New Treatment Options for Multidrug-Resistant Pseudomonas aeruginosaBy: Will Miller, PharmD, MBA; PGY2 Infectious Diseases Pharmacy Resident
Mentor: Tamara Krekel, PharmD, BCPS, BCIDP; Infectious Diseases Clinical Pharmacy Specialist
Program Number: 2021-12-05
Approved Dates: February 1, 2022-August 1, 2022
Approved Contact Hours: One Hour(s) (1) CE(s) per session
Pseudomonas aeruginosa is an aerobic Gram-negative bacillus that is found commonly in the environment and is capable of causing severe infections, particularly in hospitalized patients. As P. aeruginosa thrives in moist environments, it is often associated with pneumonia, catheter-related infections, and surgical site infections. It is capable of extensive colonization and represents a significant challenge in healthcare due to its intrinsic and acquired resistance to many common antibiotics. As a result, the Centers for Disease Control and Prevention (CDC) has described carbapenem-resistant P. aeruginosa as a serious threat, with 32,600 estimated cases and 2,700 estimated deaths in hospitalized patients in 2017.1 Despite not getting the highest level of classification as an urgent threat, the designation as a serious threat indicates that increasing incidence, decreased antimicrobial efficacy, and significant clinical and economic impact are anticipated, thus greater attention and action are needed.
Multidrug-resistant (MDR) P. aeruginosa is defined as nonsusceptibility to at least three classes of antibiotics (penicillins, cephalosporins, fluoroquinolones, aminoglycosides, and carbapenems) to which susceptibility is generally expected.3 However, some MDR P. aeruginosa isolates are resistant to all of these antibiotics (known as difficult-to-treat resistance “DTR” P. aeruginosa). P. aeruginosa can acquire resistance through a combination of mechanisms including AmpC β-lactamases, carbapenemases, porin loss, and efflux pumps.
AmpC β-lactamases are ubiquitously produced by P. aeruginosa and are responsible for the majority of its antibiotic resistance. These β-lactamases do not typically confer resistance to antipseudomonal penicillins, cephalosporins, or carbapenems; this is accomplished with the addition of a carbapenemase, porin loss mutation, and/or efflux pumps.4 Carbapenemases can include Klebsiella pneumoniae carbapenemases (KPCs), metallo-β-lactamases (MBLs: NDM, IMP, VIM), and OXA-48. These confer resistance to all β-lactams but may be overcome with the addition of a β-lactamase inhibitor such as avibactam (exception: MBLs). Porin loss mutations, specifically OprD, confer resistance to carbapenems by preventing them from entering the periplasmic space of P. aeruginosa. As this is largely specific for carbapenems, antipseudomonal cephalosporins may be unaffected by this mutation.5 Perhaps the most unpredictable resistance mechanisms of P. aeruginosa are efflux pumps. There are a variety of efflux pumps that have unique substrates and cause certain antibiotics to be exported from the cell. Through a combination of one or more of these resistance mechanisms, P. aeruginosa can develop resistance to many or all of the traditionally used antibiotics.
New Treatment Options for MDR Pseudomonas aeruginosa
Prior to 2014, the only available treatment options for DTR P. aeruginosa were polymyxin B/colistin and aminoglycoside-based regimens. As these agents have severe toxicities, there was a need for new antibiotics to combat DTR P. aeruginosa that have fewer toxicities. Since 2014, multiple new agents have been developed to meet this need. These include ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam, and cefiderocol. Of note, meropenem/vaborbactam has no added activity against P. aeruginosa as compared to meropenem alone and should not be utilized against isolates that are resistant to meropenem.
Ceftolozane/tazobactam is a combination advanced-generation cephalosporin/β-lactamase inhibitor that is known for its potent activity against P. aeruginosa. Ceftolozane/tazobactam is stable in the presence of most extended-spectrum β-lactamases (ESBLs), AmpC cephalosporinases, OprD porin loss mutations, and efflux pumps. It is currently FDA-approved for complicated intra-abdominal infections (cIAI) in combination with metronidazole, complicated urinary tract infections (cUTI) including pyelonephritis, and hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP).7
Ceftolozane/tazobactam is typically dosed at 1.5 g IV every 8 hours (exception: 3 g IV every 8 hours for treatment of HABP/VABP) and is renally adjusted for patients with CrCl < 50 mL/min.8 Ceftolozane has a half-life of 2-3 hours and is primarily eliminated in the urine as unchanged drug.9 It is generally well-tolerated but may be associated with constipation, headache, and pyrexia.
