A Review of Real-World Use of Ceftazidime-avibactam for Multidrug-Resistant Gram-Negative Bacterial Infections

Ana C. Gales; Luis Fernando Aranha Carmargo; Gabriel Trova Cuba; Gabriel Trova Cuba; Felipe Francisco Tuon; Hui Hwa Choo; Maria Lavinea Novis de Figueiredo; Alvaro Quintana; Paurus Mehelli Irani

doi:10.4172/2332-0877.1000483

A Review of Real-World Use of Ceftazidime-avibactam for Multidrug-Resistant Gram-Negative Bacterial Infections

Ana C. Gales¹^*, Luis Fernando Aranha Carmargo¹, Gabriel Trova Cuba¹, Felipe Francisco Tuon², Hui Hwa Choo³, Maria Lavinea Novis De Figueiredo⁴, Alvaro Quintana⁵ and Paurus Mehelli Irani⁶: ¹Division of Infectious Diseases, Universidade Federal de São Paulo, São Paulo, Brazil; ²Laboratory of Emerging Infectious Diseases, Pontifícia Universidade Católica do Paraná, Curitiba, Brazil; ³Tech Observer Asia Pacific Pte Ltd., Toa Payoh, Singapore; ⁴Pfizer Brazil, São Paulo, Brazil; ⁵Pfizer Inc., New York, United States; ⁶Pfizer Ltd., Hertfordshire, United Kingdom

^*Corresponding Author: Ana C. Gales, Division of Infectious Diseases, Universidade Federal de São Paulo, São Paulo, Brazil, Email: ana.gales@unifesp.br

Received: 17-Dec-2021 / Manuscript No. JIDT-21-50027 / Editor assigned: 20-Dec-2021 / PreQC No. JIDT-21-50027 (PQ) / Reviewed: 31-Dec-2021 / QC No. JIDT-21-50027 / Revised: 31-Dec-2021 / Manuscript No. JIDT-21-50027 (R) / Accepted Date: 02-Jan-2022 / Published Date: 09-Jan-2022 DOI: 10.4172/2332-0877.1000483

Abstract

The incidence of multidrug-resistant-Gram negative bacilli (MDR-GNB) infections is increasing. Ceftazidime-avibactam (CAZ-AVI) is recommended as one of the preferred agents for the treatment of infections caused by carbapenem-resistant Enterobacterales (CRE) or Pseudomonas aeruginosa with Difficult-To-Treat Resistance (DTR-PA). Given the rising threat of infections caused by MDR-GNB, in particular Carbapenem-Resistant (CR) pathogens, it is important to understand the use of CAZ-AVI for the treatment of GNB infections with limited treatment options. Evidence from 28 real-world studies suggest that CAZ-AVI is an effective and well-tolerated alternative to standard of care antibiotics for treating different types of infection caused by MDR-GNB, including CRE and MDR-Pseudomonas spp. Notably, CAZ-AVI is well tolerated even in severely or critically ill patients, patients with multiple comorbidities, or those with bacteremia. These real-life experiences provide valuable insights into the use of CAZ-AVI across diverse types of GNB infections for which limited treatment options exist.

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Keywords: Ceftazidime-avibactam ; Multidrug-resistant gramnegative bacilli infections; Carbapenem-resistant Enterobacterales;Pseudomonas aeruginosa; Real-world

Introduction

The incidence of antimicrobial resistance is increasing and continues to be a worldwide threat [1-3]. Antimicrobial resistant pathogens accounted for close to three million infections and caused over 35,000 people to die yearly in the United States (US) between 2012 and 2017 [2]. The selection of an effective antimicrobial treatment for patients infected by resistant pathogens is challenging. The Centers for Disease Control and Prevention (CDC) have identified three groups of antimicrobial resistant Gram-negative pathogens as urgent or serious antibiotic resistance threats that pose particular therapeutic challenges: carbapenem-resistant Enterobacterales (CRE), Pseudomonas aeruginosa with difficult-to-treat resistance [2] (DTR-PA; defined by the Infectious Diseases Society of America [IDSA] as “P. aeruginosa exhibiting non-susceptibility to all of the following: piperacillin-tazobactam, ceftazidime, cefepime, aztreonam, meropenem, imipenem-cilastatin, ciprofloxacin, and levofloxacin”) [4], and extended-spectrum β-lactamase (ESBL)-producing Enterobacterales. These pathogens caused a wide variety of serious infections that are associated with significant morbidity and mortality [2]. In the US, infections due to ESBL-producing Enterobacterales have increased by around 1.5 times in the US between 2012 and 2017 [5]. CRE has been reported to be associated with over 13,000 nosocomial infections and more than 1,000 deaths per year, with Klebsiella pneumoniae carbapenemases (KPCs) being the most common carbapenemases [2]. Multidrug-Resistant Pseudomonas aeruginosa (MDR-PA) accounted for 32, 600 infections in patients hospitalized in the US and caused 2,700 deaths in 2017 [2]. Appropriate treatment against these pathogens is a healthcare priority.

Limited treatment options are available for infections caused by multidrug-resistant gram-negative bacilli (MDR-GNB). Colistin (polymyxin), aminoglycosides, tigecycline, and carbapenems have been widely used to treat such infections [6,7]. However, uses of these agents have important drawbacks. Treatment with colistin or aminoglycosides is associated with toxicity issues; use of these agents was linked to reports of significant nephrotoxicity [8-10]. In addition, treatment with many of these agents are hampered by suboptimal pharmacokinetic/ pharmacodynamic of the drug, resulting in inadequate concentrations in tissues or blood [9-13]. Recent data on polymyxin (including colistin and polymyxin B) suggest that these agents have important limitations [10]. Existing evidence shows that less than half of patients with normal renal function achieve the target colistin steady state concentration and this level of exposure is not adequate to achieve bacterial stasis in pneumonia models [10,14]. Furthermore, studies demonstrate increased mortality for polymyxin compared with other agents [15,16]. Besides these challenges, the rising trends of MDR-GNB, in particular carbapenem-resistant (CR) pathogens further complicate the management of these infections and highlight the need for new antimicrobial agents [17,18].

Recent published IDSA guidelines propose recommendations on the management of MDR-GNB infections, and Include Ceftazidime- Avibactam (CAZ-AVI) as one of the preferred agents for the treatment of infections caused by CRE or DTR-PA [4]. CAZ-AVI, a β-lactam/β-lactamase inhibitor combination, is one of the recently launched antimicrobial agents developed in response to the need for novel agents to tackle the rising incidence of MDR-GNB infections [4,8,19]. CAZ-AVI is approved in the US and Europe for the treatment of complicated Urinary Tract Infections (cUTIs), complicated intra- abdominal infections (cIAIs), hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP) [20,21] in adult patients. It is also approved in the US for treating cUTIs and cIAIs in pediatric patients aged three months and above [20]. In Europe, it is additionally approved for the treatment of aerobic GNB infections with limited treatment options and its use is expanded to include pediatric patients aged three months and above [21]. CAZ-AVI represents a valuable new treatment option with the potential to treat infections caused by some of the most problematic MDR-GNB pathogens [22-24]. CAZ-AVI exhibits in vitro activity against isolates of Enterobacterales and Pseudomonas aeruginosa that harbor class A, C, and some D β-lactamases, including ESBLs, ampicillin C (AmpC) β-lactamases, KPCs, and oxacillinases (OXA)-48, but not those harboring class B metallo-β-lactamases [22- 24]. CAZ-AVI has limited activity against Acinetobacter spp. [22,25].

Data on the efficacy of CAZ-AVI against CR pathogens in clinical trials are limited. In phase III randomized control trials (RCTs) comparing CAZ-AVI with carbapenem. CAZ-AVI was non-inferior to carbapenem comparators for the treatment of cUTI, cIAI, and HAP/ VAP [26-29]. CAZ-AVI treatment was associated with high response rates at the test-of-cure (TOC) visit in patients with infections caused by ceftazidime-susceptible and resistant Gram-negative pathogens. CAZ- AVI was generally safe and well tolerated, with a profile consistent with that of ceftazidime alone. However, few CR pathogens were included in these trials [26-29]. In an open-label phase III trial (the REPRISE trial) of patients with cUTI and cIAI due to ceftazidime-resistant Gram-negative organisms, a similar proportion of patients in the CAZ- AVI group and best available therapy (mostly carbapenem-containing regimens) group achieved clinical cure at the TOC visit [30]. No new safety concerns were identified for CAZ-AVI. Among the 292 isolates of Enterobacterales recovered from the REPRISE trial, only nine isolates were CRE (six were KPC producers and three were OXA-48 producers) [31]. Real-world experience with CAZ-AVI in treating a variety of infections caused by a number of important MDR-GNB including CR pathogens has accumulated in recent years. Given the rising threat of infections caused by MDR-GNB, in particular CR pathogens, it is important to understand the use of CAZ-AVI for the treatment of GNB infections with limited treatment options.

