Review of Ceftazidime-Avibactam for the Treatment of Infections Caused by Pseudomonas aeruginosa

Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen that causes a range of serious infections that are often challenging to treat, as this pathogen can express multiple resistance mechanisms, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) phenotypes. Ceftazidime–avibactam is a combination antimicrobial agent comprising ceftazidime, a third-generation semisynthetic cephalosporin, and avibactam, a novel non-β-lactam β-lactamase inhibitor. This review explores the potential role of ceftazidime–avibactam for the treatment of P. aeruginosa infections. Ceftazidime–avibactam has good in vitro activity against P. aeruginosa relative to comparator β-lactam agents and fluoroquinolones, comparable to amikacin and ceftolozane–tazobactam. In Phase 3 clinical trials, ceftazidime–avibactam has generally demonstrated similar clinical and microbiological outcomes to comparators in patients with complicated intra-abdominal infections, complicated urinary tract infections or hospital-acquired/ventilator-associated pneumonia caused by P. aeruginosa. Although real-world data are limited, favourable outcomes with ceftazidime–avibactam treatment have been reported in some patients with MDR and XDR P. aeruginosa infections. Thus, ceftazidime–avibactam may have a potentially important role in the management of serious and complicated P. aeruginosa infections, including those caused by MDR and XDR strains.


Introduction
Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen responsible for approximately 5-14% of all nosocomial or healthcare-associated infections and 16-40% of cases of ventilator-associated pneumonia (VAP) [1][2][3][4][5]. Patients with predisposing factors, such as severe burn victims, those with reduced immune function and those admitted to the intensive care unit (ICU), are at increased risk of acute P. aeruginosa infections; patients with cystic fibrosis (CF) or bronchiectasis may also develop chronic or recurrent P. aeruginosa infections [5][6][7][8][9]. While the reported extent of co-infection with bacterial pathogens in patients hospitalized with COVID-19 varies, P. aeruginosa is among the most frequently identified species in such patients, with a higher proportion in critically ill ICU patients [10]. Moreover, ventilated patients with COVID-19 may be at higher risk of developing VAP, with P. aeruginosa accounting for a high proportion of cases [11].
For 2019, data from the European Antimicrobial Resistance Surveillance Network showed that 31.8% of >20,000 P. aeruginosa isolates from 30 European countries were resistant to at least one of five antimicrobial groups (piperacillin ± tazobactam, fluoroquinolones, ceftazidime, aminoglycosides and carbapenems). Resistance to two or more antimicrobial groups was found in 17.6% of isolates, and 3.4% were resistant to all five antimicrobial groups [56]. These data showed encouraging population-weighted mean trends of declining overall P. aeruginosa resistance across Europe compared with previous years [56,57]; however, resistance rates vary substantially among countries, with high rates prevalent in eastern and southern countries.
In the US, the antimicrobial susceptibility of 7452 P. aeruginosa isolates collected from 79 medical centres in 2012-2015 was evaluated as part of the International Network for Optimal Resistance Monitoring (INFORM) programme [33]. MDR and XDR P. aeruginosa phenotypes were observed among 15.4% and 9.4% of isolates, respectively [33]. In China, the percentage of P. aeruginosa strains isolated from patients hospitalized in burn wards increased annually from 10.2% in 2007 to 26.2% in 2014, with this species becoming the predominant one among Gram-negative bacteria by 2014 [58]. Over the study period, the proportion of MDR P. aeruginosa increased from 64.0% in 2007 to 89.9% in 2014 [58].

