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Original article

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# Real-world use, effectiveness, and safety of ceftazidime-avibactam: Results of the French cohort OZAVIE

Lionel Piroth<sup>a, *</sup>, Virginie Vitrat<sup>b</sup>, Vincent Le Moing<sup>c</sup>, Philippe Bret<sup>d</sup>, Yves Brault<sup>d, e</sup>, William Greenwood<sup>d</sup>, Marie-Charlotte Chopin<sup>e</sup>, Eric Vicaut<sup>f</sup>, Philippe Montravers<sup>g, d</sup>, Pierre Tattevin<sup>h</sup>, Alexandre Bleibtreu<sup>i</sup>, on behalf of the OZAVIE research group<sup>1</sup>

## ARTICLE INFO

### Keywords:

Ceftazidime-avibactam

Multidrug-resistant bacteria

Gram-negative bacteria

Prospective study

Effectiveness

## ABSTRACT

**Background:** While difficult-to-treat multidrug-resistant Gram-negative bacteria infections increase over time, the real-world effectiveness, use, and safety of ceftazidime-avibactam (CAZ-AVI) for treating hospitalized patients was assessed in 41 French centers.

**Procedures:** OZAVIE was a prospective, multicenter, observational study conducted between March 2019 and November 2021. Hospitalized adult patients having initiated CAZ-AVI for infections within 14 days before enrolment were eligible. Demographic, clinical, microbiological, and therapeutic data were collected. Outcome was categorized as “failure” if the patient died from the initial infection, or if the infections persisted and required another antibiotic or surgery, or if CAZ-AVI was discontinued due to intolerance, and as “global success” otherwise. Patients whose outcome was not “failure”, did not die and required no other antibiotics during the index hospitalization were categorized as “therapeutic success”.

**Results:** 257 patients were enrolled: 76 females/181 males, mean age 58.4 years, with diabetes (30.0 %), chronic renal failure (25.7 %), end-stage liver disease (9.3 %) and/or immunocompromised (31.1 %). CAZ-AVI was prescribed for nosocomial pneumonia (34.2 %), complicated urinary tract infections (17.5 %), complicated intra-abdominal infections (14.8 %) and other specified sites (27.6 %). The main pathogens were *Pseudomonas aeruginosa* (52.4 %), *Klebsiella* spp. (34.9 %), *Enterobacter* spp. (18.4 %). Global and therapeutic successes were observed in 79.0 % and 63.4 % of patients, respectively, and 28-day mortality was 20.2 %. Overall, adverse events possibly related to CAZ-AVI were reported in 17.4 % of patients, including serious AEs in 6.2 %.

**Conclusions:** CAZ-AVI is effective and well tolerated for treating various infections – including difficult-to-treat infection sites – and for treating various infections strains, including *Pseudomonas aeruginosa* and *Enterobacter* spp.

## 1. Introduction

Multidrug-resistant Gram-negative bacteria (MDR-GNB) are a serious global health problem [1,2]. Extended spectrum β-lactamases

(ESBLs), or carbapenemases, that hydrolyze the β-lactam scaffold are common mechanisms of resistance in Gram-negative (GN) bacteria.

Avibactam (AVI) is a third-generation β-lactamase inhibitor active on β-lactamases of classes A, C, some class D, but not class B [3,4]. When

<footnote><sup>a</sup> Department of Infectious Diseases, Dijon Bourgogne University Hospital, and INSERM CIC1432 University of Burgundy, Dijon, France</footnote>

<footnote><sup>b</sup> Department of Infectious Diseases and Internal Medicine, Annecy Genevois Hospital, Annecy, France</footnote>

<footnote><sup>c</sup> Department of Infectious Diseases, Montpellier University Hospital, Montpellier, France</footnote>

<footnote><sup>d</sup> Pfizer, Paris, France</footnote>

<footnote><sup>e</sup> Department of Infectious Diseases, Lille University Hospital, Lille, France</footnote>

<footnote><sup>f</sup> Clinical Research Unit, Saint Louis-Lariboisière-Fernand Widal Hospital, and Paris Cité Université, Paris, France</footnote>

