Multidrug-Resistant Pseudomonas aeruginosa Infections: Hard to Treat, But Hope on the Horizon?

February 19, 2018
JOSHUA GARCIA, PHARMD

,
KATHERINE GRUENBERG, PHARMD

,
LYNN NGUYEN, PHARMD

,
CONAN MACDOUGALL, PHARMD

Contagion, February 2018, Volume 3, Issue 1

Two recently approved agents offer significant activity against these hard-to-treat conditions.

Pseudomonas aeruginosa (P. aeruginosa) is an aerobic, gram-negative bacilli that can be found ubiquitously in soil, plants, and hospital reservoirs of water, including showers, sinks, and toilet water.1 A recent report from the National Healthcare Safety Network, summarizing the health care-associated infections from 4515 US hospitals from 2011 to 2014, reported to be the sixth most common nosocomial pathogen overall and second most common pathogen in ventilator- associated pneumonia (VAP) in US hospitals.2 On a national level, P. aeruginosa was found to have resistance or intermediate susceptibility to at least 1 carbapenem in 19.3% (4365/22,593) of isolates, resistant to at least 1 aminoglycoside in 9.7% (2631/27,197) of isolates, resistant to either cefepime or ceftazidime in 10.3% of isolates (2763/26,772) resistant to at least 1 fluoroquinolone in 21.6% (5808/26,897) of isolates, resistant to piperacillin/tazobactam in 10.0% (2378/23,662) of isolates, and multidrug resistant (MDR) in 14.2% (3871/27,289) if isolates.3

This high level of resistance is attributable to the multiple intrinsic resistance mechanisms that P. aeruginosa may express, including beta-lactamase production, efflux-mediated and porin-related resistance, and target site modification.4 These mechanisms are often present in combination, causing a broad range of antibiotics to be rendered ineffective against a given P. aeruginosa isolate. The production of beta-lactamase enzymes represents 1 of the most prominent resistance mechanisms utilized by P. aeruginosa. AmpC beta-lactamase in P. aeruginosa is a chromosomally mediated beta-lactamase that is naturally induced by the presence of some beta-lactams and beta-lactam inhibitors, conferring natural resistance to lower level penicillins and cephalosporins.5 Although the induction of AmpC beta-lactamase confers resistance to a number of beta-lactam antibiotics, it is the hyper production, or “derepression,” of AmpC through chromosomal mutation, which confers resistance to a number of antipseudomonal agents, such as piperacillin/tazobactam.6

For P. aeruginosa to acquire resistance to agents such as carbapenems and cefepime, other mechanisms of resistance are usually present in combination with hyper production of AmpC beta-lactamase, such as overexpression of efflux pumps (carbapenems), production of other beta-lactamases, or downregulation of porin production (carbapenems and cefepime).5 Finally, P. aeruginosa can express resistance to non—beta-lactam antibiotics through antibiotic target modification. The 2 more prominent antibiotic classes susceptible to this resistance mechanism are fluoroquinolones and aminoglycosides.4

…BUT, THERE’S HOPE ON THE HORIZON?

Two recently approved agents offer significant activity against multidrug-resistant P. aeruginosa infections. In addition, 2 agents in phase 2/3 trials may expand the armamentarium further. The Table describes the stage of development of these 4 agents, the mechanism of enhanced activity of these agents against P. aeruginosa, and the in vitro potency of the agents. Notably, 1 newly approved agent (meropenem-vaborbactam) and several agents in development (aztreonam-avibactam, finafloxacin, plazomicin) generally have activity against P. aeruginosa but offer little added activity against MDR isolates. Below we discuss the available clinical data for the recently approved agents.

RECENTLY APPROVED AGENTS WITH ENHANCED ACTIVITY AGAINST P. AERUGINOSA

Ceftazidime-Avibactam

Clinical Trials

In 2015, the FDA approved ceftazidime-avibactam for the treatment of complicated intra-abdominal infections (cIAIs) in combination with metronidazole and complicated urinary tract infections (cUTIs), including pyelonephritis, in adult patients. The FDA-approved dose for both indications is 2.5 grams every 8 hours in patients with creatinine clearance greater than 50 mL/ minute. In phase 3 cIAI trials, ceftazidime-avibactam demonstrated cure rates of at least 90% for both ceftazidime-susceptible and ceftazidime-resistant P. aeruginosa infections, with no statistically significant difference observed compared with the meropenem arm.7,8