Antibiotics for P. aeruginosa Infections
Antimicrobial agents commonly used for the treatment of P. aeruginosa infections include intravenous (IV) β-lactams (such as anti-pseudomonal cephalosporins, carbapenems and β-lactam/β-lactamase inhibitor combinations), fluoroquinolones and aminoglycosides, as well as polymyxins (colistin) in cases of last resort. Depending on the site and severity of infection, as well as the local resistance epidemiology, treatment guidelines for empiric and definitive antibiotic therapy of suspected or confirmed P. aeruginosa infections recommend various monotherapy or combination regimens using agents from the above classes (Table 1). Surgical source control is also recommended for patients with intra-abdominal infection (IAI). Some of the more recently published guidelines include guidance for use of ceftolozane-tazobactam and/or ceftazidime-avibactam for certain P. aeruginosa infections [59][60][61][62][63]. Include a β-lactam with activity against P. aeruginosa with (a) the highest probability to achieve the optimal value of the adequate pharmacokinetic/pharmacodynamic index, and (b) the lowest risk of selection/amplification of the resistant subpopulation. For empirical treatment, consider combination antibiotics during the first 48-72 h to rapidly decrease the bacterial population, avoid selection of resistance and increase the probability of the strain to be susceptible at least to one of the two antibiotics. For directed treatment schedules, consider combination antibiotics if the infection presents criteria for severe sepsis or septic shock, in central nervous system infections, in endocarditis or neutropenia and when P. aeruginosa is resistant to β-lactams. Whatever antibiotic is chosen, it is essential to optimize the dose and route of administration. Preferred treatment for patients with severe sepsis/septic shock * and/or with risk factors for MDR P. aeruginosa infections.
The World Society for Emergency Surgery guidelines (2017) provide similar recommendations and, also recognize ceftolozane-tazobactam and ceftazidime-avibactam as approved treatments for cIAI caused by P. aeruginosa [64].

Complicated Urinary Tract Infections
The European Association of Urology (EAU) and the Dutch Working Party on Antibiotic Policy recommend antimicrobial treatment options for patients with complicated urinary tract infection (cUTI) that provide coverage against P. aeruginosa and include amoxicillin plus an aminoglycoside, a second-generation cephalosporin plus an aminoglycoside or a third-generation cephalosporin [59,70]. A carbapenem with anti-pseudomonal activity (imipenem/meropenem) was recommended in 2013 for empiric therapy in patients with risk factors for ESBL infections [70]. The most recent EAU guidelines (2018) include recommendations for ceftazidime-avibactam and ceftolozane-tazobactam as empiric treatment options for pyelonephritis (second line) and urosepsis [59].

Hospital-Acquired Pneumonia and Ventilator-Associated Pneumonia
In patients with suspected VAP, the American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) guidelines (2016) recommend coverage for Staphylococcus aureus, P. aeruginosa and other Gram-negative bacilli in all empiric regimens [66]. Combination therapy with two anti-pseudomonal antibiotics from two different classes is recommended in units where >10% of Gram-negative isolates are resistant to an agent being considered for monotherapy, and patients in ICUs where local antimicrobial susceptibility rates are not available. For patients with hospital-acquired pneumonia (HAP) who are being treated empirically, ATS/IDSA guidelines recommend antibiotics with coverage against P. aeruginosa and other Gram-negative bacilli. If a patient has risk factors that increase the likelihood of P. aeruginosa or other Gram-negative infection (e.g., prior antimicrobials within 90 days), or is at high risk of mortality (e.g., need for ventilatory support due to HAP and septic shock), combination therapy with two anti-pseudomonal agents of different classes is recommended [66].
Similarly, international guidelines for management of patients with HAP/VAP (2017) published by the European Respiratory Society, European Society of Clinical Microbiology and Infectious Diseases, European Society of Intensive Care Medicine and Latin American Thoracic Association recommend a risk-stratification based approach, with dual anti-pseudomonal antimicrobial empiric therapy (±coverage for S. aureus) for high-risk patients including those with septic shock and in settings with high MDR pathogen risk [67]. For patients with HAP/VAP and severe signs or symptoms, or those at higher risk of resistance, the UK National Institute for Health and Care Excellence guidelines (2019) do not specify dualantipseudomonal treatment but include broad-spectrum empiric Gram-negative coverage (±coverage for S. aureus) with recommended agents including piperacillin/tazobactam, antipseudomonal cephalosporins, meropenem and ceftazidime-avibactam [62].