<footnote><sup>g</sup> Anaesthesiology and Surgical Intensive Care Unit, Bichat-Claude Bernard Hospital, APHP and Université Paris Cité, Paris, France</footnote>

<footnote><sup>h</sup> Infectious Diseases and Intensive Care Unit, Pontchaillou University Hospital, Rennes, France</footnote>

<footnote><sup>i</sup> Department of Infectious Diseases, Pitié-Salpetrière Hospital, APHP and Sorbonne Université, Paris, France</footnote>

<footnote>* Corresponding author.</footnote>

<footnote>E-mail address: lionel.piroth@chu-dijon.fr (L. Piroth).</footnote>

<footnote n="1">¹ Centers and principal investigators of the OZAVIE study to be found in the appendix.</footnote>
combined with a β-lactam agent, AVI inhibits the bacterial β-lactamase and increases the activity of the associated antibiotic. With this ratio- nale, AVI was combined with the β-lactam ceftazidime (CAZ), forming CAZ-AVI.

CAZ-AVI effectiveness and safety for treating MDR-GNB infections has been found to be acceptable in retrospective real-world studies. Prospective studies are however needed to describe the patterns of CAZ-AVI use, main indications, dosages, and combination with other anti- biotics. Data on microbiological evolution are also needed, considering the risk of bacterial resistance emergence during treatment [3,5,6].

OZAVIE was thus designed to prospectively collect real-world data on CAZ-AVI use. The study was conducted in France, Portugal, and Belgium. Herein, we report the results concerning France.

## 2. Patients and methods

### 2.1. Study design

OZAVIE was a prospective, multicenter, observational study assess- ing the use, effectiveness, and tolerability of CAZ-AVI for treating hos- pitalized patients with infections under routine clinical conditions.

### 2.2. Participants

Adult patients who initiated CAZ-AVI at the most 14 days before study enrolment were eligible. A microbiological sampling was required within the 5 days prior to initiating CAZ-AVI. Pregnant or breastfeeding women, and those of childbearing potential without effective contra- ception were not eligible. Patients under legal guardianship and those enrolled in an interventional therapeutic trial were not eligible either.

Eligible patients were informed about the study and those agreeing to share their medical data were included. Assessment was from the time of CAZ-AVI start until 28 days after discontinuation. CAZ-AVI dosage and modalities of use were at the physician's discretion.

### 2.3. Data collection

The following data were collected via electronic case report forms: administrative data (hospitalization dates, hospital unit/department and discharge dates), demographic data (age, sex, weight, and height), clinical data (comorbidities reported by the investigator), CAZ-AVI treatment indications, microbiological data (microorganisms involved, locally-assessed susceptibility to CAZ-AVI and other antibiotics and mechanisms of resistance according to the Ambler classification), and therapeutic data (treatment lines, prior antibiotics, antibiotics associ- ated with CAZ-AVI, modalities of use, etc.). Albeit no systematic sam- pling of the patients was planned, microbiological data (microorganisms and susceptibility to CAZ-AVI) following CAZ-AVI treatment were also collected when reported.

The main clinical indications for CAZ-AVI treatment in France were hospital-acquired pneumonia (HAP, including ventilator-associated pneumonia [VAP]), complicated urinary tract infections (cUTI), complicated intra-abdominal infections (cIAI), and associated bacter- emia. Patients with other infections were classified as either having a specific infection site, or unspecified (when no site was recorded). Except for the latter, patients could be classified with several types of infection.

Data were collected until discharge or on Day 28 after CAZ-AVI discontinuation, whichever occurred first.

### 2.4. Ethics

OZAVIE was approved by the French ethics committee: "Comité de Protection des Personnes 18.12.102/SI CNRIPH n° 18.11.14.48352" (National N°: 2021-A00199-32). It was conducted in compliance with national and European laws and regulations.

### 2.5. Objectives and outcomes

The primary objective of OZAVIE was to describe CAZ-AVI use for treating hospitalized patients with infections. Moreover, the study aimed to assess CAZ-AVI effectiveness and safety.

Effectiveness was assessed first by all-cause mortality during the study. Additionally, the clinical response was assessed either 28 days after CAZ-AVI discontinuation or at hospital discharge, whichever occurred first.