Literature Review

This article reviews the real-world evidence on the therapeutic effectiveness and safety of CAZ-AVI in adult patients with infections due to aerobic Gram-negative pathogens with limited treatment options, including CRE and MDR Pseudomonas spp. A structured literature search of PubMed and EMBASE databases was conducted for studies published from 2005 through Nov 2020 that evaluated clinical experience of CAZ-AVI in treating adult patients with infections caused by aerobic Gram-negative pathogens with limited alternatives available, including CRE and MDR-Pseudomonasspp. Records were restricted to those in English language. Preclinical studies, clinical trials, reviews, case reports, studies with no relevant results, or studies in pediatric patients were excluded.

Characteristics of included real-world studies on CAZ-AVI

Twenty-eight real-world studies met the selection criteria and were included. These studies described clinical experience of using CAZ-AVI in adult patients for treating infections caused by aerobic GNB with limited treatment options, including CRE and MDR-Pseudomonas spp. Collectively, these studies provided data on the use of CAZ-AVI across diverse types of infection, such as bacteremia, pneumonia, IAI, Skin- Soft Tissue Infection (SSTI), bone and joint infection, Central Nervous System Infection (CNSI), UTI, etc., with limited alternatives available. The characteristics of these studies are presented in Table 1 [32-59].

Reference (Year)	Study design	Study population/ types of infection	Target pathogens	Treatment(s)		Key effectiveness outcomes	Safety outcomes	Other relevant outcomes
Ackley (2020) [32]	Multicenter, retrospective	Patients with infections caused by KPC-producing Enterobacterales (excluded those with localized urinary tract infection and repeat study drug exposures after the first episode) [Mixed infection types]	KPC-producing CRE	CAZ-AVI (n=105) Monotherapy: 39% Types of infection: Bacteremia (42%), respiratory (29%), soft tissue (17%), IAI (11%), and others (1%)	Meropenem- Vaborbactam (n=26) Monotherapy: 85% Types of infection: Bacteremia (35%), respiratory (38%), Soft tissue (8%), IAI (19%), and others (0%)	Clinical success, 30-day mortality, 90-day mortality, 90-day infection recurrence	Treatment-related AEs	Development of resistance in patients with recurrent infection
Aitken (2016) [33]	Single center, retrospective	Cancer patients with CRE bloodstream infection Bacteremia	CRE	CAZ-AVI (n=5) Monotherapy: 0%	-	Microbiologic success, clearance of infection, 30-day mortality	-	-
^†Algwizani (2018) [34]	Single center, retrospective, case series	Patients with infections caused by CR-organisms Types of infection: VAP (2 pts), bacteremia (2 pts), and CNSI (1 pt)	CR-organisms including OXA- 48-producing Kp and CR-PA	CAZ-AVI (n=5) Monotherapy: 60%	-	Microbiological cure, clinical cure	-	-
Alraddadi (2019) [35]	Single center, retrospective	Patients with established CRE infections [Mixed infection types]	74% OXA-48- producing CRE	CAZ-AVI (n=10) Types of infection: Bacteremia (70%), HAP (50%), cUTI (30%), cIAI (30%), and SSTI (20%)	Other agents (n=28) (mostly included colistin and/or carbapenem among others) Monotherapy: 11% Types of infection: Bacteremia (54%), HAP (50%), cUTI (29%), cIAI (18%), and SSTI (11%)	Clinical remission, all- cause mortality	-	-
Bassetti (2019) [36]	Multicenter, retrospective	Patients with KPC- Kp gut colonization	KPC-Kp	CAZ-AVI (n=12) Monotherapy: 8% Types of infection: cIAI (42%), HAP (17%), sepsis (17%), surgical wound infection (8%), and others (25%)	Other regimens (n=24) (included 83% tigecycline, 46% colistin, and/or 54% carbapenem among others) Monotherapy: 0% Types of infection: cIAI (17%), HAP (21%), sepsis (42%), surgical wound infection (17%), and others (4%)	Decolonization rate	-	-
Caston (2017) [37]	Multicenter, retrospective	Patients with hematologic malignancies who had CPE bacteremia Bacteremia	CPE <61% OXA; 39% KPC>	CAZ-AVI (n=8) Monotherapy: 0%	Other agents (n=23) Monotherapy: 6%	14-day clinical cure, 30-day crude mortality	-	-
Chen (2020) [38]	Single center, retrospective	Lung transplant patients with XDR- GNB infections Types of infection: Pneumonia and/or tracheobronchitis (90%) and cholecystitis and bacteremia (10%)	XDR GNB (90% KPC-Kp)	CAZ-AVI (n=10) Monotherapy: 20%	-	Microbiological cure, 30-day and 90-day survival, infection relapse, time to microbiological cure	Treatment-related AEs	-
De la Calle (2019) [39]	Single center, retrospective	Patients with infections caused by CRE Types of infection: Bacteremia (33%), IAI (29%), UTI (25%), pneumonia (21%); osteoarticular/SSTI (17%), device- related meningitis (4%), and catheter- related bacteremia (4%)	OXA-48- producing Enterobacterales	CAZ-AVI (n=23) Monotherapy: 58%	-	30-day clinical cure, 30-day and 90- day mortality, mortality, 90- day infection recurrence	Treatment-related AEs	-
Falcone (2020) [40]	Multicenter, retrospective	Patients with BSI due to KPC-Kp hospitalized in ICU (excluded those with polymicrobial BSIs) Bacteremia	KPC-Kp	CAZ-AVI- containing regimens (n=13)	Colistin-containing regimen (n=61); other regimens (n=17)	Composite endpoint (30- day mortality or nephrotoxicity), 30-day mortality	-	-
Guimarães (2019) [41]	Multicenter, prospective, case series	Patients with severe infections caused by KPC-producing Enterobacterales coresistant to carbapenems and polymyxins Types of infection: Bacteremia (41%), UTI (28%), IAI (14%), nosocomial pneumonia (10%), and complicated SSTI (7%)	KPC-producing Enterobacterales	CAZ-AVI (n=29) Monotherapy: 52%	-	Clinical success, 14 and 30- day all-cause mortality	Treatment-related AEs	-
Iannaccone (2020) [42]	Single center, retrospective	Patients with BSI caused by KPC-Kp Bacteremia	KPC-Kp	CAZ-AVI (n=23) Monotherapy: 13%	-	Recovered from infection, in- hospital mortality, recurrent infection	-	Development of CAZ-AVI resistance in CAZ- AVI-treated patients
^†Jorgensen (2019) [43]	Multicenter, retrospective	Patients with MDR- GN infections Types of infection: Respiratory tract (37%), UTI (20%), IAI (19.7%), bacteremia (11%), SSTI (9%), and osteoarticular (7%)	MDR-GN organisms (58% CRE and 31% Pseudomonas spp.)	CAZ-AVI (n=203) Monotherapy: 67%	-	Composite clinical failure, 30-day mortality, 30-day recurrence	Treatment-related AEs	Development of CAZ-AVI resistance during treatment in patients with repeat susceptibility testing (n=61)
Jorgensen (2020) [44]	Multicenter, retrospective	Patients with CRE infections Types of infection: Respiratory tract (35%), IAI (21%), UTI (20%), SSTI (6%), osteoarticular 7 (6%), bacteremia (6%), and others (5%)	CRE	CAZ-AVI (n=109) Monotherapy: 60%	-	30-day all-cause mortality	-	-
Katchanov (2018) [45]	Single center, retrospective	Critically ill patients with severe infections due to CRE Types of infection: HAP (4 pts), bacteremia (1 pt), and cIAI (1 pt)	OXA-48 producing Kp	CAZ-AVI (n=5) Monotherapy: 0%	-	In-hospital mortality	-	-
King (2017) [46]	Multicenter, retrospective	Severely ill patients with CRE infection Types of infection: Bacteremia (38%), UTI (28%), pneumonia (27%), wound (13%), IAI (7%), and bone/joint (3%)	CRE	CAZ-AVI (n=60) Monotherapy: 55%	-	Microbiological cure, clinical success, in- hospital mortality	Treatment-related AEs	-
Krapp (2017) [47]	Single center, retrospective	Patients with infections caused by KPC-Kp. Types of infection: Pneumonia (2 pts), IAI (1 pt), peritonitis (1 pt), perinephric abscess (1 pt), and wound (1pt)	KPC-Kp	CAZ-AVI (n=6) Monotherapy: 33%	-	Clinical cure, infection relapse	-	-
Rodríguez- Núñez (2018) [48]	Single center, retrospective	Patients with infections due to MDR-or XDR-PA Types of infection: Hospital-acquired lower respiratory tract infection (5 pts), osteomyelitis (1 pt), meningitis (1 pt) and catheter-related bacteremia (1 pt).	MDR or XDR-PA (including 2 pt with CR MDR PA)	CAZ-AVI (n=8) Monotherapy: 25%	-	Clinical cure, 30- day and 90-day mortality	-	-
Santevecchi (2018) [49]	Single center, retrospective, case series	Patients with infections due to MDR-organisms other than Kp Types of infection: Pneumonia (46%), skin and soft tissue (23%), bacteremia (15%), and intra– abdominal (15%)	MDR-organisms other than Kp (most common: MDR-PA)	CAZ-AVI (n=10) Monotherapy: 50%	-	Microbiological cure, clinical success, 30- day in-hospital mortality	Treatment-related AEs	Development of CAZ-AVI resistance in CAZ- AVI-treated patients
Shield (2016) [50]	Single center, retrospective	Patients with CRE Types of infection: Pneumonia (32%), bacteremia (27%), IAI (11%), SSTI (11%), pyelonephritis (11%), mediastinitis (3%), subdural empyema/ Ventriculitis (3%), and purulent tracheobronchitis (3%)	CRE (78% KPC- producing Enterobacterales)	CAZ-AVI (n=37) Monotherapy: 70%	-	Microbiologic failure, 30-day clinical success, 30-day survival, 90-day infection recurrence	AKI, treatment discontinuation	Development of CAZ-AVI resistance in CAZ- AVI-treated patients
Shields (2017) [51]	Single center, retrospective	Patients with CR-Kp bacteremia [Bacteremia]	CR-Kp (97% KPC-Kp)	CAZ-AVI (n=13) Monotherapy: 62%	Carbapenem + colistin (n=30); carbapenem + aminoglycoside(n=25); Others (n=41)	clinical success, 90-day survival	AKI	-
Shields (2018) [52]	Single center, retrospective	Patients with CRE infections Types of infection: Pneumonia (43%), bacteremia (26%), urinary tract infection (10%), intra- abdominal (9%), skin/soft tissue (8%), and mediastinitis, subdural empyema/ ventriculitis and purulent tracheobronchitis (1% each)	75% KPC- producing Enterobacterales	CAZ-AVI (n=77) Monotherapy: 69%	-	Microbiologic failure, clinical success, 30 and 90-day survival	AKI	Development of CAZ-AVI resistance in CAZ- AVI-treated patients
Sousa (2018) [53]	Single center, prospective	Patients with infections caused by OXA-48-producing Enterobacterales Types of infection: Intra-abdominal (28%), pulmonary (26%), urinary (25%), Others (10%) Severe infection (54%)	OXA-48- producing Enterobacterales	CAZ-AVI (n=57) Monotherapy: 81%	-	Microbiological cure, clinical cure, 14 and 30-day mortality, 90-day infection recurrence	Treatment-related AEs	Development of CAZ-AVI resistance in CAZ- AVI-treated patients
Mortality, CRP level, FEV1%	Single center, retrospective	Patients with cystic fibrosis with infections due to MDR-GN organisms Types of infection: Pulmonary infection (7 pts) and systemic infection (cepacia syndrome) (1 pt) Patients had moderate-to-severe lung disease	MDR-GN organisms including MDR- PA and MDR- Burkholderia spp.	CAZ-AVI (n=8) Monotherapy: 0%	-		Treatment-related AEs
Temkin (2017) [55]	Multicenter, retrospective, case series	Patients with infections caused by CR GN organisms Types of infection: Bacteremia (68%), IAI (39%), pneumonia (18%), SSTI (11%), UTI (11%), osteomyelitis (8%), endocarditis (5%), surgical site infection (5%), others (8%) Life-threatening infection (61%)	CRE including KPC-, OXA- 48-producing Enterobacterales and CRPa	CAZ-AVI (n=38) Monotherapy: 34%	-	Microbiological cure, clinical cure, survival to hospital discharge	Treatment-related AEs	-
Tsolaki (2020) [56]	Multicenter, retrospective	Critically ill, mechanically ventilated patients with mixed infections caused by CRE [Mixed infection types; subgroup: bacteremia]	CRE (94% KPC-producing Enterobacterales)	CAZ-AVI (n=41) Monotherapy: 22% Types of infection: Bacteremia (54%), VAP (46%), IAI (10%), UTI (5%), CNSI (2%)	BAT (n=36) (86% included colistin among others) Monotherapy: 3% Types of infection: Bacteremia (78%), VAP (19%), IAI (11%), UTI (3%), CNSI (3%)	10-day microbiological cure, clinical cure, 28-day survival, relapse, Sequential Organ Failure Assessment (SOFA) score on days 4 and 10,	Liver and renal function and coagulation tests	Development of resistance in patients with relapse
Tumbarello (2019) [57]	Multicenter, retrospective	Patients with KPC- Kp infections [Mixed infection types; subgroup: bacteremia]	KPC-Kp	CAZ-AVI (n=104) Monotherapy: 21%	Other agents (n=104) Monotherapy: 26%	30-day mortality, infection relapse	-	-
Van Duin (2018) [58]	Multicenter, prospective	Patients with infections caused by KPC–producing Enterobacterales Types of infection (all): Bacteremia (46%), pneumonia (22%), UTI (14%), wound (10%), and others (8%)	KPC-producing Enterobacterales	CAZ-AVI (n=38) Monotherapy: 37% Types of infection: Bacteremia (39%), pneumonia (24%), UTI (16%), wound (16%), and others (5%)	Colistin (n=99) (~60% included tigecycline and/or carbapenem among others) Monotherapy: 6% Types of infection: Bacteremia (48%), pneumonia (21%), UTI (13%), wound (8%), and others (9%)	30-day adjusted all-cause-hospital mortality; 30-day disposition	-	-
Vena (2020) [59]	Multicenter, retrospective	Patients with infections caused by MDR-GNB other than CRE Types of infection: Nosocomial pneumonia (49%), bacteremia (17%), IAI (10%), bone infection (10%), acute bacterial skin and skin structure infection (5%), and other infections (10%)	MDR-GNB other than CRE (89% MDR-PA)	CAZ-AVI (n=37) Monotherapy: 20%	-	Clinical cure, 5-day infection recurrence	MDR-GNB other than CRE (89% MDR-PA)	Development of CAZ-AVI resistance in CAZ- AVI-treated patients