A retrospective cohort study comparing 200 patients with resistant P. aeruginosa highlighted the potential benefit of ceftolozane/tazobactam over traditional polymyxin or aminoglycoside-based therapy.10 Of the patients included in this analysis, 69% were in the intensive care unit, 63% were mechanically ventilated, and 42% were in severe sepsis or septic shock at enrollment. 65% of patients were treated for HABP/VABP, 14% for cUTI, and 7% of patients for a bloodstream infection. The authors conducted a multivariate logistic regression looking at the impact of ceftolozane/tazobactam on clinical cure (defined as the resolution of the signs and symptoms of infection with the initial study regimen without the need for therapy modification due to clinical failure or toxicity), acute kidney injury (AKI), and in-hospital mortality. They found that ceftolozane/tazobactam was independently associated with clinical cure [adjusted odds ratio (aOR) 2.63; 95% confidence interval (CI) 1.31–5.30] and was protective against AKI (aOR 0.08; 95% CI 0.03–0.22), with no difference in in-hospital mortality. This was associated with a number needed to treat of five for clinical cure with ceftolozane/tazobactam and a number needed to harm of four for AKI with a polymyxin or aminoglycoside-based regimen, indicating substantial benefits of ceftolozane/tazobactam.
Ceftazidime/avibactam is a combination third-generation cephalosporin/β-lactamase inhibitor that is active against many carbapenemases (exception: MBLs) and is not stable to porin loss mutations or efflux pumps. It is currently FDA-approved for cIAI in combination with metronidazole, cUTI including pyelonephritis, and HABP/VABP.11
Ceftazidime/avibactam is typically dosed at 2.5 g IV every 8 hours and is renally adjusted for patients with CrCl < 50 mL/min. It has a half-life of 3-4 hours and is primarily excreted in the urine as unchanged drug. Adverse reactions associated with ceftazidime/avibactam include CNS effects (e.g., seizures, coma, anxiety) and constipation.12
Clinical trial data for ceftazidime/avibactam in the treatment of MDR P. aeruginosa became available in a 2018 pooled data subgroup analysis of the phase III clinical trial data.13 Of the 95 patients that were included, 56 had received ceftazidime/avibactam and 39 had received a carbapenem comparator. The majority of patients were being treated for a cUTI, with fewer patients being treated for HABP/VABP or cIAI. In this analysis, microbiological response was assessed (defined as absence of causative organism or presumed eradication as determined by clinical cure without repeat cultures) and found a 57.1% microbiological response rate with ceftazidime/avibactam and a 53.8% microbiological response rate with carbapenems. Clinical efficacy was assessed as well but was not specifically reported for the cohort of patients with MDR P. aeruginosa infections. Therefore, the authors concluded that ceftazidime/avibactam demonstrated similar clinical and microbiological efficacy to carbapenems against MDR P. aeruginosa.
Imipenem/cilastatin/relebactam is a combination carbapenem/β-lactamase inhibitor that has activity against some carbapenemases (KPCs) and also often retains activity in the presence of efflux pumps. However, it not active against MBLs or in the presence of porin loss mutations. It is currently FDA-approved for cIAI in patients who have limited or no alternative treatment options, cUTI including pyelonephritis in patients who have limited or no treatment options, and HABP/VABP.14
Imipenem/cilastatin/relebactam is typically dosed at 1.25 g IV every 6 hours and is renally adjusted for patients with CrCl < 90 mL/min. It has a half-life of 1 hour and is excreted in the urine as mostly unchanged drug. Adverse reactions associated with imipenem/cilastatin/relebactam include nausea, diarrhea, headache, and CNS reactions including seizures.15
To assess the utility of imipenem/cilastatin/relebactam in treating MDR bacterial infections, investigators conducted the RESTORE-IMI 1 trial, a multicenter, randomized, double-blind trial that compared imipenem/cilastatin/relebactam to colistin plus imipenem in patients with imipenem-nonsusceptible bacterial infections.16 Thirty-one hospitalized patients with HABP/VABP, cIAI, or cUTI were assigned 2:1 to imipenem/cilastatin/relebactam versus colistin plus imipenem. 77% of patients had P. aeruginosa as their qualifying pathogen. The primary endpoint of this study was favorable overall response (HABP/VABP, 28-day all-cause mortality; cIAI, day 28 clinical response; cUTI, composite clinical and microbiologic response at the end-of-therapy visit) and secondary endpoints included clinical response, 28-day all-cause mortality, and treatment-emergent toxicity. For the primary endpoint, 71% of patients who received imipenem/cilastatin/relebactam achieved a favorable overall response, compared to 70% of patients who received a combination of colistin and imipenem (90% CI -27.5%-21.4%), indicating no difference between groups. However, imipenem/cilastatin/relebactam was associated with a significantly higher favorable clinical response [71% v. 40% (90% CI 1.3%-51.5%)], numerically lower 28-day all-cause mortality [10% v. 30% (90% CI -46.4%-6.7%)], and significantly less treatment-emergent nephrotoxicity (10% v. 56%, p=0.002). As a result, the authors concluded that imipenem/cilastatin/relebactam is an efficacious and well-tolerated treatment option for carbapenem-nonsusceptible infections.