The clinical response was classified as "failure" if the patient died from a cause related to the initial infection, if signs of infection persisted and required another antibiotic or surgery, or if CAZ-AVI was dis- continued following an adverse event. Clinical response was classified as "global success" if no failure was observed. Another definition, not mutually exclusive, was used: "therapeutic success", which corresponds to a patient's outcome not classified as "failure", not dying during the study (irrespective of the cause), and when no other antibiotics were used – neither for the initial infection nor for another infection – irre- spective of their spectrum. When these points could not be assessed, patients were not considered as successful in the latter definition.

Safety was assessed until the end of study visit, 28 days after CAZ- AVI discontinuation or at hospital discharge, whichever occurred first. Adverse effects were graded using the Common terminology criteria for adverse events (CTCAE, version 5.0).

### 2.6. Statistical analysis

CAZ-AVI effectiveness was analyzed in all treated patients (overall study population), and in patients with a causal bacteria identified at baseline (microbiologically documented population).

Data are presented using descriptive statistics. Quantitative data are presented as means with standard deviation (SD). Qualitative data are presented as numbers with percentages. Missing data were not replaced. Inferential statistical analyses were not planned. Analyses were per- formed using SAS version 9.4 software (SAS Institute, Cary NC, USA).

## 3. Results

Between March 2019 and November 2021, 257 patients were included in OZAVIE, in 41 centers. Demographic and baseline charac- teristics are detailed in Table 1. CAZ-AVI indications were nosocomial pneumonia (NP) (34.2 %), cUTI (17.5 %) cIAI (14.8 %), other infected sites (27.6 %), and unspecified infection sites (10.9 %). Among the 71 patients treated for other specified sites, the infections were pulmonary (other than nosocomial) in 6.6 %, bacteriaemia in 6.6 %, bone and joint in 5.8 %, skin and soft tissue (SSI) in 4.7 %, vascular in 3.1 %, and ear nose and throat in 0.8 %.

Causal bacteria were identified in 252 patients (microbiologically documented population): 131 *Pseudomonas aeruginosa*, 89 *Klebsiella* spp., 47 *Enterobacter* spp., 33 *Escherichia coli*, 18 *Stenotrophomonas* spp., 4 *Acinetobacter* spp., and 73 other bacteria, including 44 Gram-positive cocci (26 enterococci). These latter were involved in polymicrobial in- fections (39 % of the cases, more often in cIAI [68.8 %] and NP [41.5 %]). Causal bacteria distribution by indication is shown in Table 2.

Most bacteria produced ESBLs or carbapenemases (Table 3). Resis- tance to carbapenems was observed in 57.9 % of cases, whereas resis- tance to CAZ-AVI was observed in 9.1 %. Production of metallo- β-lactamase (class B) was recorded in 19 cases.

### 3.1. Characteristics of treatment with CAZ-AVI

CAZ-AVI was prescribed as first-line treatment in 28.5 % of patients, second-line in 43.8 %, third-line in 22.3 %, and beyond in 5.5 % (Table 4).