In phase 3 cUTIs trials, P. aeruginosa was isolated rarely (~5% of isolates), with microbiological response rates for P. aeruginosa infections similar between the ceftazidime/avibactam and doripenem arms.9 REPRISE was a pathogen-directed phase 3 trial that specifically enrolled patients with ceftazidime-resistant enterobacteriaceae and P. aeruginosa cUTIs and cIAIs.10 For cUTIs due to P. aeruginosa, the microbiological response was 79% and 60% with ceftazidime/avibactam and best available therapy (most commonly a carbapenem), respectively. Two patients in the study had cIAIs due to P. aeruginosa (1 in each treatment arm); both had a favorable microbiological response. REPROVE was a recently completed phase 3 trial comparing ceftazidime/ avibactam to meropenem for nosocomial pneumonia.11 The second most common Gram-negative pathogen was P. aeruginosa, isolated from approximately 30% of patients. Ceftazidime/avibactam demonstrated noninferiority to meropenem for the primary endpoint of clinical cure across all patients (per-pathogen analysis is not yet available).

Experience for MDR P. aeruginosa

One case series described the successful treatment of 2 patients with extremely drug-resistant (XDR) P. aeruginosa infections using the combination of ceftazidime/avibactam and colistin. The first patient had XDR P. aeruginosa bacteremia with septic emboli to the lungs. The second patient had XDR P. aeruginosa sinusitis and meningitis. Both patients were previously treated with meropenem in combination with colistin, without clinical improvement, before they were started on ceftazidime/avibactam at 2.5 g/8 h plus colistin at 2 MU/8 h. Both patients demonstrated clinical and radiological resolution with ceftazidime/avibactam.12

Ceftolozane-Tazobactam

Clinical Trials

Ceftolozane-tazobactam was approved by the FDA in 2014, shortly before ceftazidime-avibactam was approved for the same indications. The FDA-approved dose for both indications is 1.5 g/8 h in patients with creatinine clearance greater than 50 mL/minute. In the phase 3 ASPECT-cIAI trial, ceftolozane/tazobactam plus metronidazole demonstrated noninferiority to meropenem in the primary endpoint of clinical cure rate at the test of cure visit; for infections due to P. aeruginosa specifically, clinical cure rates were 100% with ceftolozane/tazobactam and 93.1% with meropenem.13 In the phase 3 ASPECT-cUTI trial, ceftolozane/tazobactam was studied against levofloxacin; in infections due to P. aeruginosa specifically, microbiological eradication was higher with ceftolozane/tazobactam (85.7%) compared with levofloxacin (58.3%), although statistical conclusions could not be drawn based on the small sample.14 A phase 3 trial for nosocomial pneumonia is in progress (NCT02070757), where ceftolozane/tazobactam will be studied at a higher dose of 3 g/8 h and patients in the comparator arm will receive meropenem.

Experience for MDR P. aeruginosa

Clinical experience with ceftolozane/tazobactam for MDR P. aeruginosa has been described in several case series and retrospective studies, primarily with pneumonia. In a retrospective review of 21 patients treated with ceftolozane/tazobactam for MDR P. aeruginosa infections (86% with pneumonia), the clinical success rate was 71%. The emergence of resistance to ceftolozane/tazobactam was found in 3 patients and occurred as quickly as 8 days into therapy.15 In a retrospective review of 12 patients with MDR P. aeruginosa infections, salvage therapy with ceftolozane/tazobactam resulted in microbiological eradication within 30 days in 83% of patients. However, 2 of those patients subsequently grew P. aeruginosa resistant to ceftolozane/tazobactam, 1 of whom experienced clinical recurrence.16 In another case series of 3 patients, ceftolozane/tazobactam was used successfully in the treatment of health care-associated and VAP secondary to MDR P. aeruginosa. All patients had previously been treated with meropenem or ciprofloxacin, and all isolates were susceptible to ceftolozane/tazobactam with a minimum inhibitory concentration (MIC) of 1 mcg/mL or less. Ceftolozane/tazobactam was dosed at 3 g/8 h and all 3 patients were cured with microbiological eradication.17 Although the data are more limited, ceftolozane/tazobactam has also been used in the treatment of bloodstream infections18,19, skin and soft tissue infections20,21, osteomyelitis22, mycotic pseudoanerysm23, a left ventricular assist device infection24, and a cystic fibrosis pulmonary exacerbation (at a dose of 3 g/8 h) due to MDR P. aeruginosa.25

