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Gram-negative Bacterial Infections

There has been a worldwide increase in the number of infections caused by Gram-negative bacteria. In a study of 1265 intensive care units in 75 countries, Gram-negative bacteria were present in 62% of patients with an infection, while Gram-positive bacteria were present in 47% of patients.1

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Given the increasing danger posed by
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Gram-negative bacteria are highly adaptive pathogens that can develop resistance through several mechanisms.2-6 Resistant Gram-negative bacteria are a serious global public health concern , as noted in the recent U.S. Centers for Disease Control and Prevention (CDC) report Antibiotic Resistant Threats in the United States, 2013.

In the U.S., it has been estimated that as many as 2 million patients each year become infected with a bacterial infection that is resistant to antibiotics, with an estimated 23,000 deaths associated with these infections.7 The prevalence of resistant Gram-negative bacteria can vary at local, regional, national, and international levels.8

Antibiotic-resistant infections pose considerable challenges to the health care system in relation to diagnosis, treatment, and infection control, as well as considerable costs. In most cases, antibiotic-resistant infections require extended hospital stays, additional doctor visits and healthcare use. The estimates of the healthcare costs to the U.S. economy for antibiotic-resistant infections have ranged as high as $20 billion.7

Gram-negative bacteria are common causes of intra-abdominal infections (IAIs), urinary tract infections (UTIs), nosocomial pneumonia, and bacteremia.9 Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae), and Pseudomonas aeruginosa (P. aeruginosa) are important pathogens in the hospital setting, accounting for 27% of all pathogens and 70% of all Gram-negative pathogens causing healthcare-associated infections.9

Gram-negative bacteria are showing rising rates of resistance to current therapies. The production of extended-spectrum β-lactamase (ESBL) enzymes is a common mechanism of resistance. Although the prevalence of ESBL-producing E. coli can vary from country to country, resistance rates to many commonly used therapies have increased throughout the world.8, 10-15 Rates of ESBL-producing K. pneumoniae have risen substantially, with the result that these bacteria are increasingly resistant to widely used antimicrobials.16,17

P. aeruginosa is the most common Gram-negative cause of nosocomial pneumonia and the second most common cause of catheter-related UTIs in the U.S..9 P. aeruginosa has several mechanisms that can confer resistance.4,5 Resistance rates for P. aeruginosa to antimicrobials vary widely in Europe; rates are lowest (<10%) in the north and highest (25%-50%) in the south.10 In comparison, rates are intermediate in the U.S..9 Some P. aeruginosa can also be resistant to multiple classes of drugs. Reported rates of this multidrug-resistant (MDR) strain of P. aeruginosa can vary widely, but recent U.S. studies found that 17-22% of P. aeruginosa from patients with pneumonia and 14% from patients with UTI were MDR.9,18-20

E. coli is the most common cause of UTIs.9, 21-23 Cases of UTI caused by ESBL-producing E. coli and K. pneumonia as well as P. aeruginosa, including MDR strains, are increasing.19 ESBL-producing E. coli and K. pneumoniae are also frequently isolated in patients with complicated IAI (cIAI).24

P. aeruginosa is a problematic and virulent pathogen that can be a cause of common infections in humans such as nosocomial pneumonia, UTI, IAI, and bloodstream infections. P. aeruginosa is the most common Gram-negative organism causing ventilator associated pneumonia and the second most common cause of catheter-associated UTIs.9

The prevalence of P. aeruginosa in nosocomial pneumonia has recently been documented as 19% in the U.S. and 22.4% in other regions.25 Across several studies of cIAI, including peritonitis, P. aeruginosa has been isolated in 5%-17% of cases.26-31 In complicated UTI, P. aeruginosa has been found present in up to 13% of patients.32

The increase in the number of infections caused by Gram-negative bacteria is being accompanied by rising rates of resistance. Treatment options to meet this challenge are increasingly limited. There is a critical need for new antibiotics to meet the needs of patients now and in the future.