Before CAZ-AVI, the following antibiotics were administered in ≥ 30 % of patients: 63.4 % penicillin with β-lactamase inhibitors, 62.8 %
<table><caption>**Table 1**
Demographic and baseline characteristics by indication, in the overall study population (n = 257).</caption><thead><tr><th rowspan="2">Characteristics</th><th colspan="3">Type of infection<sup>a</sup></th><th colspan="2">Other infections</th><th rowspan="2">Overall study population (n = 257)</th></tr><tr><th>Complicated intra-abdominal infection (n = 38)</th><th>Complicated urinary tract infection (including pyelonephritis) (n = 45)</th><th>Nosocomial pneumonia (n = 88)</th><th>Infected site specified (n = 71)</th><th>Infected site unspecified (n = 28)</th></tr></thead><tbody><tr><td>Age, years</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Mean (SD)</td><td>55.9 (17.7)</td><td>63.2 (16.7)</td><td>56.9 (14.3)</td><td>58.2 (18.7)</td><td>60.8 (13.7)</td><td>58.4 (16.3)</td></tr><tr><td>Sex, n (%)</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Male</td><td>30 (78.9)</td><td>34 (75.6)</td><td>68 (77.3)</td><td>41 (57.7)</td><td>19 (67.9)</td><td>181 (70.4)</td></tr><tr><td>Body mass index, kg/m<sup>2</sup></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Mean (SD)</td><td>27.1 (6.9)</td><td>24.9 (6.3)</td><td>26.6 (7.6)</td><td>27.6 (8.8)</td><td>26.0 (5.9)</td><td>26.7 (7.5)</td></tr><tr><td>Comorbidities, n (%)</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Diabetes</td><td>14 (36.8)</td><td>18 (40.0)</td><td>21 (23.9)</td><td>22 (31.0)</td><td>5 (17.9)</td><td>77 (30.0)</td></tr><tr><td>Kidney failure</td><td>7 (18.4)</td><td>23 (51.1)</td><td>17 (19.3)</td><td>18 (25.4)</td><td>6 (21.4)</td><td>66 (25.7)</td></tr><tr><td>End-stage liver disease</td><td>9 (23.7)</td><td>3 (6.7)</td><td>5 (5.7)</td><td>4 (5.6)</td><td>4 (14.3)</td><td>24 (9.3)</td></tr><tr><td>Immunosuppressed</td><td>12 (31.6)</td><td>18 (40.0)</td><td>22 (25.0)</td><td>19 (26.8)</td><td>13 (46.4)</td><td>80 (31.1)</td></tr><tr><td>Mac Cabe score, n (%)</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Comorbidity fatal within 1 year</td><td>7 (18.4)</td><td>2 (4.4)</td><td>33 (37.5)</td><td>17 (23.9)</td><td>8 (28.6)</td><td>63 (24.5)</td></tr></tbody></table>

SD standard deviation.

<sup>a</sup> Patients can be classified with more than 1 type of infection, except for "Infected site unspecified".

<table><caption>**Table 2**
Causal bacteria by indication in the overall study population (n = 257).</caption><thead><tr><th rowspan="2"></th><th colspan="3">Type of infection<sup>a</sup></th><th colspan="2">Other infections</th><th rowspan="2">Overall study population (n = 257)</th></tr><tr><th>Complicated intra-abdominal infection (n = 38)</th><th>Complicated urinary tract infection (including pyelonephritis) (n = 45)</th><th>Nosocomial pneumonia (n = 88)</th><th>Infected site specified (n = 71)</th><th>Infected site unspecified (n = 28)</th></tr></thead><tbody><tr><td>Causal bacteria<sup>b</sup>, n (%)</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><em>Pseudomonas aeruginosa</em></td><td>10 (26.3)</td><td>19 (42.2)</td><td>64 (74.4)</td><td>12 (16.9)</td><td>3 (10.7)</td><td>131 (52.4)</td></tr><tr><td><em>Klebsiella</em> spp.</td><td>14 (36.8)</td><td>18 (40.0)</td><td>29 (33.7)</td><td>22 (31.0)</td><td>10 (35.7)</td><td>89 (34.9)</td></tr><tr><td><em>Enterobacter</em> spp.</td><td>12 (31.6)</td><td>9 (20.0)</td><td>16 (18.6)</td><td>2 (2.8)</td><td>0 (0.0)</td><td>47 (18.4)</td></tr><tr><td><em>Escherichia coli</em></td><td>11 (28.9)</td><td>4 (8.9)</td><td>8 (9.3)</td><td>3 (4.2)</td><td>2 (7.1)</td><td>33 (12.9)</td></tr><tr><td><em>Stenotrophomonas</em> spp.</td><td>1 (2.6)</td><td>1 (2.2)</td><td>12 (14.0)</td><td>34 (47.9)</td><td>10 (35.7)</td><td>18 (7.1)</td></tr><tr><td><em>Acinetobacter</em> spp.</td><td>0 (0.0)</td><td>0 (0.0)</td><td>3 (3.5)</td><td>12 (16.9)</td><td>1 (3.6)</td><td>4 (1.6)</td></tr><tr><td>Other</td><td>14 (36.8)</td><td>11 (24.4)</td><td>24 (27.9)</td><td>13 (18.3)</td><td>3 (10.7)</td><td>73 (28.6)</td></tr></tbody></table>

SD: standard deviation. Percentages calculated according to patients with data.

