1706
• 10 Talbot G H, Bradley J, Edwards Jr J E, Gilbert D, Scheld M, Bartlett J G. Antimicrobial Availability Task Force of the Infectious Diseases Society of America . Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America.  Clin Infect Dis. 2006;  42 (5) 657-668
• 11 McGowan Jr J E. Resistance in nonfermenting gram-negative bacteria: multidrug resistance to the maximum.  Am J Med. 2006;  119 (6, Suppl 1) S29-S36 discussion S62-S70
• 12 Rice L B. Unmet medical needs in antibacterial therapy.  Biochem Pharmacol. 2006;  71 (7) 991-995
• 13 Mesaros N, Nordmann P, Plésiat P et al.. Pseudomonas aeruginosa: resistance and therapeutic options at the turn of the new millennium.  Clin Microbiol Infect. 2007;  13 (6) 560-578
• 14 Hidron A I, Edwards J R, Patel J National Healthcare Safety Network Team et al. NHSN annual update: antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006-2007.  Infect Control Hosp Epidemiol. 2008;  29 (11) 996-1011
• 15 Paterson D L, Lipman J. Returning to the pre-antibiotic era in the critically ill: the XDR problem.  Crit Care Med. 2007;  35 (7) 1789-1791
• 16 Valencia R, Arroyo L A, Conde M et al.. Nosocomial outbreak of infection with pan-drug-resistant Acinetobacter baumannii in a tertiary care university hospital.  Infect Control Hosp Epidemiol. 2009;  30 (3) 257-263
• 17 Paterson D L. The epidemiological profile of infections with multidrug-resistant Pseudomonas aeruginosa and Acinetobacter species.  Clin Infect Dis. 2006;  43 (Suppl 2) S43-S48
• 18 Pinheiro M R, Lacerda H R, Melo R G, Maciel M A. Pseudomonas aeruginosa infections: factors relating to mortality with emphasis on resistance pattern and antimicrobial treatment.  Braz J Infect Dis. 2008;  12 (6) 509-515
• 19 Aloush V, Navon-Venezia S, Seigman-Igra Y, Cabili S, Carmeli Y. Multidrug-resistant Pseudomonas aeruginosa: risk factors and clinical impact.  Antimicrob Agents Chemother. 2006;  50 (1) 43-48
• 20 Gaynes R, Edwards J R. National Nosocomial Infections Surveillance System . Overview of nosocomial infections caused by gram-negative bacilli.  Clin Infect Dis. 2005;  41 (6) 848-854
• 21 Koulenti D, Lisboa T, Brun-Buisson C EU-VAP/CAP Study Group et al. Spectrum of practice in the diagnosis of nosocomial pneumonia in patients requiring mechanical ventilation in European intensive care units.  Crit Care Med. 2009;  37 (8) 2360-2368
• 22 Gilligan P H. Microbiology of airway disease in patients with cystic fibrosis.  Clin Microbiol Rev. 1991;  4 (1) 35-51
• 23 Martínez-Solano L, Macia M D, Fajardo A, Oliver A, Martinez J L. Chronic Pseudomonas aeruginosa infection in chronic obstructive pulmonary disease.  Clin Infect Dis. 2008;  47 (12) 1526-1533
• 24 Chastre J, Fagon J Y. Ventilator-associated pneumonia.  Am J Respir Crit Care Med. 2002;  165 (7) 867-903
• 25 Marshall J C, Christou N V, Meakins J L. The gastrointestinal tract: the “undrained abscess” of multiple organ failure.  Ann Surg. 1993;  218 (2) 111-119
• 26 Vincent J L. Nosocomial infections in adult intensive-care units.  Lancet. 2003;  361 (9374) 2068-2077
• 27 Kipnis E, Sawa T, Wiener-Kronish J. Targeting mechanisms of Pseudomonas aeruginosa pathogenesis.  Med Mal Infect. 2006;  36 (2) 78-91