References

  • Vincent JL, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302:2323-2329.
  • Bradford PA. Extended-spectrum beta-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat. Clin Microbiol Rev. 2001;14:933-951.
  • Livermore DM, Woodford N. The ß-lactamase threat in Enterobacteriaceae, Pseudomonas and Acinetobacter. Trends Microbiol. 2006;14:413-420.
  • Breidenstein EB, Fuente-Nunez C, Hancock RE. Pseudomonas aeruginosa: all roads lead to resistance. Trends Microbiol. 2011;19:419-426.
  • Lister PD, Wolter DJ, Hanson ND. Antibacterial-resistant Pseudomonas aeruginosa: clinical impact and complex regulation of chromosomally encoded resistance mechanisms. Clin Microbiol Rev. 2009;22:582-610.
  • Livermore DM. Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: our worst nightmare? Clin Infect Dis. 2002;34:634-640.
  • CDC. Antibiotic resistance threats in the US, 2013. Accessed on October 10, 2013.
  • Livermore D. Current epidemiology and growing resistance of gram-negative pathogens. Korean J Intern Med. 2012;27:128-142.
  • Sievert DM, Ricks P, Edwards JR, et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009-2010. Infect Control Hosp Epidemiol. 2013;34:1-14.
  • Antimicrobial resistance surveillance in Europe. European Centre for Disease Prevention and Control Web site. Accessed August 12, 2013.
  • Hawser SP, Badal RE, Bouchillon SK, Hoban DJ. Trending eight years of in vitro activity of ertapenem and comparators against Escherichia coli from intra-abdominal infections in North America--SMART 2002-2009. J Chemother. 2011;23:266-272.
  • Gagliotti C, Balode A, Baquero F, et al. Escherichia coli and Staphylococcus aureus: bad news and good news from the European Antimicrobial Resistance Surveillance Network (EARS-Net, formerly EARSS), 2002 to 2009. Euro Surveill. 2011;16(11).
  • Nakamura T, Komatsu M, Yamasaki K, et al. Epidemiology of Escherichia coli, Klebsiella species, and Proteus mirabilis strains producing extended-spectrum beta-lactamases from clinical samples in the Kinki region of Japan. Am J Clin Pathol. 2012;137:620-626.
  • Hawser SP, Badal RE, Bouchillon SK, et al. Monitoring the global in vitro activity of ertapenem against Escherichia coli from intra-abdominal infections: SMART 2002-2010. Int J Antimicrob Agents. 2013;41:224-228.
  • Pitout JD. Infections with extended-spectrum ß-lactamase-producing Enterobacteriaceae: changing epidemiology and drug treatment choices. Drugs. 2010;70:313-333.
  • Falagas ME, Karageorgopoulos DE. Extended-spectrum beta-lactamase-producing organisms. J Hosp Infect. 2009;73:345-354.
  • Sanchez GV, Master RN, Clark RB, et al. Klebsiella pneumoniae antimicrobial drug resistance, United States, 1998-2010. Emerg Infect Dis. 2013;19:133-136.
  • Zilberberg MD, Shorr AF. Prevalence of multidrug-resistant pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae among specimens from hospitalized patients with pneumonia and bloodstream infections in the United States from 2000 to 2009. J Hosp Med. Online ahead of print Sept 10, 2013. 10.1002/jhm.2080 [doi].
  • Zilberberg MD, Shorr AF. Secular trends in Gram-negative resistance among urinary tract infection hospitalizations in the United States, 2000-2009. Infect Control Hosp Epidemiol. 2013;34:940-946.
  • Sun HY, Fujitani S, Quintiliani R, Yu VL. Pneumonia due to Pseudomonas aeruginosa: part II: antimicrobial resistance, pharmacodynamic concepts, and antibiotic therapy. Chest. 2011;139:1172-1185.
  • Chen YH, Ko WC, Hsueh PR. Emerging resistance problems and future perspectives in pharmacotherapy for complicated urinary tract infections. Expert Opin Pharmacother. 2013;14:587-596.
  • Lu PL, Liu YC, Toh HS, et al. Epidemiology and antimicrobial susceptibility profiles of Gram-negative bacteria causing urinary tract infections in the Asia-Pacific region: 2009-2010 results from the Study for Monitoring Antimicrobial Resistance Trends (SMART). Int J Antimicrob Agents. 2012;40(Suppl):S37-S43.
  • Hoban DJ, Lascols C, Nicolle LE, et al. Antimicrobial susceptibility of Enterobacteriaceae, including molecular characterization of extended-spectrum beta-lactamase-producing species, in urinary tract isolates from hospitalized patients in North America and Europe: results from the SMART study 2009-2010. Diagn Microbiol Infect Dis. 2012;74:62-67.
  • Babinchak T, Badal R, Hoban D, et al. Trends in susceptibility of slected Gram-negative bacilli isolated from Intra-abdominal infections in North America: SMART 2005-2010. Diagn Microbiol Infect Dis. 2013;76:379-81.
  • Jones RN. Microbial etiologies of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. Clin Infect Dis. 2010;51(Suppl 1):S81-S87.
  • Augustin P, Dinh AT, Valin N, et al. Pseudomonas aeruginosa post-operative peritonitis: clinical features, risk factors, and prognosis. Surg Infect (Larchmt). 2013;14:297-303.
  • Sartelli M, Catena F, Ansaloni L, et al. Complicated intra-abdominal infections in a worldwide context: an observational prospective study (CIAOW Study). World J Emerg Surg. 2013;8:1.
  • Sartelli M, Catena F, Ansaloni L, et al. Complicated intra-abdominal infections in Europe: a comprehensive review of the CIAO study. World J Emerg Surg. 2012;7:36.
  • Seguin P, Fédun Y, Laviolle B, et al. Risk factors for multidrug-resistant bacteria in patients with post-operative peritonitis requiring intensive care. J Antimicrob Chemother. 2010;65:342-346.
  • Riché FC, Dray X, Laisné MJ, et al. Factors associated with septic shock and mortality in generalized peritonitis: comparison between community-acquired and postoperative peritonitis. Crit Care. 2009;13:R99.
  • Montravers P, Lepape A, Dubreuil L, et al. Clinical and microbiological profiles of community-acquired and nosocomial intra-abdominal infections: results of the French prospective, observational EBIIA study. J Antimicrob Chemother. 2009;63:785-794.
  • Wagenlehner FM, Naber KG. Current challenges in the treatment of complicated urinary tract infections and prostatitis. Clin Microbiol Infect. 2006;12(Suppl 3):67-80.