<sup>a</sup> Patients can be classified with more than one type of infection, except for "Infected site unspecified".

<sup>b</sup> Multiple causal bacteria possible.

carbapenems, 60.1 % aminoglycosides, 49.7 % third-generation cephalosporins, 32.2 % fluoroquinolones, and 30.6 % fourth-generation cephalosporins (several possible answers).

Overall, 77.8 % of patients received CAZ-AVI as monotherapy and 22.2 % combined with other antibiotics also targeting GN bacteria. In patients receiving combination therapy, CAZ-AVI was associated with aminoglycoside in 19 %, fluoroquinolone in 14.3 %, trimethoprim-sulfamethoxazole in 10.9 %, colistin in 10.5 %, monobactam in 10.1 %, tetracycline in 5.4 %, and carbapenem in 3.9 %.

## 3.2. Clinical outcomes

Fifty-two patients (20.2 %) died during the study (Table 5, left part). The response to CAZ-AVI was failure in 21.0 %, global success in 79.0 %, and therapeutic success in 63.4 %. The failure rates were higher in patients with NP (26.1 %). By contrast, success rates were higher in patients with cUTI (global success rate 80.0 %, therapeutic success rate 77.8 %). In SSI (n = 12) the global success rate was 91.7 % and the therapeutic success rate 66.7 %. In bone and joint infections (n = 15), these were respectively 93.3 % and 60 %.

Clinical response rates were similar whether CAZ-AVI was administered with or without a loading dose, continuously or not and as

monotherapy or combined with another antibiotic (data not shown).

In the microbiologically documented population, global success rates according to the different causal bacteria ranged from 75.0 % to 91.5 % (Table 5, right part). Out of the 19 patients infected with metallo-β-lactamase-producing bacteria, 12 of them were treated with a combination of CAZ-AVI + aztreonam, with global and therapeutic success rates of 91.7 % and 66.7 %, respectively. The remaining seven patients received CAZ-AVI combined with polymyxins, extended-spectrum penicillins, tetracyclines, and various other antibiotics.

## 3.3. Microbiological outcomes

Bacteria were isolated in 33 patients with CAZ-AVI treatment failure. Klebsiella spp. (n = 10) and Pseudomonas aeruginosa (n = 10) were the most frequent, followed by E. coli (n = 4) and Stenotrophomonas spp. (n = 2). Resistance to CAZ-AVI was observed in 14 cases, mainly in Pseudomonas aeruginosa (n = 8) and in Klebsiella spp. (n = 3). The observed global resistance rate following CAZ-AVI treatment was thus 5.4 % (14/257).
<caption>**Table 3**</caption>

β-lactamases production and resistance to antibiotics according to the causal bacteria in the microbiologically documented population (n = 252).