Abbreviations: AKI: Acute Kidney Injury; BAT: Best Available Therapy; BSI: Blood Stream Infections; CRE: Carbapenem-Resistant Enterobacterales; CR-Kp: Carbapenem-Resistant Klebsiella Pneumonia; CR-PA: Carbapenem-Resistant Pseudomonas Aeruginosa; CAZ-AVI : Ceftazidime-avibactam ; ESBL: Extended- Spectrum ?-Lactamase; XDR:Extensively Drug-Resistant; GNB: Gram-Negative Bacilli; KPC:Klebsiella Pneumoniae Carbapenemase; KPC-Kp: Klebsiella Pneumoniae Carbapenemase-Producing Klebsiella Pneumoniae; MDR-GN: Multidrug-Resistant Gram-Negative; MDR-GNI: Multidrug-Resistant Gram-Negative Infection; MDR-PA: Multidrug-Resistant Pseudomonas Aeruginosa; PA: Pseudomonas Aeruginosa; OXA: Oxacillinase; UTI: Urinary Tract Infection; VAP: Ventilator-Associated Pneumonia; IAI: Intra-Abdominal Infection; CNSI: Central Nervous System Infection; SSTI: Skin-Soft Tissue Infection; cIAI: Complicated Intra-Abdominal Infection, cUTI: Chronic Urinary Tract Infection; ICU: Intensive Care Unit.

Table 1: Characteristics of real-world studies on CAZ-AVI.

All 28 studies described the effects of CAZ-AVI treatment on clinical outcomes and the key findings are summarized according to the type of target pathogens in Table 2 [32-59]. More than half of the studies reported safety of CAZ-AVI treatment and the results are presented in Table 3 [32,38,39,41,43,46,49-56,59]. About one-third of the studies reported findings on development of resistance to CAZ- AVI treatment [32,42,43,49,50,52,53,56,59] and the relevant results are shown in Table 2.