Cystic Fibrosis
The impaired mucociliary clearance in patients with CF provides a microenvironment in which pathogenic bacteria, including P. aeruginosa, can become the source of chronic pulmonary infections. The incidence of chronic P. aeruginosa infection in people with CF patients increases with age, and such individuals have worse health status and experience more rapid disease progression than age-matched controls [71]. The European Cystic Fibrosis Society recommendations for the management of new and chronic P. aeruginosa infections in patients with CF (2018) include tobramycin solution or dry powder for inhalation, aztreonam inhalation solution or a combination of nebulized colistimethate and oral ciprofloxacin; the aim of treatment should be eradication (documented by follow-up cultures) [68]. Acute exacerbations of pulmonary infections in patients with CF can result in hospitalization and require IV antibiotic treatment [68].

Approved Indications
In Europe and the US, ceftazidime-avibactam is approved for the treatment of adults cUTI (including pyelonephritis), cIAI (in combination with metronidazole) and HAP (including VAP), including bacteraemia associated with these infections caused by susceptible P. aeruginosa and Enterobacterales. In Europe, it is also approved for infections caused by aerobic Gram-negative organisms in adult patients with limited treatment options. European and US approvals were recently extended to include paediatric patients ≥3 months old (cUTI and cIAI indications only in the US) [72,73].

Mechanism of Action
β-lactams, including ceftazidime, exert antimicrobial effects through binding to penicillin binding proteins in bacterial cell walls, thereby disrupting cell wall synthesis and bacterial growth. As noted above, numerous antimicrobial resistance mechanisms can be expressed by MDR P. aeruginosa. Anti-pseudomonal cephalosporins such as ceftazidime, cefepime and ceftolozane have lower affinity for AmpC cephalosporinases (commonly expressed by P. aeruginosa) and additional stability against enzymatic hydrolysis than other cephalosporins [74,75]. However, susceptibility to these agents can be reduced by hyperexpression of AmpC. The addition of avibactam to ceftazidime overcomes AmpC cephalosporinase-mediated ceftazidime resistance among P. aeruginosa isolates in vitro (including those co-expressing EBSLs), but the combination is unable to overcome resistance mediated by porin mutations, efflux pumps or MBLs [76][77][78][79]. Moreover, alterations in AmpC-encoding and control genes conferring reduced susceptibility to ceftazidimeavibactam, ceftolozane/tazobactam and carbapenems have been reported in laboratory studies and/or identified in P. aeruginosa clinical isolates from patients undergoing antimicrobial therapy [50,[80][81][82][83]. These findings are a salient reminder of the propensity of P. aeruginosa to undergo rapid evolution to develop novel resistance phenotypes and highlight the vital importance of microbiological cultures, susceptibility testing (as well as local and regional susceptibility patterns) and use of molecular diagnostics wherever possible to guide treatment of P. aeruginosa infections. In vitro data suggest that combining ceftazidime-avibactam with other antibiotics such as aminoglycosides or colistin may be synergistic against MDR P. aeruginosa [84][85][86].

In Vitro Activity
Numerous international and regional antimicrobial surveillance studies have reported on the in vitro activity of ceftazidime-avibactam using Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EU-CAST) interpretative criteria (also referred to as minimum inhibitory concentration (MIC) breakpoints), which define isolates of P. aeruginosa and Enterobacterales with ceftazidimeavibactam MICs ≤8 mg/L as susceptible [87,88]. Key susceptibility data for P. aeruginosa are summarized in Table 2.