• 28 Woods D E. Comparative genomic analysis of Pseudomonas aeruginosa virulence.  Trends Microbiol. 2004;  12 (10) 437-439
• 29 Lambert P A. Mechanisms of antibiotic resistance in Pseudomonas aeruginosa.  J R Soc Med. 2002;  95 (Suppl 41) 22-26
• 30 Hauser A R, Cobb E, Bodi M et al.. Type III protein secretion is associated with poor clinical outcomes in patients with ventilator-associated pneumonia caused by Pseudomonas aeruginosa.  Crit Care Med. 2002;  30 (3) 521-528
• 31 Lisboa T, Rello J. Finding the hidden target in Pseudomonas aeruginosa management.  Crit Care Med. 2008;  36 (9) 2675-2676
• 32 Queenan A M, Bush K. Carbapenemases: the versatile beta-lactamases.  Clin Microbiol Rev. 2007;  20 (3) 440-458
• 33 Juan Nicolau C, Oliver A. Carbapenemases in Pseudomonas spp.  Enferm Infecc Microbiol Clin. 2010;  28 (Suppl 1) 19-28
• 34 Giamarellou H, Poulakou G. Multidrug-resistant gram-negative infections: what are the treatment options?.  Drugs. 2009;  69 (14) 1879-1901
• 35 Kallen A J, Hidron A I, Patel J, Srinivasan A. Multidrug resistance among gram-negative pathogens that caused healthcare-associated infections reported to the National Healthcare Safety Network, 2006-2008.  Infect Control Hosp Epidemiol. 2010;  31 (5) 528-531
• 36 Veesenmeyer J L, Hauser A R, Lisboa T, Rello J. Pseudomonas aeruginosa virulence and therapy: evolving translational strategies.  Crit Care Med. 2009;  37 (5) 1777-1786
• 37 Eggimann P, Revelly J P. Should antibiotic combinations be used to treat ventilator-associated pneumonia?.  Semin Respir Crit Care Med. 2006;  27 (1) 68-81
• 38 Garnacho-Montero J, Sa-Borges M, Sole-Violan J et al.. Optimal management therapy for Pseudomonas aeruginosa ventilator-associated pneumonia: an observational, multicenter study comparing monotherapy with combination antibiotic therapy.  Crit Care Med. 2007;  35 (8) 1888-1895
• 39 Sandiumenge A, Diaz E, Bodí M, Rello J. Therapy of ventilator-associated pneumonia: a patient-based approach based on the ten rules of “The Tarragona Strategy”.  Intensive Care Med. 2003;  29 (6) 876-883
• 40 Adeboyeku D, Scott S, Hodson M E. Open follow-up study of tobramycin nebuliser solution and colistin in patients with cystic fibrosis.  J Cyst Fibros. 2006;  5 (4) 261-263
• 41 Ryan G, Mukhopadhyay S, Singh M. Nebulised anti-pseudomonal antibiotics for cystic fibrosis.  Cochrane Database Syst Rev. 2003;  (3) CD001021
• 42 Rappaz I, Decosterd L A, Bille J, Pilet M, Bélaz N, Roulet M. Continuous infusion of ceftazidime with a portable pump is as effective as thrice-a-day bolus in cystic fibrosis children.  Eur J Pediatr. 2000;  159 (12) 919-925
• 43 Falagas M E, Kasiakou S K. Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections.  Clin Infect Dis. 2005;  40 (9) 1333-1341
• 44 Li J, Nation R L. Old polymyxins are back: is resistance close?.  Clin Infect Dis. 2006;  43 (5) 663-664
• 45 Fekety Jr F R, Norman P S, Cluff L E. The treatment of gram-negative bacillary infections with colistin: the toxicity and efficacy of large doses in forty-eight patients.  Ann Intern Med. 1962;  57 214-229
• 46 Koyama Y, Kurosasa A, Tsuchiya A, Takakuta K. A new antibiotic “colistin” produced by spore forming soil bacteria.  J Antibiot. 1950;  3 457-458