COMPARATIVE ACTIVITY OF CEFTAZIDIME/AVIBACTAM AND CEFTOLOZONE/TAZOBACTAM

Ceftolozane/tazobactam appears to have greater in vitro activity against P. aeruginosa than that of ceftazidime/avibactam, particularly against strains with meropenem resistance. Two studies comparing the activity of these agents against meropenem-resistant P. aeruginosa have been published.26,27 Both studies reported MIC distributions demonstrating more potent activity with ceftolozane/tazobactam than with ceftazidime/ avibactam. A higher proportion of isolates had ceftazidime/avibactam MICs at the susceptibility breakpoint (8 mg/L) compared with ceftolozane/tazobactam MICs. In contrast to the large surveillance studies, which report susceptibility rates greater than 85% for both agents, much lower susceptibility rates were described in an evaluation of beta-lactam resistant P. aeruginosa patient isolates from Los Angeles-area hospitals.28 As expected, a greater proportion were susceptible to ceftolozane/tazobactam than to ceftazidime/avibactam, but susceptibility rates were more modest than previously reported (72.5% vs 61.8%). These findings highlight the importance of using local susceptibility data to guide decision making, as susceptibility rates can vary greatly depending on local resistance patterns. Of note, only 9% of ceftolozane/tazobactam-resistant isolates were susceptible to ceftazidime/avibactam, whereas 36% of ceftazidime/avibactam resistant isolates were susceptible to ceftolozane/tazobactam, again suggesting that ceftolozane/tazobactam may have greater utility as a last-line treatment option against MDR P. aeruginosa.

There appears to be a modest potency advantage and more clinical experience with ceftolozane/tazobactam for MDR P. aeruginosa than with ceftazidime/avibactam. However, of particular concern are the multiple reported cases of the emergence of resistance to ceftolozane/tazobactam. Whether or not this is a problem with ceftazidime/avibactam is largely unknown given the paucity of data for its use in MDR P. aeruginosa infections. The possibility of resistance development should be considered in patients who have recurrence or poor response to therapy.

Note: This is an edited version of an upcoming paper in Current Infectious Diseases Reports.

Joshua Garcia is an assistant professor in the Department of Pharmacy Practice at Marshall B. Ketchum University College of Pharmacy. He received a PharmD from the University of the Sciences—Philadelphia College of Pharmacy and completed both years of postgraduate training (PGY-1 & PGY-2-Infectious Diseases) at the University of California San Francisco (UCSF). He is an active member of SIDP.

Dr. Gruenberg is an assistant professor of Clinical Pharmacy at the University of California San Francisco (UCSF) School of Pharmacy. She received a PharmD from UCSF and completed postgraduate training at Northwestern Memorial Hospital (PGY-1) and UCSF (PGY-2-Infectious Diseases/Education). She is an active member of SIDP.

Lynn Nguyen is currently completing her PGY-2 specialty residency training in infectious diseases at University of California San Francisco (UCSF) Medical Center. She earned a PharmD from The University of Texas at Austin College of Pharmacy and completed PGY-1 residency training at the Veterans Affairs San Diego Healthcare System. She is an active member of SIDP.

Dr. MacDougall is a professor of clinical pharmacy at the University of California San Francisco (UCSF) School of Pharmacy and clinical pharmacist in infectious diseases pharmacotherapy at UCSF Medical Center. He received a PharmD from UCSF, and received postgraduate training at Duke University (PGY-1), UCSF (PGY-2- Infectious Diseases), and Virginia Commonwealth University (ID fellowship). He is an active member of SIDP.