<table><thead><tr><th rowspan="2"></th><th colspan="6">Causal bacteria<sup>a</sup></th><th rowspan="2">Microbiologically documented<br>population<br>(n = 252)</th></tr><tr><th>Pseudo-monas<br>aeruginosa<br>(n = 131)</th><th>Klebsiella<br>spp.<br>(n = 89)</th><th>Entero-bacter<br>spp.<br>(n = 47)</th><th>Escherichia<br>coli<br>(n = 33)</th><th>Stenotrophomonas<br>spp.<br>(n = 18)</th><th>Acinetobacter<br>spp.<br>(n = 4)</th></tr></thead><tbody><tr><td>ESBL production</td><td>23 (17.6 %)</td><td>42 (47.2 %)</td><td>23 (48.9 %)</td><td>17 (51.5<br>%)</td><td>5 (27.8 %)</td><td>3 (75.0 %)</td><td>80 (31.7 %)</td></tr><tr><td>AmpC β-lactamases<br>hyper-production<br>carbenemase<br>production<br>Class A</td><td>13 (9.9 %)</td><td>5 (5.6 %)</td><td>6 (12.8 %)</td><td>4 (12.1 %)</td><td>1 (5.6 %)</td><td>0 (0.0 %)</td><td>24 (9.5 %)</td></tr><tr><td>Class B</td><td>9 (6.9 %)</td><td>10 (11.2 %)</td><td>2 (4.3 %)</td><td>3 (9.1 %)</td><td>0 (0.0 %)</td><td>1 (25.0 %)</td><td>19 (7.5 %)</td></tr><tr><td>Class D</td><td>2 (2.3 %)</td><td>19 (21.3 %)</td><td>6 (12.8 %)</td><td>5 (15.2 %)</td><td>0 (0.0 %)</td><td>1 (25.0 %)</td><td>27 (10.7 %)</td></tr><tr><td>Resistance to:<br>carbenems</td><td>87 (66.4 %)</td><td>33 (37.1 %)</td><td>10 (21.3 %)</td><td>4 (12.1 %)</td><td>NA<sup>b</sup></td><td>2 (50.0 %)</td><td>57.9 %<sup>c</sup></td></tr><tr><td>colistin</td><td>1 (0.8 %)</td><td>8 (9.0 %)</td><td>2 (4.3 %)</td><td>0 (0.0 %)</td><td>NA<sup>b</sup></td><td>NA<sup>b</sup></td><td>7.0 %<sup>c</sup></td></tr><tr><td>aztreonam</td><td>71 (54.2 %)</td><td>45 (50.6 %)</td><td>25 (53.2 %)</td><td>11 (33.3<br>%)</td><td>NA<sup>b</sup></td><td>NA<sup>b</sup></td><td>63.9 %<sup>c</sup></td></tr><tr><td>ceftolozane-<br>tazobactam</td><td>12 (9.2 %)</td><td>26 (29.2 %)</td><td>12 (25.5 %)</td><td>5 (15.2 %)</td><td>NA<sup>b</sup></td><td>2 (50.0 %)</td><td>25.4 %<sup>c</sup></td></tr><tr><td>ceftazidime-<br>avibactam</td><td>6 (4.6 %)</td><td>9 (10.1 %)</td><td>3 (6.4 %)</td><td>2 (6.1 %)</td><td>NA<sup>b</sup></td><td>1 (25.0 %)</td><td>9.1 %<sup>c</sup></td></tr></tbody></table>

ESBL: extended spectrum β-lactamases.

a Multiple responses possible. b Not assessed c Not available for all strains d Non species-specific EUCAST breakpoints were used.

<caption>**Table 4**</caption>

CAZ-AVI patterns of use by indication, in the overall study population (n = 257).

<table><thead><tr><th rowspan="2"></th><th colspan="3">Type of infection<sup>a</sup></th><th rowspan="2">Other infections</th><th rowspan="2">Overall study<br>population<br>(n = 257)</th></tr><tr><th>Complicated intra-<br>abdominal infection<br>(n = 38)</th><th>Complicated urinary tract<br>infection (including<br>pyelonephritis)<br>(n = 45)</th><th>Nosocomial<br>pneumonia<br>(n = 88)</th><th>Infected site<br>specified<br>(n = 71)</th><th>Infected site<br>unspecified<br>(n = 28)</th></tr></thead><tbody><tr><td><strong>Line of treatment, n (%)</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>First line</td><td>9 (23.7)</td><td>18 (40.0)</td><td>19 (21.6)</td><td>25 (35.2)</td><td>7 (25.9)</td><td>73 (28.5)</td></tr><tr><td>Second line</td><td>12 (31.6)</td><td>18 (40.0)</td><td>42 (47.7)</td><td>30 (42.3)</td><td>14 (51.9)</td><td>112 (43.8)</td></tr><tr><td>Third line</td><td>14 (36.8)</td><td>8 (17.8)</td><td>21 (23.9)</td><td>13 (18.3)</td><td>5 (18.5)</td><td>57 (22.3)</td></tr><tr><td>Beyond third line</td><td>3 (7.9)</td><td>1 (2.2)</td><td>6 (6.8)</td><td>3 (4.2)</td><td>1 (3.7)</td><td>14 (5.5)</td></tr><tr><td>Missing data</td><td>0</td><td>0</td><td>0</td><td>0</td><td>1</td><td>1</td></tr><tr><td><strong>Treatment characteristics</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>3 x (2 g [ceftazidime] + 0.5 g<br>[avibactam]) per day, n (%)</td><td>33 (86.8)</td><td>27 (61.4)</td><td>63 (71.6)</td><td>54 (76.1)</td><td>24 (85.7)</td><td>190 (74.2)</td></tr><tr><td>2-hour infusion, n (%)</td><td>36 (94.7)</td><td>44 (97.8)</td><td>69 (80.2)</td><td>65 (91.5)</td><td>26 (92.9)</td><td>227 (89.0)</td></tr><tr><td>ceftazidime-avibactam alone (not<br>combined with another antibiotic),<br>n (%)</td><td>29 (76.3)</td><td>37 (82.2)</td><td>70 (79.5)</td><td>53 (74.6)</td><td>22 (78.6)</td><td>200 (77.8)</td></tr><tr><td>Duration of treatment, in days (SD)</td><td>20.4 (19.5)</td><td>14.4 (10.2)</td><td>10.0 (7.2)</td><td>21.6 (27.5)</td><td>11.3 (6.0)</td><td>15.6 (17.9)</td></tr></tbody></table>