Cefiderocol is a novel siderophore cephalosporin with activity against MDR P. aeruginosa, including most isolates with carbapenemases (including KPCs, MBLs, and OXA-48), porin loss mutations, and efflux pumps. Cefiderocol has a unique mechanism in that it binds to free iron and is actively transported into the periplasmic space of Gram-negative bacteria through iron transport channels. Once gaining entry into the cell, it acts like other β-lactams to inhibit bacterial cell wall synthesis.17
Cefiderocol is FDA-approved for the treatment of cUTI, including pyelonephritis, and HABP/VABP. It is typically dosed at 2 g IV every 8 hours and is renally adjusted for patients with CrCl < 60 mL/min. Of note, cefiderocol is also dose-escalated to 2 g IV every 6 hours for patients with CrCl > 120 mL/min. It has a half-life of 2-3 hours and is primarily excreted in the urine as unchanged drug.18 Listed adverse reactions and warnings include neurotoxicity and increased risk of mortality as compared to best available therapy in critically ill patients with carbapenem-resistant Gram-negative bacterial infections.
The CREDIBLE-CR study, a randomized, open-label, phase III study, compared cefiderocol to best available therapy for the treatment of serious carbapenem-resistant Gram-negative infections.19 Of the 118 patients who were included in the analysis, 22 of them had P. aeruginosa as the causative pathogen, 12 of whom were assigned to the cefiderocol arm and 10 of whom were assigned to the best available therapy arm. Best-available therapy was left to the discretion of the provider and most often included combination therapy (71%) and/or colistin-based treatment (66%). Of patients with P. aeruginosa infection, 18% of patients receiving cefiderocol and 18% receiving best-available therapy met the outcome of all-cause mortality at 28 days following the end of therapy.
While the CREDIBLE-CR study included a subgroup of patients with carbapenem-resistant P. aeruginosa infection, the study as a whole included patients with carbapenem-resistant Acinetobacter spp (n=59), Klebsiella pneumoniae (n=43), P. aeruginosa (n=22), Escherichia coli (n=4), or Stenotrophomonas maltophilia (n=3). 59% of patients were treated for nosocomial pneumonia, 31% for bacteremia or sepsis, and 24% for cUTI. The primary endpoint differed by indication (nosocomial pneumonia or bacteremia/sepsis, clinical cure at day 7; cUTI, microbiological eradication at test of cure visit). Overall, 66% of patients receiving cefiderocol achieved clinical cure versus 58% of patients receiving best available therapy. Comparative efficacy was seen within the nosocomial pneumonia population (50% cefiderocol v. 53% best available therapy) and bacteremia/sepsis population (43% in each group), with higher rates of clinical cure with cefiderocol in the cUTI group (53% v. 20%). As such, the study concluded that cefiderocol had similar clinical and microbiological efficacy to best available therapy in infections caused by carbapenem-resistant Gram-negative bacteria.
The CREDIBLE-CR trial also reported other results that may have important clinical implications. First, cefiderocol was associated with substantially higher cure rates as compared to best available therapy in isolates producing MBLs (75% v. 29%), suggesting that cefiderocol may be a good treatment option for organisms known to harbor this resistance mechanism. Second, more patients in the cefiderocol arm died by the end of the study (34% v. 18%), which led to the mortality warning on the package insert of cefiderocol. However, it is important to note that this difference was mostly attributed to patients with Acinetobacter as the causative pathogen (50% v. 18%). With all other included organisms, including P. aeruginosa, there was no difference in mortality.
As part of an effort to identify the place in therapy of each of these new agents and to improve the outcomes of patients with MDR Gram-negative infections, Infectious Diseases Society of America (IDSA) recently published a living guidance document titled ““Infectious Diseases Society of America Guidance on the Treatment of Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa)”, that includes recommendations for treating DTR P. aeruginosa. These recommendations account for the source of infection and assume that in vitro activity of the antibiotics has been demonstrated.3
Treatment of MDR and DTR P. aeruginosa infections should be guided by susceptibility testing and first-line treatment options should be utilized as appropriate. In isolates that are non-susceptible to all first-line treatment options, utilization of ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam, or cefiderocol is appropriate. However, susceptibility of these agents must also be confirmed.
When susceptibility testing indicates the activity of multiple agents against DTR P. aeruginosa, there are several areas to consider when selecting an agent, some of which include antibiotic stewardship, duration of therapy, and presence of a mixed infection. From a stewardship perspective, ceftolozane/tazobactam may be an ideal option as it has increased activity against P. aeruginosa and does not have activity against most other MDR organisms, allowing agents that have this extra activity to be spared for that purpose. Duration of therapy considerations may influence agent selection as it relates to patient tolerability, affordability, and ability to utilize outpatient parenteral antibiotic therapy. Lastly, in patients with mixed infections, agents with broader coverage such as ceftazidime/avibactam, imipenem/cilastatin/relebactam, and cefiderocol may allow the consolidation of therapy and decreased antibiotic use.
The treatment of P. aeruginosa is increasingly difficult due to the emergence of MDR and DTR isolates. However, newly developed agents including ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam, and cefiderocol provide new treatment options that may be more effective and better tolerated than previous agents. Therefore, it is imperative that pharmacists have a solid understanding of these agents in order to employ them in appropriate clinical scenarios.