Pharmacokinetics and Pharmacodynamics
Population pharmacokinetic (PK) and pharmacodynamic (PD) analyses and probability of target attainment (PTA) simulations using an iterative modelling approach encompassing additional data at various points during clinical development supported the selection of doses for Phase 2 and 3 evaluation (including adjustments for renal impairment) and the determination of MIC susceptibility breakpoints for target pathogens, including P. aeruginosa [101][102][103][104].
For β-lactam antibiotics, the primary driver of PD is the amount of time free drug concentrations are maintained above the MIC of the target pathogen (%f T > MIC). For ceftazidime, the β-lactam component of ceftazidime-avibactam, 50% f T > MIC is the established PK/PD target based on neutropenic mouse infection models and is associated with microbiological eradication in patients with Gram-negative infections [101]. In global surveillance studies, ceftazidime-avibactam MIC 90 values of ≤8 mg/L were reported for phenotypically and genotypically unselected clinical isolates of P. aeruginosa [101]. Therefore, a target plasma concentration of 8 mg/L (i.e., matching the upper MIC 90 value for target pathogens from contemporary surveillance studies) was selected for the ceftazidime component of the joint PK/PD target [101].
Based on in vitro hollow fibre and in vivo data, a PK/PD index for avibactam in combination with ceftazidime defined as percentage of time that free drug concentrations exceed a threshold concentration (C T ) of 1 mg/L over a dose interval (%f T > CT) (in combination with ceftazidime) was associated with bacteriostasis in a P. aeruginosa neutropenic mouse thigh infection model and 2-log 10 killing in a P. aeruginosa neutropenic mouse lung infection model [101,105,106]. Accordingly, joint attainment of 50% f T > 8 mg/L for ceftazidime and 50% f T > 1 mg/L for avibactam, to be achieved simultaneously, was considered as the main PK/PD target for the PTA analyses.
The final population PK models, which included ceftazidime and avibactam PK data from eighteen Phase 1-3 clinical trials, were used to predict steady-state exposures and joint target attainment in the Phase 3 patient population and to conduct PTA analyses in simulated patients with cIAI, cUTI, nosocomial pneumonia and VAP, using the joint PK/PD target described above [102]. Ceftazidime and avibactam steady-state PK exposure parameters and joint target attainment rates were compared across a range of clinical scenarios, including the presence/absence of systemic inflammatory response syndrome, bacteraemia or fever, white blood cell count (≤12,000/mm 3 or >12,000/mm 3 ) and various patient subgroups such as obesity, age, Acute Physiology and Chronic Health Evaluation II score and renal function categories (based on estimated creatinine clearance). With the exception of the 8-15 mL/min renal function group (which was limited by a small sample size of four patients), high joint target attainment rates (>93%) were attained for each indication in different clinical scenarios across patient subgroups [102].
PTA simulations using the final ceftazidime and avibactam population PK models were used to validate the approved ceftazidime-avibactam dosage regimen (2000 mg ceftazidime plus 500 mg avibactam 2-h IV infusions every 8 h), including adjustments for renal impairment. In these analyses, PTA values for target pathogens, including P. aeruginosa at MICs ≤8 mg/L, were 95-100% across indications and renal function groups; lower PTA values were associated with MICs of 16 and ≥32 mg/L [102]. These analyses also supported the current EUCAST and CLSI susceptible MIC breakpoints of ≤8 mg/L for ceftazidime-avibactam against P. aeruginosa [87,88,104]. Separate analyses evaluating the lung penetration of ceftazidime-avibactam have demonstrated linear PK in epithelial lining fluid in mice and humans, with approved doses achieving clinically-relevant exposures against diverse P. aeruginosa isolates in an infection murine model [107][108][109].