SD: standard deviation.

a Patients can be classified with more than one type of infection, except for "Infected site unspecified".

### 3.4. Analysis of tolerance

During the study, 72 adverse events (AEs) possibly related to CAZ-AVI were reported in 43 patients (16.7 %), including 28 serious AEs (SAEs) in 16 (6.2 %) patients (3 infections due to *Clostridioides difficile*, 3 hepatobiliary disorders, 2 nervous system disorders, and 2 respiratory failures, in particular). One patient, classified as having non-nosocomial pulmonary infection, had a lung disorder with diminished respiratory function, considered related to treatment, that led to death.

### 4. Discussion

OZAVIE is one of the largest prospective real-world studies on CAZ-AVI post-marketing use. This study provides further evidence on the effectiveness and safety of CAZ-AVI in the main indications. It also provides exploratory data in other infection types and when CAZ-AVI is

combined with other antibiotics. We also collected microbiological data to assess bacterial resistance.

In our study, 66.5 % of patients received CAZ-AVI for cIAI, cUTI, or NP. In addition, 38.5 % of patients were prescribed CAZ-AVI for other infection sites, including bone and joints, vascular, and SSI. In nearly three quarters of the cases, CAZ-AVI was used as a single-drug regimen with the usually recommended dose. The mean duration of treatment ranged from 10.0 days for NP to 27.5 days for other infection sites.

The overall mortality rate at hospital discharge or 28 days after CAZ-AVI discontinuation was 20.2 % (ranging from 6.7 % for cUTI to 30.7 % for NP). This rate is close to that reported by the European and South-American real-world EZTEAM study assessing 516 patients treated with CAZ-AVI and reporting an in-hospital mortality rate of 23.1 %, a cumulative mortality rate 30 days after hospital discharge of 24.6 %, and an overall mortality rate of 28.2 % [7].