References

  1. Jefferies JMC, Cooper T, Yam T, Clarke SC. Pseudomonas aeruginosa outbreaks in the neonatal intensive care unit — a systematic review of risk factors and environmental sources. J Med Microbiol. 2012;61(8):1052-1061. doi:10.1099/jmm.0.044818-0.
  2. Weiner LM, Webb AK, Limbago B, 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, 2011—2014. Infect Control Amp Hosp Epidemiol. 2016;37(11):1288-1301. doi:10.1017/ice.2016.174.
  3. National Healthcare Safety Network. NHSN antibiotic resistance data. CDC website. gis.cdc.gov/grasp/PSA/index.html. Accessed December 13, 2017.
  4. Strateva T, Yordanov D. Pseudomonas aeruginosa - a phenomenon of bacterial resistance. J Med Microbiol. 2009;58(9):1133-1148. doi:10.1099/jmm.0.009142-0.
  5. Wolter DJ, Lister PD. Mechanisms of β-lactam resistance among Pseudomonas aeruginosa. Curr Pharmaceutical Design. 2013;19(2):209-222. eurekaselect.com/104921/article. Published December 31, 2012. Accessed December 13, 2017.
  6. Juan C, Moya B, Perez JL, Oliver A. Stepwise upregulation of the Pseudomonas aeruginosa chromosomal cephalosporinase conferring high-level beta-lactam resistance involves three AmpD homologues. Antimicrob Agents Chemother. 2006;50(5):1780-1787.
  7. Mazuski JE, Gasink LB, Armstrong J, et al. Efficacy and safety of ceftazidime-avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infection: results from a randomized, controlled, double-blind, phase 3 program. Clin Infect Dis. 2016;62(11):1380-1389. doi: 10.1093/cid/ciw133.
  8. Qin X, Tran BG, Kim MJ, et al. A randomised, double-blind, phase 3 study comparing the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem for complicated intra-abdominal infections in hospitalised adults in Asia. Int J Antimicrob Agents. 2017;49(5):579-588. doi: 10.1016/j.ijantimicag.2017.01.010.
  9. Wagenlehner FM, Sobel JD, Newell P, et al. Ceftazidime-avibactam versus doripenem for the treatment of complicated urinary tract infections, including acute pyelonephritis: RECAPTURE, a phase 3 randomized trial program. Clin Infect Dis Off Publ Infect Dis Soc Am. 2016;63(6):754-762. doi: 10.1093/cid/ciw378.
  10. Carmeli Y, Armstrong J, Laud PJ, et al. Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study. Lancet Infect Dis. doi: 10.1016/S1473-3099(16)30004-4.
  11. Torres A. Phase 3, randomized, multicentre study of ceftazidime-avibactam versus meropenem in adults with nosocomial pneumonia including ventilator-associated pneumonia (REPROVE). In: Vienna, Austria; 2017.
  12. Xipell M, Bodro M, Marco F, Losno RA, Cardozo C, Soriano A. Clinical experience with ceftazidime/avibactam in patients with severe infections, including meningitis and lung abscesses, caused by extensively drug-resistant Pseudomonas aeruginosa. Int J Antimicrob Agents. 2017;49(2):266-268. doi: 10.1016/j.ijantimicag.2016.11.005.
  13. Solomkin J, Hershberger E, Miller B, et al. Ceftolozane/tazobactam plus metronidazole for complicated intra-abdominal infections in an era of multidrug resistance: results from a randomized, double-blind, phase 3 trial (ASPECT-cIAI). Clin Infect Dis. February 2015. doi:10.1093/cid/civ097.
  14. Wagenlehner FM, Umeh O, Steenbergen J, Yuan G, Darouiche RO. Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI). The Lancet. 2015;385(9981):1949-1956.
  15. Haidar G, Philips NJ, Shields RK, et al. Ceftolozane-tazobactam for the treatment of multidrug-resistant Pseudomonas aeruginosa infections: clinical effectiveness and evolution of resistance. Clin Infect Dis. 2017;65(1):110-120. doi:10.1093/cid/cix182.
  16. Castón JJ, Torre ÁD la, Ruiz-Camps I, Sorlí ML, Torres V, Torre-Cisneros J. Salvage Therapy with ceftolozane-tazobactam for multidrug-resistant Pseudomonas aeruginosa infections. Antimicrob Agents Chemother. 2017;61(3):e02136-16. doi:10.1128/AAC.02136-16.
  17. Gelfand MS, Cleveland KO. Ceftolozane/tazobactam therapy of respiratory infections due to multidrug-resistant Pseudomonas aeruginosa. Clin Infect Dis. 2015;61(5):853-855. doi:10.1093/cid/civ411.
  18. Patel UC, Nicolau DP, Sabzwari RK. Successful treatment of multi-drug resistant Pseudomonas aeruginosa bacteremia with the recommended renally adjusted ceftolozane/tazobactam regimen. Infect Dis Ther. 2016;5(1):73-79. doi:10.1007/s40121-016-0104-3.