• 47 Giamarellou H, Poulakou G. Multidrug-resistant gram-negative infections: what are the treatment options?.  Drugs. 2009;  69 (14) 1879-1901
• 48 Gales A C, Reis A O, Jones R N. Contemporary assessment of antimicrobial susceptibility testing methods for polymyxin B and colistin: review of available interpretative criteria and quality control guidelines.  J Clin Microbiol. 2001;  39 (1) 183-190
• 49 Hogardt M, Schmoldt S, Götzfried M, Adler K, Heesemann J. Pitfalls of polymyxin antimicrobial susceptibility testing of Pseudomonas aeruginosa isolated from cystic fibrosis patients.  J Antimicrob Chemother. 2004;  54 (6) 1057-1061
• 50 Markou N, Apostolakos H, Koumoudiou C et al.. Intravenous colistin in the treatment of sepsis from multiresistant gram-negative bacilli in critically ill patients.  Crit Care. 2003;  7 (5) R78-R83
• 51 Linden P K, Paterson D L. Parenteral and inhaled colistin for treatment of ventilator-associated pneumonia.  Clin Infect Dis. 2006;  43 (Suppl 2) S89-S94
• 51a Plachouras D, Karvanen M, Friberg L E et al.. Population pharmacokinetic analysis of colistin methanelsulphonate and colistin after intravenous administration in critically ill patients with Gram-negative bacterial infections.  Antimicrob Agents Chemother. 2009;  53 (6) 3430-3436
• 52 Kumar A, Roberts D, Wood K E et al.. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock.  Crit Care Med. 2006;  34 (6) 1589-1596
• 53 Koch-Weser J, Sidel V W, Federman E B, Kanarek P, Finer D C, Eaton A E. Adverse effects of sodium colistimethate: manifestations and specific reaction rates during 317 courses of therapy.  Ann Intern Med. 1970;  72 (6) 857-868
• 54 Giamarellou H. Treatment options for multidrug-resistant bacteria.  Expert Rev Anti Infect Ther. 2006;  4 (4) 601-618
• 55 Michalopoulos A, Kasiakou S K, Mastora Z, Rellos K, Kapaskelis A M, Falagas M E. Aerosolized colistin for the treatment of nosocomial pneumonia due to multidrug-resistant gram-negative bacteria in patients without cystic fibrosis.  Crit Care. 2005;  9 (1) R53-R59
• 56 Hamer D H. Treatment of nosocomial pneumonia and tracheobronchitis caused by multidrug-resistant Pseudomonas aeruginosa with aerosolized colistin.  Am J Respir Crit Care Med. 2000;  162 (1) 328-330
• 57 Cunningham S, Prasad A, Collyer L, Carr S, Lynn I B, Wallis C. Bronchoconstriction following nebulised colistin in cystic fibrosis.  Arch Dis Child. 2001;  84 (5) 432-433
• 58 Bhavnani S M, Hammel J P, Cirincione B B, Wikler M A, Ambrose P G. Use of pharmacokinetic-pharmacodynamic target attainment analyses to support phase 2 and 3 dosing strategies for doripenem.  Antimicrob Agents Chemother. 2005;  49 (9) 3944-3947
• 59 Psathas P A, Kuzmission A, Ikeda K, Yasuo S. Stability of doripenem in vitro in representative infusion solutions and infusion bags.  Clin Ther. 2008;  30 (11) 2075-2087
• 60 Ikawa K, Morikawa N, Uehara S et al.. Pharmacokinetic-pharmacodynamic target attainment analysis of doripenem in infected patients.  Int J Antimicrob Agents. 2009;  33 (3) 276-279
• 61 Poulakou G, Giamarellou H. Doripenem: an expected arrival in the treatment of infections caused by multidrug-resistant Gram-negative pathogens.  Expert Opin Investig Drugs. 2008;  17 (5) 749-771