Reference (Year)	Study population/ Types of Infection	Target pathogens	Treatment(s)		Safety outcomes	Definitions
King (2017) [46]	Severely ill patients with CRE infection Types of infection: Bacteremia (38%), UTI (28%), pneumonia (27%), wound (13%), IAI (7%), and bone/ joint (3%)	CRE	CAZ-AVI (n=60) Monotherapy: 55%	-	No treatment-related AEs reported
Spoletini (2019) [54]	Patients with cystic fibrosis with infections due to MDR-GN organisms not responding to standard of care antibiotic treatment Types of infection: Pulmonary infection (7 pts) and systemic infection (cepacia syndrome) (1 pt) Patients had moderate-to-severe lung disease	MDR-GN organisms including MDR-PA and MDR-Burkholderia spp.	CAZ-AVI (n=8)	-	No episodes of AKI or elevation in transaminase were observed. Mouth dryness: 1 pt No other AEs were observed
Chen (2020) [38]	Lung transplant patients with XDR- GNB infections Types of infection: Pneumonia and/ or tracheobronchitis (90%), cholecystitis and bacteremia (10%)	XDR GNB (90% KPC-Kp)	CAZ-AVI (n=10) Monotherapy: 20%	-	Increased blood urea and creatinine: 3 pts (including 1 who had combined polymyxin B treatment) Increased ALT and AST: 2 pts (including 1 with concomitant tigecycline and the other with concomitant voriconazole) Elevated ALP, GGT, TBIL: 3 pts (including 2 who received combined treatment with tigecycline) Thrombosytosis: 1 pt No severe AEs were reported.
De la Calle (2019) [39]	Patients with infections caused by CRE Types of infection: Bacteremia (33%), IAI (29%), UTI (25%), pneumonia (21%); osteoarticular/SSSTI (17%), device-related meningitis (4%), and catheter-related bacteremia (4%)	CRE (96% OXA- 48-producing Enterobacterales and 96% ESBL Enterobacterales)	CAZ-AVI (n=23) Monotherapy: 58%	-	AE: 17% Diarrhoea: 4% Thrombocytopenia and cholestasis: 4% Neurological symptoms (myclonus and encephalopathy): 9%
Guimarães (2019) [41]	Patients with infections caused by KPC-producing Enterobacterales coresistant to carbapenems and polymyxins Types of infection: Bacteremia (41%), UTI (28.%), IAI (14%), nosocomial pneumonia (10%), and complicated SSTI (7%)	KPC-producing Enterobacterales	CAZ-AVI (n=29) Monotherapy: 52%	-	AEs: 14% Diarrhea (not associated with Clostridioides difficile): 7% Rash: 3% Gastrointestinal bleeding: 3%
Jorgensen (2019) [43]	Patients with MDR-GN infections Types of infection: Respiratory tract (37%), UTI (20%), IAI (19.7%), bacteremia (11%), SSTI (9%), and osteoarticular (7%)	MDR-GN organisms (58% CRE and 31% Pseudomonas spp.)	CAZ-AVI (n=203) Monotherapy: 67%	-	AE: 8% AKI: 10/177 (6%) Among the 10 pts who developed AKI, 9 (90%) received concomitant nephrotoxic agents Clostridioides difficile- associated diarrhea: 2% Rash: 1% Neutropenia and GI intolerance: 1%	Acute kidney injury (AKI) was evaluated in patients not receiving hemodialysis at the time of CAZ initiation and was defined as a serum creatinine increase of ≥ 0.5 mg/dL or 50% from baseline on 2 consecutive measurements while on CAZ and up to 72 hours after the last dose.
Santevecchi (2018) [49]	Patients with infections due to MDR-organisms other than Kp Types of infection: Pneumonia (46%), skin and soft tissue (23%), bacteremia (15%), and intra–abdominal (15%)	MDR-organisms other than Kp (most common: MDR-PA)	CAZ-AVI (n=10) Monotherapy: 50%	-	No treatment-related AEs were reported.
Shield (2016) [50]	Patients with CRE Types of infection: Pneumonia (32%), bacteremia (27%), IAI (11%), SSTI (11%), pyelonephritis (11%), mediastinitis (3%), subdural empyema/ Ventriculitis (3%) and purulent tracheobronchitis (3%)	CRE (78% KPC-producing Enterobacterales)	CAZ-AVI (n=37) Monotherapy: 70%	-	AKI: 3/31 (10%) 1 of 3 (33%) who developed AKI received concomitant colistin) Treatment discontinuation: 1 pt who developed leukopenia; (pt was also receiving receiving IV penicillin and quetiapine)	AKI within 7 days of treatment initiation (defined by 1.5X increase in serum creatinine from baseline) Leukopenia (absolute neutrophil count=90 × 109/L)
Shields (2018)[52]	Patients with CRE infections [Mixed infection types]	CRE (75% KPC-producing Enterobacterales)	CAZ-AVI (n=61)	-	AKI: 7/61 (11%) Among the 7 patients who developed AKI, 1 (14%) and 2 (29%) pts received concomitant colistin and aminoglycosides, respectively)	AKI; defined by modified KDIGO guidelines as a 1.5X increase in serum creatinine levels from baseline within 7 days of treatment initiation
Sousa (2018)[53]	Patients with infections caused by OXA-48- producing Kp Types of infection: Intra-abdominal (28%), pulmonary (26%), urinary (25%), Others (10%) Severe infection (54%)	OXA-48-producing Kp	CAZ-AVI (n=57) Monotherapy: 81%	-	AKI: 2/57 (4%) 1 of 2 patients [50%] who developed AKI was on concomitant IV colistin No other treatment- related AEs were observed.
Temkin (2017) [55]	Patients with infections caused by CR GN organisms Types of infection: Bacteremia (68%), IAI (39%), pneumonia (18%), SSTI (11%), UTI (11%), osteomyelitis (8%), endocarditis (5%), surgical site infection (5%), others (8%) Life-threatening infection (61%)	CR GN organims including KPC-, OXA-48-producing Enterobacterales and CR-PA	CAZ-AVI (n=38) Monotherapy: 34%	-	AE: 16% Increased blood ALP: 5% Nausea/vomiting: 3% Clostridium difficile- associated diarrhea: 3% Convulsions: 3% Disorientation progressing to stupor: 3%
Vena (2020) [59]	Patients with infections caused by MDR-GNB other than CRE Types of infection: Nosocomial pneumonia (49%), bacteremia (17%), IAI (10%), bone infection (10%), acute bacterial skin and skin structure infection (5%), and other infections (10%)	MDR-GNB other than CRE (89% MDR-PA)	CAZ-AVI (n=37) Monotherapy: 20%	-	No treatment-related AEs were reported.
Tsolaki (2020) [56]	Critically ill, mechanically ventilated patients with mixed infections caused by CRE [Mixed infection types]	CRE (94% KPC-producing Enterobacterales)	CAZ-AVI (n=41) Monotherapy: 22% Types of infection: Bacteremia (54%), VAP (46%), IAI (10%), UTI (5%), CNSI (2%)	BAT (n=36) (86% included colistin among others) Monotherapy: 3% Types of infection: Bacteremia (78%), VAP (19%), IAI (11%), UTI (3%), CNSI (3%)	No differences in the results of liver and renal function and coagulation tests between the two groups. No significant worsening of any of these results in each group.
Shields (2017)[51]	Patients with CR-Kp bacteremia [Bacteremia]	CR-Kp (97% KPC-Kp)	CAZ-AVI (n=11) Monotherapy: 64% The remaining (4/11; 36%) received combination with aminoglycoside	Carbapenem + colistin (n=23)	ⴕEOT AKI: 2/11 (18%) vs. 13/23 (57%) 1 of 2 (50%) patients who developed AKI received CAZ-AVI with aminoglycosides	Acute kidney injury was defined by KDIGO criteria as a 1.5X increase in serum creatinine from baseline at the end of treatment.
				Carbapenem + aminoglycoside (n=18)	ⴕEOT AKI: 2/11 (18%) vs. 8/18 (44%) 1 of 2 (50%) patients who developed AKI received CAZ-AVI with aminoglycosides
				Others (n=33)	ⴕEOT AKI: 2/11 (18%) vs. 6/33 (18%) 1 of 2 (50%) patients who developed AKI received CAZ-AVI with aminoglycosides
Ackley (2020) [32]	Patients with infections caused by KPC-producing Enterobacterales (excluded those with localized urinary tract infection and repeat study drug exposures after the first episode) [Mixed infection types]	KPC-producing CRE	CAZ-AVI (n=105) Monotherapy: 39% Types of infection: Bacteremia (42%), respiratory (29%), soft tissue (17%), IAI (11%), and others (1%)	Meropenem- Vaborbactam (n=26) Monotherapy: 85% Types of infection: Bacteremia (35%), respiratory (38%), Soft tissue (8%), IAI (19%), and others (0%)	AE: 34% vs 23% ⴕNephrotoxicity (most frequent AE): 26/89 (29%) vs. 3/21 (14%) Leukopenia: 11% vs. 8% Rash: 4% vs. 4% Neurotoxicity: 1% vs. 0 Among the 26 pts who experienced nephrotoxicity in the CAZ-AVI group, 16 (62%) received combination therapy: 23% received colistin, 15% polymyxin B, 15% tigecycline, 12% fluoroquinolone, and 4% aminoglycoside. In the meropenem- vaborbactam group, one of three (33%)pts who had nephrotoxicity received combination therapy with colistin, the remaining two patients received monotherapy.	Nephrotoxicity was defined using the Acute Kidney Injury Network (AKIN) classification and/ or the initiation of RRT while receiving treatment. Leukopenia=white blood cell count of <4,000 cells/mm3.