  19. Hernández-Tejedor A, Merino-Vega CD, Martín-Vivas A, et al. Successful treatment of multidrug-resistant Pseudomonas aeruginosa breakthrough bacteremia with ceftolozane/tazobactam. Infection. 2017;45(1):115-117. doi: 10.1007/s15010-016-0944-5.
  20. Sousa Dominguez A, Perez-Rodríguez MT, Nodar A, Martinez-Lamas L, Perez-Landeiro A, Crespo Casal M. Successful treatment of MDR Pseudomonas aeruginosa skin and soft-tissue infection with ceftolozane/tazobactam. J Antimicrob Chemother. 2017;72(4):1262-1263. doi: 10.1093/jac/dkw526.
  21. Castaldo N, Givone F, Peghin M, Righi E, Sartor A, Bassetti M. Multidrug-resistant Pseudomonas aeruginosa skin and soft-tissue infection successfully treated with ceftolozane/tazobactam. J Glob Antimicrob Resist. 2017;9:100-102. doi:10.1016/j.jgar.2017.02.012.
  22. Gentile I, Buonomo AR, Maraolo AE, et al. Successful treatment of post-surgical osteomyelitis caused by XDR Pseudomonas aeruginosa with ceftolozane/tazobactam monotherapy. J Antimicrob Chemother. 2017;72(9):2678-2679. doi:10.1093/jac/dkx172.
  23. Aye C, Williams M, Horvath R. Multidrug-Resistant Pseudomonas Mycotic Pseudoaneurysm following Cardiac Transplant Bridged by Ventricular Assistant Device., Multidrug-Resistant Pseudomonas Mycotic Pseudoaneurysm following Cardiac Transplant Bridged by Ventricular Assistant Device. Case Rep Infect Dis. 2017;2017:1402320. doi: 10.1155/2017/1402320.
  24. Peghin M, Maiani M, Castaldo N, et al. Ceftolozane/tazobactam for the treatment of MDR Pseudomonas aeruginosa left ventricular assist device infection as a bridge to heart transplant. Infection. October 2017. doi: 10.1007/s15010-017-1086-0.
  25. Vickery SB, McClain D, Wargo KA. Successful use of ceftolozane-tazobactam to treat a pulmonary exacerbation of cystic fibrosis caused by multidrug-resistant Pseudomonas aeruginosa. Pharmacother J Hum Pharmacol Drug Ther. 2016;36(10):e154-e159. doi:10.1002/phar.1825.
  26. Buehrle DJ, Shields RK, Chen L, et al. Evaluation of the in vitro activity of ceftazidime-avibactam and ceftolozane-tazobactam against meropenem-resistant Pseudomonas aeruginosa isolates. Antimicrob Agents Chemother. 2016;60(5):3227-3231. doi:10.1128/AAC.02969-15.
  27. Grupper M, Sutherland C, Nicolau DP. Multicenter evaluation of ceftazidime-avibactam and ceftolozane-tazobactam inhibitory activity against meropenem-nonsusceptible Pseudomonas aeruginosa from blood, respiratory tract, and wounds. Antimicrob Agents Chemother. 2017;61(10):e00875-17. doi:10.1128/AAC.00875-17.
  28. Humphries RM, Hindler JA, Wong-Beringer A, Miller SA. Activity of ceftolozane-tazobactam and ceftazidime-avibactam against beta-lactam-resistant Pseudomonas aeruginosa isolates. Antimicrob Agents Chemother. 2017;61(12):e01858-17. doi:10.1128/AAC.01858-17.
  29. Sader HS, Castanheira M, Flamm RK, Farrell DJ, Jones RN. Antimicrobial activity of ceftazidime-avibactam against gram-negative organisms collected from U.S. medical centers in 2012. Antimicrob Agents Chemother. 2014;58(3):1684-1692. doi:10.1128/AAC.02429-13.
  30. Sader HS, Castanheira M, Mendes RE, Flamm RK, Farrell DJ, Jones RN. Ceftazidime-avibactam activity against multidrug-resistant Pseudomonas aeruginosa isolated in U.S. medical centers in 2012 and 2013. Antimicrob Agents Chemother. 2015;59(6):3656-3659. doi:10.1128/AAC.05024-14.
  31. Farrell DJ, Flamm RK, Sader HS, Jones RN. Antimicrobial activity of ceftolozane-tazobactam tested against Enterobacteriaceae and Pseudomonas aeruginosa with various resistance patterns isolated in U.S. hospitals (2011-2012). Antimicrob Agents Chemother. 2013;57(12):6305-6310. doi:10.1128/AAC.01802-13.
  32. Hackel MA, Tsuji M, Yamano Y, Echols R, Karlowsky JA, Sahm DF. In vitro activity of the siderophore cephalosporin, cefiderocol, against carbapenem-non-susceptible and multidrug-resistant isolates of gram-negative bacilli collected worldwide in 2014-2016. Antimicrob Agents Chemother. November 2017:AAC.01968-17. doi:10.1128/AAC.01968-17.
  33. Lob SH, Hackel MA, Kazmierczak KM, et al. In vitro activity of imipenem-relebactam against gram-negative ESKAPE pathogens isolated by clinical laboratories in the United States in 2015 (Results from the SMART Global Surveillance Program). Antimicrob Agents Chemother. 2017;61(6):e02209-16. doi:10.1128/AAC.02209-16.
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