• 62 Feldman C, White H, O'Grady J, Flitcroft A, Briggs A, Richards G. An open, randomised, multi-centre study comparing the safety and efficacy of sitafloxacin and imipenem/cilastatin in the intravenous treatment of hospitalised patients with pneumonia.  Int J Antimicrob Agents. 2001;  17 (3) 177-188
• 63 Lynch A S. Efflux systems in bacterial pathogens: an opportunity for therapeutic intervention? An industry view.  Biochem Pharmacol. 2006;  71 (7) 949-956
• 64 Nakayama K, Ishida Y, Ohtsuka M et al.. MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa, II: Achieving activity in vivo through the use of alternative scaffolds.  Bioorg Med Chem Lett. 2003;  13 (23) 4205-4208
• 65 Lomovskaya O, Warren M S, Lee A et al.. Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: novel agents for combination therapy.  Antimicrob Agents Chemother. 2001;  45 (1) 105-116
• 66 Garnacho J, Sole-Violan J, Sa-Borges M, Diaz E, Rello J. Clinical impact of pneumonia caused by Acinetobacter baumannii in intubated patients: a matched cohort study.  Crit Care Med. 2003;  31 (10) 2478-2482
• 67 Baraibar J, Correa H, Mariscal D, Gallego M, Vallés J, Rello J. Risk factors for infection by Acinetobacter baumannii in intubated patients with nosocomial pneumonia.  Chest. 1997;  112 (4) 1050-1054
• 68 Muñoz-Price L S, Weinstein R A. Acinetobacter infection.  N Engl J Med. 2008;  358 (12) 1271-1281
• 69 Peleg A Y, Seifert H, Paterson D L. Acinetobacter baumannii: emergence of a successful pathogen.  Clin Microbiol Rev. 2008;  21 (3) 538-582
• 70 Cisneros-Herreros J M, Garnacho-Montero J, Pachón-Ibáñez M E. Nosocomial pneumonia due to Acinetobacter baumannii.  Enferm Infecc Microbiol Clin. 2005;  23 (Suppl 3) 46-51
• 71 Alvarez-Lerma F, Palomar M, Insausti J Grupo de Estudio Nacional de Vigilancia de Infección Nosocomial en UCI et al. Infections caused by Acinetobacter spp. in critically ill UCI patients [in Spanish].  Enferm Infecc Microbiol Clin. 2005;  23 (9) 533-539
• 72 Falagas M E, Bliziotis I A, Siempos I I. Attributable mortality of Acinetobacter baumannii infections in critically ill patients: a systematic review of matched cohort and case-control studies.  Crit Care. 2006;  10 (2) R48
• 73 Falagas M E, Kasiakou S K, Rafailidis P I, Zouglakis G, Morfou P. Comparison of mortality of patients with Acinetobacter baumannii bacteraemia receiving appropriate and inappropriate empirical therapy.  J Antimicrob Chemother. 2006;  57 (6) 1251-1254
• 74 Wisplinghoff H, Bischoff T, Tallent S M, Seifert H, Wenzel R P, Edmond M B. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study.  Clin Infect Dis. 2004;  39 (3) 309-317
• 75 Fournier P E, Richet H. The epidemiology and control of Acinetobacter baumannii in health care facilities.  Clin Infect Dis. 2006;  42 (5) 692-699
• 76 Jawad A, Heritage J, Snelling A M, Gascoyne-Binzi D M, Hawkey P M. Influence of relative humidity and suspending menstrua on survival of Acinetobacter spp. on dry surfaces.  J Clin Microbiol. 1996;  34 (12) 2881-2887
• 77 Corbella X, Montero A, Pujol M et al.. Emergence and rapid spread of carbapenem resistance during a large and sustained hospital outbreak of multiresistant Acinetobacter baumannii.  J Clin Microbiol. 2000;  38 (11) 4086-4095