Abbreviations: AKI:Acute Kidney Injury; ALP:Alkaline Phosphatase; ALT:Alanine Aminotransferase; AST:Aspartate Aminotransferase; BAT:Best Available Therapy; BSI:Blood Stream Infections CRE Carbapenem-Resistant Enterobacterales; CR-Kp:Carbapenem-Resistant Klebsiella Pneumoniae; CR-PA:Carbapenem-Resistant Pseudomonas Aeruginosa; CAZ-AVI:Ceftazidime-avibactam ; ESBL:Extended-Spectrum Β-Lactamase, XDR:Extensively Drug-Resistant; GGT:Γ-Glutamyltranspeptadase; GNB:Gram-Negative Bacilli; KPC:Klebsiella Pneumoniae Carbapenemase; KPC-Kp:Klebsiella Pneumoniae Carbapenemase-Producing Klebsiella Pneumoniae; MDR-GN:Multidrug-Resistant Gram-Negative; MDR-GNI:Multidrug-Resistant Gram-Negative Infection; MDR-PA:Multidrug-Resistant Pseudomonas Aeruginosa; PA:Pseudomonas Aeruginosa; OXA:Oxacillinase; RRT:Renal Replacement Therapy; TBIL:Total Bilirubin.

Fifteen studies were single-center studies and the remaining 13 were multi-center studies (Table 1). Twenty-five studies were retrospective and only three were prospective studies. About two-thirds of the studies focused on only CAZ-AVI treatment whereas the remaining one-third also included a comparison group of patients treated with other antimicrobial agents. Six had included more than 100 patients whereas the remaining 22 studies had smaller sample sizes of 5-77 patients. Fourteen studies included severely ill or critically ill patients who were in intensive care unit (ICU), required mechanical ventilation, or had cancer, cystic fibrosis or lung transplant, and had serious or severe infections (predominantly bacteremia or those from respiratory sources) [33,37,38,40-42, 45,46,51,53-57].

Effectiveness of CAZ-AVI for GNB infections with limited treatment options

Findings on the effects of CAZ-AVI treatment on key clinical outcomes are presented according to the target pathogens-CRE and MDR- PA in Table 2 [32-59]. Figure 1 shows the breakdown of the included studies by target pathogens and treatment [32-59]. Twenty-four studies described the effects of CAZ-AVI in treating infections due to CRE and six studies in infections due to MDR-PA. Key outcomes reported included microbiological cure or failure, clinical cure/success or failure, mortality or survival, and infection recurrence/relapse among others. The outcomes were reported heterogeneously across studies. For instance, mortality was defined as 14-, 28-, 30-, or 90-day mortality, in-hospital mortality, all-cause mortality, etc. or not specified. Outcome definitions used in the studies (where available) are included in Table 2. Therefore, caution should be exercised when interpreting the results.