Ceftazidime-Avibactam in Clinical Trials
Two Phase 2 and five Phase 3, randomized, multicentre active-comparator trials have evaluated the efficacy and safety of ceftazidime-avibactam against carbapenems/best available therapy in adults hospitalized with serious Gram-negative infections (Table 3). Each trial, which enrolled patients with cIAI, cUTI or HAP including VAP, included a treatment period (5-21 days) and primary efficacy evaluations at a protocol-defined test-of-cure (TOC) visit [110][111][112][113][114][115][116]. Apart from REPRISE, which did not use formal statistical comparisons, noninferiority of ceftazidime-avibactam versus the comparator treatment was demonstrated in the other four Phase III trials for their respective primary efficacy endpoints [112][113][114][115][116]. Clinical and microbiological efficacy outcomes at TOC for the cohorts of patients with P. aeruginosa isolated at baseline in the Phase 2 and 3 adult trials are summarized in Table 3. Across the trials, ceftazidime-avibactam was generally effective in treating hospitalized adults with cUTI, cIAI and HAP/VAP caused by P. aeruginosa, as assessed by clinical cure and favourable microbiological response rates at the TOC visit [112][113][114][115][116]. In a pooled analysis of outcomes for patients with MDR Gram-negative isolates from the adult Phase 3 clinical trials, ceftazidime-avibactam demonstrated similar efficacy to comparators against MDR P. aeruginosa [117]. In the pooled microbiologically modified intention-to-treat (mMITT) population, a total of 56 patients in the ceftazidime-avibactam arm had MDR P. aeruginosa isolated at baseline. The ceftazidime-avibactam MIC range, MIC 50 and MIC 90 were 1 to >256, 8 and 64 mg/L, respectively, with 66.1% of isolates susceptible (MIC ≤ 8 mg/L). Favourable microbiological responses at TOC (pooled mMITT population) were observed in 32 of 56 (57.1%) patients in the ceftazidime-avibactam group and 21 of 39 patients (53.8%) in the comparator group [117]. For patients with bacteraemia due to P. aeruginosa, a pooled analysis of the five Phase 3 trials found that clinical and microbiological responses were similar to those in the overall set; among bacteraemic patients with P. aeruginosa, the response rates were somewhat lower, but similar between treatment groups [118]. Across the Phase 3 trials, 28-day mortality rates were between 0% and 9.6% (per-pathogen mortality rates have not been reported). Decreased susceptibility of some microbiological isolates to study treatments was reported in the REPROVE trial; however, for P. aeruginosa, 10 patients in the meropenem group and none in the ceftazidimeavibactam group had isolates with decreased susceptibility [116].

Real-World Experience
A growing body of literature reporting on real-world use of ceftazidime-avibactam infections is available and has recently been reviewed [119]; available publications (as of August 2021) reporting outcomes of P. aeruginosa infections treated with ceftazidimeavibactam are summarized in Table 4 [120][121][122][123][124][125][126][127][128][129][130][131]. Several other publications report aggregated outcomes for cohorts of patients with infections caused by other pathogens as well as P. aeruginosa or Pseudomonas species [132][133][134]. Most of these studies are limited by generally small samples and retrospective, non-comparative, observational designs. However, these data provide important insights into the real-world therapeutic effectiveness of ceftazidime-avibactam in the treatment of often severely ill patients with complicated and difficult-to-treat infections.
In another example of the efficacy of ceftazidime-avibactam in polymicrobial P. aeruginosa and Enterobacterales infections, Gofman et al. (2018) reported on a patient with polymicrobial ventriculitis caused by P. aeruginosa and carbapenem-resistant K. pneumoniae, who was successfully treated with ceftazidime-avibactam and intrathecal amikacin [121].
Rodriguez-Nunez et al. (2018) evaluated outcomes for eight patients with infections caused by MDR or XDR P. aeruginosa admitted to a teaching hospital in Spain (2016-2017) treated with ceftazidime-avibactam for ≥72 h [127]. Infection sources were HAP in four patients (50.0%) and tracheobronchitis, osteomyelitis, meningitis and catheterrelated bacteraemia in one patient each. The clinical cure rate was 50%; 30-day and 90-day mortality rates were 13% and 38%, respectively; no cases of ceftazidime-avibactam resistance emergence were reported. Metafuni et al. (2019) and Xipell et al. (2017) have reported positive outcomes in individual patients with severe drug-resistant P. aeruginosa infections treated with ceftazidimeavibactam without documented emergence of resistance [126,131]. Spoletini et al. (2019) reported on eight adults with CF who received a total of 15 courses of ceftazidime-avibactam for pulmonary exacerbations not responding to conventional antibiotic treatment [129]. Four patients were colonized with P. aeruginosa, two with Burkholderia cepacia complex and two with both pathogens; and five were on the active waiting list for lung transplantation. Treatment with ceftazidime-avibactam was associated with an effective clinical response in 13 of 15 (86.7%) treatment courses. Four of six patients with P. aeruginosa infections who had been suspended from the active transplant list were reactivated following clinical stabilization; one patient received a successful transplant while on treatment, and one who was on the transplant list died whilst on ceftazidime-avibactam due to respiratory failure. No cases of ceftazidime-avibactam resistance emergence were reported.

