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

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 infections^18,19, skin and soft tissue infections^20,21, 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.

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