Reference (Year)	Study population/ Types of infection	Treatment(s)		Effectiveness outcomes	Other relevant outcomes	Definitions
Target pathogen: CRE (24 studies)*
Target pathogen: CRE subtype: Kp carbapenemase (KPC)-producing Enterobacterales
Treatment: CAZ-AVI vs. other agents
Types of infection: bacteremia or mixed infection types (predominantly bacteremia, VAP or cIAIs)
^§Tumbarello (2019) [57]	Patients with infections caused by KPC-Kp [Bacteremia]	CAZ-AVI (n=104) Monotherapy: 21%	Others (n=104) Monotherapy: 26%	30-day mortality: 37% vs. 56% Infection relapse: 10% vs 9%		Relapse was defined as the onset, during the index hospitalization, of a second microbiologically documented KPC- Kp infection in a patient whose original infection had been classified as a clinical cure (with or without microbiological confirmation).
Tsolaki (2020) [56]	Critically ill, mechanically ventilated patients with mixed infections caused by CRE (94% KPC-producing Enterobacterales) [Mixed infection types]	CAZ-AVI (n=41) Monotherapy: 22% Types of infection: Bacteremia (54%), VAP (46%), IAI (10%), UTI (5%), CNSI (2%)	BAT (n=36) (86% included colistin among others)) Monotherapy: 3% Types of infection: Bacteremia (78%), VAP (19%), IAI (11%), UTI (3%), CNSI (3%)	10-day microbiological cure: 94% vs. 68% Clinical cure: 81% vs. 53% 28-day survival: 85% vs. 61% Relapse: 5% vs. 33%	Development of resistance in patients with relapse: 0/2 (0%)=10/12 (83%)* *developed resistance to colistin, 5 pts received monotherapy with colistin	Interpretation of the susceptibility results was based on EUCAST criteria.
Tsolaki (2020) [56]	Critically ill, mechanically ventilated patients with bacteremia caused by CRE (94% KPC-producing Enterobacterales) Bacteremia	CAZ-AVI (n=22) Monotherapy: 32%	Best available therapy (n=28) Monotherapy: 4%	10-day microbiological cure: 100% vs. 74% Clinical cure: 82% vs. 54% 28-day survival: 82% vs. 57% Relapse rate: 0% vs. 21%	Development of resistance in patients with relapse: 0/0 (0%)=5/6 (83%)* *developed resistance to colistin
Bassetti (2019) [36]	Patients with KPC-Kp gut colonization	CAZ-AVI (n=12) Monotherapy: 8% Types of infection: cIAI (42%), HAP (17%), sepsis (17%), surgical wound infection (8%), and others (25%)	Other regimens (n=24) (included 83% tigecycline, 46% colistin, and/or 54% carbapenem among others) Monotherapy: 0% Types of infection: cIAI (17%), HAP (21%), sepsis (42%), surgical wound infection (17%), and others (4%)	Gut decolonization: 92% vs. 0%.
Treatment: CAZ-AVI vs. other specific agents
Types of infection: bacteremia or mixed infection types (predominantly bacteremia or pneumonia)
Van Duin (2018) [58]	Patients with infections caused by KPC–producing Enterobacterales Types of infection (all): Bacteremia (46%), pneumonia (22%), UTI (14%), wound (10%), and others (8%)	CAZ-AVI (n=38) Monotherapy: 37% Types of infection: Bacteremia (39%), pneumonia (24%), UTI (16%), wound (16%), and others (5%)	Colistin (n=99) (~60% included tigecycline and/or carbapenem among others) Monotherapy: 6% Types of infection: Bacteremia (48%), pneumonia (21%), UTI (13%), wound (8%), and others (9%)	30-day adjusted all-cause-hospital mortality: 9% vs. 32%
Falcone (2020) [40]	Patients with BSI due to KPC-Kp hospitalized in ICU (excluded those with polymicrobial BSIs) Bacteremia	CAZ-AVI-containing regimens (n=13)	Colistin-containing regimen (n=61)	Composite endpoint (30-day mortality or nephrotoxicity): 23%vs.69% 30-day mortality: 23%vs.44%		Composite endpoint of mortality or nephrotoxicity (postbaseline increase in serum creatinine > 1.0 mg/dL or adverse events preferred term of renal failure, renal failure acute, or renal impairment).
Falcone (2020) [40]		CAZ-AVI-containing regimens (n=13)	Other regimens (n = 17)	Composite endpoint (30-day mortality or nephrotoxicity): 23% vs. 47% 30-day mortality: 23% vs. 41%
Shields (2017) [51]	Patients with CR-Kp bacteremia (97% are KPC-Kp) [Bacteremia]	CAZ-AVI (n=13) Monotherapy: 62%	Carbapenem + colistin (n=30)	Clinical success: 85% vs. 40% 90-day survival: 92% vs. 63%		Clinical success was defined at 30 days as survival, resolution of signs and symptoms of infection, sterilization of blood cultures within 7 days of treatment initiation, and absence of recurrent infections.
			Carbapenem + aminoglycoside (n=25)	Clinical success: 85% vs. 48% 90-day survival: 92% vs. 56%
			Others (n=41)	Clinical success: 85% vs. 37% 90-day survival: 92% vs. 49%
Ackley (2020) [32]	Patients with infections caused by KPC-producing Enterobacterales (excluded those with localized urinary tract infection and repeat study drug exposures after the first episode) [Mixed infection types]	CAZ-AVI (n=105) Monotherapy: 39% Types of infection: Bacteremia (42%), respiratory (29%), soft tissue (17%), IAI (11%), and others (1%)	Meropenem- vaborbactam (n=26) Monotherapy: 85% Types of infection: Bacteremia (35%), respiratory (38%), Soft tissue (8%), IAI (19%), and others (0%)	Clinical success: 62% vs. 69% 30-day mortality: 19% vs. 12% 90-day mortality: 29% vs. 27% 90-day infection recurrence: 14% vs. 12%	Development of resistance in patients with recurrent infection: 3/15 (20%)* vs. 0/3 (0%) *all on CAZ-AVI monotherapy and had respiratory infection (and received RRT)	Clinical success was defined as survival at 30 days, resolution of signs and symptoms of infection, sterilization of blood cultures within 7 days of treatment initiation. Recurrent infections were defined as the same organism at the same site within 90 days of the index infection. Development of resistance per FDA- approved breakpoints for CAZ-AVI and MVB were evaluated in patients with recurrent infection.
Treatment: CAZ-AVI
Types of infection: bacteremia
Iannaccone (2020) [42]	Patients with BSI caused by KPC-Kp Bacteremia	CAZ-A (n=23) Monotherapy: 13%	-	Recovered from infection: 74% In-hospital mortality: 26% Recurrent infection: 17%	Development of CAZ- AVI resistance in CAZ- AVI-treated patients: 2/23 (9%)* *Both were on combination therapy with other resistant antimicrobials
Types of infection: mixed infection types (predominantly bacteremia)
^§Tumbarello (2019) [57]	Patients with infections caused by KPC-Kp Types of infection: Bacteremia (75%), lower respiratory tract infections (9%), abdominal infections (9%), UTI (4%), others (2%)	CAZ-AVI (n=138) Monotherapy: 21%	-	30-day mortality: 34% Infection relapse: 9% 30-day mortality by infection types Bacteremia: 37% Lower respiratory tract infections: 30% Abdominal infections: 25% UTI: 17% Others: 33%)		Relapse was defined as the onset, during the index hospitalization, of a second microbiologically documented KPC- Kp infection in a patient whose original infection had been classified as a clinical cure (with or without microbiological confirmation).
^†Temkin (2017) [55]	Patients with infections caused by KPC-producing Enterobacterales [Mixed infection types]	CAZ-AVI (n=23)	-	Microbiological cure: 78% Clinical cure: 74% Survival to hospital discharge: 74%
Guimarães (2019) [41]	Patients with infections caused KPC-producing Enterobacterales coresistant to carbapenems and polymyxins Types of infection: Bacteremia (41%), UTI (28%), IAI (14%), nosocomial pneumonia (10%), and complicated SSTI (7%)	CAZ-AVI (n=29) Monotherapy: 52%	-	Clinical success: 83% 14-day all-cause mortality: 31% 30-day all-cause mortality: 52% Outcomes by infection types Clinical success Bacteremia: 75% 14-day mortality Bacteremia: 33% Pneumonia: 33% Microbiological cure Bacteremia: 100%		Clinical success was classified as improved signs and symptoms from baseline to the end of therapy with defervescence based on information entered in the medical records. Microbiological cure was classified as a negative culture at the same site as basal culture after treatment.
Types of infection: mixed infection types (predominantly from respiratory sources)
Chen (2020) [38]	Lung transplant patients with XDR- GNB infections (90% KPC-Kp) Types of infection: Pneumonia and/ or tracheobronchitis (90%), cholecystitis and bacteremia (10%)	CAZ-AVI (n=10) Monotherapy: 20%	-	Microbiological cure: 90% 30-day survival:100% 90-day survival: 90% Infection relapse: 50%		Relapse was defined as the onset of a second microbiologically documented XDR- GNB infection in a patient whose original infection had been classified as a clinical cure (with or without microbiological confirmation).
Krapp (2017) [47]	Patients with infections caused by KPC-Kp Types of infection: Pneumonia (2 pts), IAI (1 pt), peritonitis (1 pt), perinephric abscess (1 pt), and wound (1pt)	CAZ-AVI (n=6) Monotherapy: 33%	-	Clinical cure: 83% Infection relapse: 33% (among those who achieved clinical cure)		Clinical cure was defined as symptom resolution or significant improvement at completion of antibiotic treatment.
Types of infection: mixed infection types (predominantly bacteremia and pneumonia)
Shields (2018) [52]	Patients with CRE infections (75% KPC-producing Enterobacterales) [Mixed infection types] Types of infection: Pneumonia (43%), bacteremia (26%), urinary tract infection (10%), intra-abdominal (9%), skin/soft tissue (8%), and mediastinitis, subdural empyema/ventriculitis and purulent tracheobronchitis (1% each)	CAZ-AVI (n=77) Monotherapy: 69%	-	Microbiologic failure: 32% Clinical success: 55% 30-day survival: 81% 90-day survival: 69% 90-day infection recurrence: 17% (among those who received clinical success) Clinical success rates by infection types Urinary tract: 88% Bacteremia: 75% Skin/soft tissue: 67% Intra-abdominal: 43% Pneumonia: 36% Others: 33%	Development of CAZ- AVI resistance in CAZ- AVI-treated patients: 8/77 (10%)* *6 on monotherapy, 7 had pneumonia, 1 had intra-abdominal infection. Resistant isolates carried mutant blaKPC- encoding variant KPC-3 enzymes. Receipt of RRT was an independent predictor of the development of CAZ-AVI resistance.	Microbiologic failure was defined as isolation of CRE following ≥7 days of ceftazidime-avibactam treatment. Clinical success was defined as survival and absence of recurrence at 30 days following the onset of infection, resolution of signs and symptoms of infection, and sterilization of site- specific cultures within 7 days of treatment initiation. Recurrences within 90 days of onset were defined by microbiologic failure and concomitant signs of infection. Ceftazidime-avibactam resistance (MIC > 8 mg/L)
Shield (2016) [50]	Patients with infections due to CRE (78% KPC-producing Enterobacterales) Types of infection: Pneumonia (32%), bacteremia (27%), IAI (11%), SSTI (11%), pyelonephritis (11%), mediastinitis (3%), subdural empyema/ Ventriculitis (3%) and purulent tracheobronchitis (3%)	CAZ-AV (n=37) Monotherapy: 70%	-	Microbiologic failure: 27% 30-day clinical success: 59% 30-day survival: 76% 90-day infection recurrence: 23% (among those who achieved clincial success) Clinical success rates by infection types Pyelonephritis: 100% Bacteremia: 70% Pneumonia: 50% Skin/soft tissue: 50% Intra-abdominal: 50% Others: 33%	Development of CAZ- AVI resistance in CAZ- AVI-treated patients: 3/37 (8%)* *all on monotherapy, 2 had pneumonia, 1 had intra-abdominal infection.	Microbiologic failure was defined as isolation of CRE following ≥7 days of ceftazidime-avibactam treatment. Clinical success was defined as survival and absence of recurrence at 30 days following the onset of infection, resolution of signs and symptoms of infection, and sterilization of site- specific cultures within 7 days of treatment initiation. Recurrences within 90 days of onset were defined by microbiologic failure and concomitant signs of infection. Ceftazidime-avibactam resistance (MIC > 8 mg/L)
Target pathogen: CRE subtype: OXA-48-producing Enterobacterales
Treatment: CAZ-AVI vs.* others*
Types of infection: mixed infection types (predominantly bacteremia and HAP)
Alraddadi (2019) [35]	Patients with established CRE infections (74% OXA-48- producing CRE)	CAZ-AVI (n=10) Types of infection: Bacteremia (70%), HAP (50%), cUTI (30%), cIAI (30%), SSTI (20%)	Other agents (n=28) (mainly colistin and/ or carbapenem among others) Monotherapy: 11% Types of infection: Bacteremia (54%), HAP (50%), cUTI (29%), cIAI (18%), SSTI (11%)	Clinical remission: 80% vs. 54% 30-day all-cause mortality: 50% vs. 57%		Complete remission is defined as resolution of fever and eradication of bacteria in subsequent cultures.
Target pathogen: CRE subtype: OXA-48-producing Enterobacterales
Treatment: CAZ-AVI
Types of infection: mixed infection types
Sousa (2018) [53]	Patients with infections caused by OXA-48-producing Enterobacterales Types of infection: Intra-abdominal (28%), pulmonary (26%), urinary (25%), Others (10%), Severe infection (54%)	CAZ-AVI (n=57) Monotherapy: 81%	-	Microbiological cure: 65% Clinical cure: 77% 14-day all-cause mortality: 14% 30-day all-cause mortality: 22% 90-day infection recurrence: 10%	Development of CAZ- AVI resistance in CAZ- AVI-treated patients: 0/57 (0%)	Clinical cure was defined as resolution of signs and symptoms of infection (assessed according to vital signs, the course of the SOFA score and laboratory data) within 7 days of treatment initiation. Microbiological cure was defined as sterilization of site- specific cultures and/ or blood cultures after treatment ending and/ or within 7 days after treatment initiation. Recurrence within 90 days of onset was defined as microbiological failure and concomitant signs of infection. Microbiological failure was defined as isolation of CPE from a sample obtained from the same source of infection and/or blood cultures following ≥7 days of ceftazidime/ avibactam treatment initiation. A disc diffusion zone diameter of <=21 mm was interpreted as resistance (equivalent to MIC>8/4 mg/L for ceftazidime/ avibactam).
De la Calle (2019) [39]	Patients with infections caused by CRE (96% OXA-48-producing Enterobacterales) Types of infection: Bacteremia (33%), IAI (29%), UTI (25%), pneumonia (21%); osteoarticular/SSSTI (17%), device-related meningitis (4%), and catheter-related bacteremia (4%)	CAZ-AVI (n=23) Monotherapy: 58%	-	30-day clinical cure: 63% 30-day mortality: 8% 90-day mortality: 21% 90-day infection recurrence: 35% Outcomes by infection types Clinical cure Bacteremia: 63% IAI: 43% UTI: 83% Pneumonia: 40% 90-day survival Bacteremia: 75% IAI: 71% UTI: 83% Pneumonia: 75%		Clinical cure was defined as the survival, resolution of symptoms and signs of infection, and absence of recurrence within 30 days following the onset of treatment with ceftazidime-avibactam , with negative infection site cultures in those patients in whom control samples were obtained. Recurrence of infection was defined as the appearance of signs and symptoms of infection in the same or different location with positive cultures for OXA-48 CPE within 90 days of the end of treatment with ceftazidime-avibactam
^†Algwizani (2018) [34]	Patients with infections caused by OXA-48- producing Kp Types of infection: bacteremia (1 pts), CNSI (1 pt)	CAZ-AVI (n=2) Monotherapy: 0%	-	Microbiological cure: 100% Clinical cure: 100%
Types of infection: mixed infection types (predominantly pneumonia or bacteremia)
Katchanov (2018) [45]	Critically ill patients with severe infections due to OXA-48- producing Kp Types of infection: HAP (4 pts), bacteremia (1 pt), and cIAI (1 pt)	CAZ-AVI (n=5) Monotherapy: 0%	-	In-hospital mortality: 100%
^†Temkin (2017) [55]	Patients with infections caused by OXA-48-producing Enterobacterales [Mixed infection types]	CAZ-AVI (n=13)	-	Microbiological cure: 46% Clinical cure: 62% Survival to hospital discharge: 38%
CRE (mixed strains/mechanisms of carbapenem resistance not specified)
Treatment: CAZ-AVI vs. other agents
Types of infection: bacteremia
Caston (2017) [37]	Patients with hematologic malignancies who had CPE bacteremia Bacteremia	CAZ-AVI (n=8) Monotherapy: 0%	Other agents (n=23) Monotherapy: 6%	14-day clinical cure: 86% vs. 35% 30-day crude mortality: 25% vs. 52%		i) crude mortality at 30 days from the day the blood cultures were taken, and ii) clinical cure (resolution of all signs and symptoms of infection) at 14 days after the onset of antibiotic treatment.
Treatment: CAZ-AVI
Types of infection: mixed infection types (most common – infections from respiratory sources)
^†Jorgensen (2019) [43]	Patients with MDR- GNIs caused by CRE Types of infection: Respiratory tract (33%), UTI (20%), IAI (22%), bacteremia (9%), SSTI (9%), and osteoarticular (6%)<CRE; no mention of specific CRE genes>	CAZ-AVI (n=117) Monotherapy: 62%		Composite clinical failure: 29% 30-day mortality: 16% 30-day recurrence: 6%	Development of CAZ-AVI resistance during treatment in patients with repeat susceptibility testing: 0%	Composite clinical failure was defined as a composite of all- cause 30-day mortality, microbiological failure, and/or failure to resolve or improve signs and symptoms of infections during CAZ therapy.
Jorgensen (2020) [44]	Patients with CRE infections Types of infection: Respiratory tract (35%), IAI (21%), UTI (20%), SSTI (6%), osteoarticular 7 (6%), bacteremia (6%), and others (5%)	CAZ-AVI (n=109) Monotherapy: 60%	-	30-day all-cause mortality: 17% 30-day all-cause mortality by infection types: Pneumonia: 24% IAI: 9% UTI: 5%		30-day all-cause mortality, measured from infection onset.
Types of infection: mixed infection types (predominantly bacteremia and pneumonia)
King (2017)[46]	Severely ill patients with CRE infection Types of infection: Bacteremia (38%), UTI (28%), pneumonia (27%), wound (13%), IAI (7%), and bone/ joint (3%)	CAZ-AVI (n=60) Monotherapy: 55%	-	Microbiological cure: 53% Clinical success: 65% In-hospital mortality:32% Outcomes by infection types Microbiological cure Bacteremia: 82% Pneumonia: 44% Urinary tract: 41% Wound: 38% Clinical success Bacteremia: 61% Pneumonia: 56% Urinary tract: 88% Wound: 63% In-hospital mortality Bacteremia: 39% Pneumonia: 56% Urinary tract: 12% Wound: 25%		Microbiologic cure, defined as a negative culture at the end of therapy, and clinical success, defined as improved signs and symptoms from baseline to the end of therapy with defervescence.
Types of infection: bacteremia
Aitken (2016) [33]	Cancer patients with CRE bloodstream infection Bacteremia	CAZ-AVI (n=5) Monotherapy: 0%		Microbiologic cure: 80% Clearance of infection: 100% Mortality: 40%		microbiologic cure (ie, failure to isolate the bacteria in subsequent blood cultures after at least one negative blood culture)
Target pathogen: MDR-Pseudomonas spp. (six studies)*
Treatment: CAV-AZI
Types of infection: mixed infection types (predominantly infection from respiratory sources)
^†Jorgensen (2019) [43]	Patients with MDR- GNIs caused by Pseudomonas spp. Types of infection: Respiratory tract (60%), UTI (11%), IAI (5%), bacteremia (5%), SSTI (10%), and osteoarticular (10%) <MDR-Pseudomonas spp., data on mechanisms of resistance not available>	CAZ-AVI (n=63) Monotherapy: 68%	-	Composite clinical failure: 30% 30-day mortality: 18% 30-day recurrence: 6%	Development of CAZ-AVI resistance during treatment in patients with repeat susceptibility testing: 0%	Composite clinical failure was defined as a composite of all- cause 30-day mortality, microbiological failure, and/or failure to resolve or improve signs and symptoms of infections during CAZ therapy.
Vena (2020) [59]	Patients with infections due to MDR-PA (including strains resistant to carbapenem) Types of infection: Nosocomial pneumonia (55%), bacteremia (15%), IAI (6%), bone infection (9%), acute bacterial skin and skin structure infection (6%), and other infections (9%)	CAZ-AVI (n=33)	-	Clinical cure: 88% Recurrent infection: 3%	Development of CAZ- AVI resistance in CAZ- AVI-treated patients: 0/33 (0%)	Cure, patients had complete resolution of clinical signs and symptoms related to the infection and/or infection cleared with no positive cultures reported at the end of ceftazidime-avibactam therapy MIC values of ceftazidime-avibactam were determined by E-test (bioMérieux, Marcy l’Etoile, France) and interpreted according to the current European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoints [37]. EUCAST. Breakpoint Tables for Interpretation of MICs and Zone Diameters. Version 8.1, M.. 2018. Available online: http:// www.eucast.org/ clinical_breakpoints/ (accessed on 22 May 2019).
^†Spoletini (2019)[54]	Patients with cystic fibrosis with infections due to MDR-PA not responding to standard of care antibiotic treatment Types of infection: Pulmonary infection (5 pts) and systemic infection (cepacia syndrome) (1 pt)<100% MDR-PA, 33% Burkholderia spp.>	CAZ-AVI (n=6) Monotherapy: 0%	-	Mortality: 17%
Santevecchi (2018) [49]	Patients with infections caused by MDR-PA. Types of infection: VAP (3 pts), SSTI (3 pts), and IAI (1 pt) <MDR-PA, data on mechanisms of resistance not available>	CAZ-AVI (n=6) Monotherapy: 33%	-	Microbiological cure: 100% Clinical success: 83% 30-day in-hospital mortality: 17%	Development of CAZ- AVI resistance in CAZ- AVI-treated patients: 1/6 (17%)* *patient had VAP, were on combination therapy, and had fluctuating renal function during treatment, requiring multiple dose adjustments throughout the course of therapy	Microbiological cure was defined as clearance of site- specific cultures following initiation of ceftazidime/avibactam. Clinical success was defined as resolution of all signs and symptoms of infection and survival at completion of ceftazidime/avibactam therapy. The FDA MIC breakpoint for ceftazidime/avibactam susceptibility for PA is ≤ 8/4 mg/L [13]. Ref: Avycaz (ceftazidime and avibactam). Irvine (CA): Allergan USA, Inc.; 2017. Package insert.
^†Algwizani (2018) [34]	Patients with infections caused by CR-PA Types of infection: VAP (2 pts) and bacteremia (1 pt)	CAZ-AVI (n=3) Monotherapy: 100%	-	Microbiological cure: 100% Clinical cure: 100%
Rodríguez-Núñez (2018) [48]	Patients with infections due to MDR or XDR- PA (including 2 pt with CR MDR PA) Types of infection: Hospital-acquired lower respiratory tract infection (5 pts), osteomyelitis (1 pt), meningitis (1 pt) and catheter-related bacteremia (1 pt).	CAZ-AVI (n=8) Monotherapy: 25%	-	Clinical cure: 50% 30-day mortality: 13% 90-day mortality: 38%		Clinical cure was considered as survival, resolution of symptoms and signs of infection, and absence of relapse at 30 days following the end of treatment with CAZ/ AVI.

