Despite notable advances in medical care, infections due to Pseudomonas aeruginosa remain problematic and are a major public health concern. This is due, in part, to the fact that P aeruginosa is a very hardy and ubiquitous pathogen. It also has the ability to survive on surfaces including catheters and sinks. Its ubiquity is a testament to the bacterium’s ability to survive in hostile environments and is reflected in the array of infections it causes in humans, particularly in the hospital setting where it is one of the top 3 causes of opportunistic human infections.1
P aeruginosa is intrinsically resistant to many commercially available antibiotics. It also has a remarkable capacity to develop resistance to commonly used antibiotics like carbapenems, aminoglycosides, and fluoroquinolones through several resistance mechanisms that often present simultaneously.2-5 The term “multidrug resistant” (MDR) is often used to characterize the different patterns of multiple drug resistance exhibited by P aeruginosa, which has become a serious clinical concern and a prevalent topic of research.
A number of posters at IDWeek, which took place October 3-7, 2018, in San Francisco, California, presented results that shed new light on the risk factors for and treatment of MDR P aeruginosa. A crucial aspect of MDR P aeruginosa commonly addressed is the use of combination drug treatments. Because multiple mechanisms of resistance may be operating simultaneously, a multipronged approach using drugs that have been judiciously selected with respect to their molecular targets is becoming a more commonplace treatment strategy due to growing efficacy and resistance concerns with the use of single-agent therapy.
Ceftazidime/avibactam was approved within the past 3 years by the US Food and Drug Administration (FDA) for the treatment of infections caused by MDR gram-negative bacteria, including P aeruginosa. In combination with metronidazole, ceftazidime/avibactam is approved to treat complicated intra-abdominal infections; it is also approved for the treatment of complicated urinary tract infections, including acute pyelonephritis, in adult patients. Earlier this year, ceftazidime/avibactam received an FDA indication for hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP).
A poster6 at IDWeek 2018 assessed the use of ceftazidime/avibactam in 168 US hospitals. Its use increased from 5/168 hospitals in 2015 to 92/168 in 2017. Therapy was empiric in 42% and targeted in 62% of the 2128 total encounters. For the latter, ceftazidime/avibactam was the sole antibiotic in 57% of encounters, with combination therapy including aminoglycosides, colistin, or tigecycline for the remaining 43%. The mortality rate was 22% and 25% for monotherapy and combination therapy, respectively.
Another IDWeek 2018 study7 also involved a nationwide analysis but focused on antimicrobial susceptibility patterns from patients with pneumonia. The survey of 70 US medical centers included ceftazidime/avibactam treatment of pneumonia caused by P aeruginosa. Isolates from VABP (n = 183) were comparably susceptible to ceftazidime/avibactam vs ceftolozane/tazobactam (97.8% vs 99.5%). The similarity extended to MDR and extensively drug-resistant (XDR) P aeruginosa.
Ceftolozane/tazobactam is approved by the FDA for the treatment of complicated urinary tract infections and, in combination with metronidazole, for complicated intra-abdominal infections. The combination has also been studied for the treatment of adult patients with either HABP or VABP, and news of ceftolozane/tazobactam meeting its phase 3 primary end point of all-cause mortality and clinical cure rate was recently announced.8
The IDWeek data focused on the real-world value of ceftolozane/tazobactam. One poster9 assessed the performance of ceftolozane/tazobactam in 253 US hospitals nationwide. The majority (78%) of the infections were due to P aeruginosa, and most patients had at least 3 comorbidities. Despite the complex nature of these patients, the outcomes among patients treated with ceftolozane/tazobactam were positive, although the lack of a comparator group limited full interpretation. Future comparator studies are needed to better understand outcomes associated with ceftolozane/tazobactam relative to other commonly used antibiotics in patients with highly antibiotic-resistant gram-negative infections.
Another poster10 described retrospective chart review outcomes of ceftolozane/tazobactam therapy in patients with MDR P aeruginosa bloodstream infections. The primary outcome was 30-day mortality (28% and 43% overall and for patients receiving concomitant therapy, respectively) and in-hospital mortality (24% and 29%, respectively). Mortality was highest (63%) for patients with pneumonia. Secondary outcomes included microbiologic cure assessed as described above (80% and 79%, respectively) and clinical success as described above (76% and 71%, respectively). These and other data presented in the poster support the use of ceftolozane/tazobactam for patients with MDR P aeruginosa bloodstream infections, although the strategy may not be optimal if the bacteremia arises because of pneumonia.
A retrospective, multisite cohort study11 analyzed the treatment of MDR/XDR P aeruginosa infection in 117 patients. At the time the infection developed, 42% of the patients had severe sepsis or septic shock, and 68% were in the intensive care unit. Ceftolozane/tazobactam produced a higher rate of clinical cure (79% vs 62%; P = .046) and a lower incidence of acute kidney injury (7% vs 33%; P < .001) compared with polymyxin/aminoglycoside-based therapy. The real-world findings demonstrate that ceftolozane/tazobactam can improve outcomes in invasive infections due to MDR/XDR P aeruginosa in comparison with polymyxin/aminoglycoside treatment.