• 78 Seifert H, Stefanik D, Wisplinghoff H. Comparative in vitro activities of tigecycline and 11 other antimicrobial agents against 215 epidemiologically defined multidrug-resistant Acinetobacter baumannii isolates.  J Antimicrob Chemother. 2006;  58 (5) 1099-1100
• 79 Pachón-Ibáñez M E, Jiménez-Mejías M E, Pichardo C, Llanos A C, Pachón J. Activity of tigecycline (GAR-936) against Acinetobacter baumannii strains, including those resistant to imipenem.  Antimicrob Agents Chemother. 2004;  48 (11) 4479-4481
• 80 Karageorgopoulos D E, Kelesidis T, Kelesidis I, Falagas M E. Tigecycline for the treatment of multidrug-resistant (including carbapenem-resistant) Acinetobacter infections: a review of the scientific evidence.  J Antimicrob Chemother. 2008;  62 (1) 45-55
• 81 Rice L B. Challenges in identifying new antimicrobial agents effective for treating infections with Acinetobacter baumannii and Pseudomonas aeruginosa.  Clin Infect Dis. 2006;  43 (Suppl 2) S100-S105
• 82 Levin A S, Levy C E, Manrique A E, Medeiros E A, Costa S F. Severe nosocomial infections with imipenem-resistant Acinetobacter baumannii treated with ampicillin/sulbactam.  Int J Antimicrob Agents. 2003;  21 (1) 58-62
• 83 Levin A S, Barone A A, Penço J et al.. Intravenous colistin as therapy for nosocomial infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii.  Clin Infect Dis. 1999;  28 (5) 1008-1011
• 84 Bottone E J, Reitano M, Janda J M, Troy K, Cuttner J. Pseudomonas maltophilia exoenzyme activity as correlate in pathogenesis of ecthyma gangrenosum.  J Clin Microbiol. 1986;  24 (6) 995-997
• 85 Di Bonaventura G, Spedicato I, D'Antonio D, Robuffo I, Piccolomini R. Biofilm formation by Stenotrophomonas maltophilia: modulation by quinolones, trimethoprim-sulfamethoxazole, and ceftazidime.  Antimicrob Agents Chemother. 2004;  48 (1) 151-160
• 86 Saiman L, Siegel J. Infection control in cystic fibrosis.  Clin Microbiol Rev. 2004;  17 (1) 57-71
• 87 Avgeri S G, Matthaiou D K, Dimopoulos G, Grammatikos A P, Falagas M E. Therapeutic options for Burkholderia cepacia infections beyond co-trimoxazole: a systematic review of the clinical evidence.  Int J Antimicrob Agents. 2009;  33 (5) 394-404
• 88 Sedlak-Weinstein E, Cripps A W, Kyd J M, Foxwell A R. Pseudomonas aeruginosa: the potential to immunise against infection.  Expert Opin Biol Ther. 2005;  5 (7) 967-982
• 89 Ambrose P G, Bhavnani S M, Ellis-Grosse E J, Drusano G L. Pharmacokinetic-pharmacodynamic considerations in the design of hospital-acquired or ventilator-associated bacterial pneumonia studies: look before you leap!.  Clin Infect Dis. 2010;  51 (Suppl 1) S103-S110
• 90 Moriyama B, Henning S A, Childs R et al.. High-dose continuous infusion beta-lactam antibiotics for the treatment of resistant Pseudomonas aeruginosa infections in immunocompromised patients.  Ann Pharmacother. 2010;  44 (5) 929-935
• 91 Lu Q, Rouby J J, Laterre P F et al.. Pharmacokinetics and safety of panobacumab: specific adjunctive immunotherapy in critical patients with nosomial Pseudomonal aeruginosa 011 pneumonia.  J Antimicrob Chemother. [E-pub ahead of print March 10, 2011]