*Some of the studies had findings for more than one type of pathogens and are included in more than one categories, but are counted as one study; ^†Had findings for more than one type of pathogens; ^§Had findings for CAZ-AVI treatment for all patients and CAZ-AVI=other agents for bacteremia subgroup. Abbreviations: BAT: Best Available Therapy; BSI: Blood Stream Infections; CRE: Carbapenem-Resistant Enterobacterales; CR-Kp: Carbapenem-Resistant Klebsiella Pneumoniae; CR-PA: Carbapenem-Resistant Pseudomonas Aeruginosa; CAZ-AVI Ceftazidime-avibactam ; ESBL: Extended-Spectrum Β-Lactamase; XDR:Extensively Drug-Resistant; GNB Gram-Negative Bacilli; KPC: Klebsiella Pneumoniae Carbapenemase; KPC-Kp: Klebsiella Pneumoniae Carbapenemase-Producing Klebsiella Pneumoniae; MDR-GN: Multidrug-Resistant Gram-Negative; MDR-GNI: Multidrug-Resistant Gram-Negative Infection; MDR-PA: Multidrug-Resistant Pseudomonas Aeruginosa; PA: Pseudomonas Aeruginosa; OXA: Oxacillinase; VAP: Ventilator-Associated Pneumonia; CRP: C-Reactive Protein; FEV1%: Forced Expiratory Volume In The First Second 1%); ICU: Intensive Care Unit.