Conclusions
P. aeruginosa infections can be challenging to treat, as the species has limited intrinsic susceptibility to many antibiotics as well as great propensity to express further multiple resistance mechanisms through mutation and horizonal gene acquisition [41,42]. P. aeruginosa is relatively common in infections in healthcare settings, causing around 10-20% of skin, lower respiratory and urinary tract infections in hospitalized patients, and is particularly associated with severe and critical illness, such as in ICU and haematological patients. Patients with acute P. aeruginosa infections are at significantly greater risk of 30-day mortality when receiving inappropriate initial antimicrobial therapy (IAT) vs. those receiving appropriate IAT; however, selection of appropriate IAT in some settings and regions is challenged by increasing antimicrobial resistance, including MDR and DTR P. aeruginosa [135,136].
Ceftazidime-avibactam demonstrates good in vitro activity against P. aeruginosa relative to comparator β-lactam agents, aminoglycosides and fluoroquinolones [79,[89][90][91][92]97], with susceptibility rates comparable to amikacin and ceftolozane-tazobactam [79,90,91,94,97]. Ceftazidime-avibactam is not active against MBL-producing pathogens, and P. aeruginosa is capable of expressing multiple resistance mechanisms (including MBLs) that render some isolates, particularly MDR strains, non-susceptible to ceftazidime-avibactam. Accordingly, as with all antimicrobials, ceftazidime-avibactam usage should be guided by local susceptibility patterns and microbiological/antibiogram data whenever possible.   In Phase 3 clinical trials, ceftazidime-avibactam was associated with generally similar clinical and microbiological outcomes to comparators (carbapenems/best available therapy) in adult patients with cIAI, cUTI or HAP/VAP caused by P. aeruginosa, including ceftazidime non-susceptible and MDR strains [112][113][114][115][116][117]. In population PK modelling and exposure simulations of patients with cIAI, cUTI or HAP/VAP, >95% PTA was predicted for approved ceftazidime-avibactam dosage regimens (2000 mg ceftazidime plus 500 mg avibactam 2-h IV infusions every 8 h, adjusted for renal function) against P. aeruginosa with MICs ≤ 8 mg/L [104]. While there are relatively few published real-world data for ceftazidime-avibactam treatment of serious P. aeruginosa infections, favourable outcomes with ceftazidime-avibactam treatment have been reported in some patients with infections caused by MDR and XDR P. aeruginosa, without documented resistance emergence (albeit from a small sample of anecdotal reports) [121,122,[126][127][128][129][130][131]. The efficacy and safety of ceftazidime-avibactam in patients with CF have not been evaluated in randomized controlled trials; however, available in vitro and real-world data suggest a potential role for this agent in managing acute P. aeruginosa infections in cases where other antibiotics have failed [92,129], subject to local/institutional formularies and national product labelling.
As the risk factors for infections with different MDR bacteria, including P. aeruginosa and Enterobacterales, are often the same, ceftazidime-avibactam offers a good empiric treatment option for patients considered at risk of MDR Gram-negative infections, including those caused by non MBL-producing MDR and DTR P. aeruginosa, and its potential role in such settings is recognized in various national and international treatment guidelines [59,[62][63][64]. Appropriate use of all antibiotics, including ceftazidime-avibactam, guided by diagnostic susceptibility data (where available) and knowledge of local resistance patterns, are vital to support antimicrobial stewardship and limit the emergence and spread of resistance. Funding: Medical writing support was funded by Pfizer.

Institutional Review Board Statement:
Ethical approval is not applicable to this review article.

Informed Consent Statement:
Informed consent is not applicable to this review article.

Data Availability Statement:
No new data were created or analysed in this review article. Data sharing is not applicable to this article. Acknowledgments: Medical writing support was provided by Atif Riaz and Mark Waterlow of Prime Medica Ltd., Knutsford, Cheshire, UK, and was funded by Pfizer.