Table 2: Effectiveness of CAZ-AVI for GNB infections with limited treatment options.

CRE

A total of 14 studies described clinical experience with CAZ- AVI in treating infections predominantly caused by KPC-producing Enterobacterales and six studies in infections mainly due to OXA-48- producing Enterobacterales(Figure 1). Five studies described the experience in treating infections caused by a mixture of CRE strains (including KPC- , OXA-48-producing Enterobacterales, and/or New Delhi metallo-β- lactamase [NDM]-producing CRE) or CRE with unspecified mechanism of carbapenem resistance (Figure 1).

KPC-producing Enterobacterales

Fourteen studies involving a total of 924 patients described the effects of CAZ-AVI treatment against a variety of infections predominantly caused by KPC-producing Enterobacterales, including bacteremia, pneumonia, cIAIs, SSTIs, CNSIs, bone infections, and wound infections, etc., (Table 2). Six studies compared CAZ-AVI with other agents and seven studies focused only on CAZ-AVI treatment. Another study examined only CAZ-AVI treatment for the total study population and compared CAZ-AVI vs. other agents for the bacteremia subgroup (Figure 1). CAZ-AVI monotherapy was used in 52%-70% of patients in four studies whereas CAZ-AVI in combination with other antimicrobial agents was predominantly used in the remaining studies (Table 2).

Among studies that examined the effects of CAZ-AVI vs. standard of care antibiotics in treating a range of infections caused by KPC-producers (predominantly bacteremia, pneumonia, or cIAIs) [36,56,57], CAZ-AVI treatment exhibited more favorable outcomes compared with other agents. CAZ-AVI treatment was associated with higher microbiological cure (94%-100%), decolonization (9

Conclusion

This review provides valuable insights into the utility of CAZ-AVI across diverse types of infection with limited alternatives available. Collectively, data from RCTs and real-world studies support the use of CAZ-AVI in adult patients with infections caused by aerobic GNB with limited treatment options, including CRE and MDR-Pseudomonas spp. CAZ-AVI is a useful addition to the limited antimicrobial armamentarium against MDR-GNB infections, offering an effective and well-tolerated alternative to standard of care antibiotic treatment.

The treatment of MDR-GNB infections remains challenging, especially given the rising trends of CR strains. Rational use of CAZ- AVI would be crucial to ensure its longevity in the armamentarium. Treatment decisions should be guided by the characteristics of the pathogen(s) (e.g. mechanism of resistance), unique characteristics of the patient (e.g. site of infection, presence of comorbidities, prior antibiotic treatment, drug allergies, etc.), and antimicrobial properties (e.g. effectiveness and safety profile) to slow down the spread of antimicrobial resistance.

Declaration of Completing Interest

Ana C. Gales has received consulting fees from Cristália and InfectoPharm. She has served on the advisory boards and speaker’s bureaus for Eurofarma, Merck Sharp & Dohme, Pfizer, United Medical, and Zambon. She has received grants from Eurofarma which was awarded to her institution, and support from Merck Sharp & Dohme and Pfizer for attending meetings and/or travel. Luis Fernando Aranha Carmargo declared no potential conflict of interest. Gabriel Trova Cuba has received support from Pfizer for the present manuscript and has received consulting fees from Eurofarma. He has also received honoraria from Merck Sharp & Dohme, Pfizer, Sanofi, and Eurofarma, and support from Merck Sharp & Dohme for attending meetings and/ or travel. Felipe Francisco Tuon has received support from Pfizer for the present manuscript and has received grants from Merck Sharp & Dohme, Abbott, Teva, and Beckman Coulter. He has also received honoraria from Merck Sharp & Dohme, Teva, and Abbott. Hui Hwa Choo is employed by Tech Observer Asia Pacific Pte Ltd., which received funding from Pfizer for providing medical writing support. Maria Lavinea Novis de Figueiredo, Alvaro Quintana, and Paurus Mehelli Irani are employees of Pfizer. Alvaro Quintana owns stocks in Pfizer.

Acknowledgments

Medical writing support was provided by Hui Hwa Choo at Tech Observer Asia Pacific Pte Ltd., Singapore and was funded by Pfizer.

Funding

This work was supported by Pfizer.

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Citation: Gales AC, Carmargo LFA, Cuba GT, Tuon FF, Choo HH, et al. (2022) A Review of Real-World Use of Ceftazidime-Avibactam for Multidrug-Resistant Gram- Negative Bacterial Infections. J Infect Dis Ther 10:483 DOI: 10.4172/2332-0877.1000483

Copyright: © 2022 Gales AC, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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A Review of Real-World Use of Ceftazidime-avibactam for Multidrug-Resistant Gram-Negative Bacterial Infections

Abstract

Introduction

Literature Review

Conclusion

Declaration of Completing Interest

Acknowledgments

Funding

References

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Journal of Infectious Diseases & Therapy Open Access

A Review of Real-World Use of Ceftazidime-avibactam for Multidrug-Resistant Gram-Negative Bacterial Infections

Abstract

Introduction

Literature Review

Conclusion

Declaration of Completing Interest

Acknowledgments

Funding

References

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