"Global success" was achieved in 79 % of patients and remained high
<table><caption>**Table 5**
CAZ-AVI effectiveness in the overall study population (n = 257, left) and in the microbiologically documented population (n = 252, right).</caption><thead><tr><th rowspan="2">Characteristics</th><th colspan="4">Type of infection<sup>a</sup></th><th rowspan="2">Overall study population (n = 257)</th><th colspan="4">Causal bacteria<sup>b</sup></th><th rowspan="2">Microbiologically documented population (n = 252)</th></tr><tr><th>Complicated intra-abdominal (n = 38)</th><th>Complicated urinary tract (n = 45)</th><th>Nosocomial pneumonia (n = 88)</th><th>Other infections</th><th>Compudomonas aeruginosa (n = 131)</th><th>Klebsiella spp. (n = 89)</th><th>Enterobacter spp. (n = 47)</th><th>Escherichia coli (n = 33)</th><th>Stenotrophomonas spp. (n = 18)</th><th>Acinetobacter spp. (n = 4)</th></tr></thead><tbody><tr><td>Deaths reported during the study</td><td>9 (23.7)</td><td>3 (6.7)</td><td>27 (30.7)</td><td>11 (15.5)</td><td>4 (14.3)</td><td>23 (17.6)</td><td>19 (21.3)</td><td>12 (25.5)</td><td>7 (21.2)</td><td>3 (16.7)</td><td>1 (25.0)</td><td>51 (20.2)</td></tr><tr><td>Response to treatment</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Failure</td><td>8 (21.1)</td><td>9 (20.0)</td><td>23 (26.1)</td><td>12 (16.9)</td><td>6 (21.4)</td><td>24 (18.3)</td><td>22 (24.7)</td><td>4 (8.5)</td><td>8 (24.2)</td><td>3 (16.7)</td><td>1 (25.0)</td><td>50 (19.8)</td></tr><tr><td>Global success</td><td>30 (78.9)</td><td>36 (80.0)</td><td>65 (73.9)</td><td>59 (83.1)</td><td>22 (78.6)</td><td>110 (81.7)</td><td>73 (75.3)</td><td>44 (91.5)</td><td>27 (75.8)</td><td>16 (83.3)</td><td>3 (75)</td><td>202 (80.2)</td></tr><tr><td>Therapeutic success</td><td>20 (52.6)</td><td>35 (77.8)</td><td>55 (62.5)</td><td>41 (57.7)</td><td>18 (64.3)</td><td>86 (65.6)</td><td>56 (62.9)</td><td>34 (72.3)</td><td>20 (60.6)</td><td>14 (77.8)</td><td>2 (50.0)</td><td>161 (63.9)</td></tr></tbody></table>

CAZ-AVI: ceftazidime-avibactam.

a Patients can be classified with more than one type of infection, except for "infected site unspecified."

b Multiple responses possible.

c 28 days after CAZ-AVI discontinuation or at hospital discharge.

irrespective of the type of infection. This success rate is similar to the 77.3 % success (with 11.6 % indeterminate) reported by the EZTEAM study [7] and with the 75.4 % clinical cure rate of a Chinese retrospective study on carbapenem-resistant GN bacterial infections [8]. Definitions of success may vary from one study to another and/or may not be clearly defined. Furthermore, it may be difficult to establish the causal relation between death and initial infection, or the role played by other antibiotics added later. OZAVIE's outcome definition thus considered these events, using a more stringent definition ("therapeutic success"), considering non-related deaths and additional antibiotics post-CAZ-AVI initiation as failures, regardless of underlying reasons. This success rate was 63.4 %. The rate difference between the two definitions reflects both the uncertainty of the causal relations previously discussed and the severity of underlying diseases.

The range of therapeutic success rates varied more widely than the rate of global success: from 52.6 % in cIAI to 77.8 % in cUTI. Therapeutic success rates were similar (around 60 %) in other clinical situations such as SSI, vascular, and bone and joint infections. In this latter indication, the 93.3 % global and 60 % therapeutic success rates we observed are in line with the 85.7 % in the main study providing data (n = 14) [9]. These findings underline the need for additional data in bone and joint infections, considering the limited number of patients and wide diversity of clinical situations.

Pseudomonas aeruginosa was the most common causative bacteria in OZAVIE (131 patients), unlike in the other published studies. Ceftolozane-tazobactam was not available in France at the time of the study, due to an international stockout, leading many clinicians to use CAZ-AVI in resistant Pseudomonas infections. The reported death rate in these patients (13.7 %) was slightly lower than those observed (17.5 % and 19.0 %) in two retrospective studies [9,10]. The global and therapeutic success rates (81.7 % and 65.6 %) suggest good clinical effectiveness of CAZ-AVI in P. aeruginosa infections, in line with the 74.3 % clinical success rate observed in EZTEAM [7]. These rates support international recommendations stating that CAZ-AVI is an option for P. aeruginosa infection with difficult-to-treat resistance [11,12].

Regarding Klebsiella spp. infections, the death rate we observed (21.3 %) seems slightly lower than that reported in the American Tumbarello et al. study (31.4 %) [13] and closer to the 20 % observed in the Greek study by Karaiskos et al. [14]. These data, as well as our global success rate of 75.3 % similar to the 79.5 % of the EZTEAM study [7], suggest that CAZ-AVI is a suitable therapeutic option in Klebsiella spp. infections.

Enterobacter spp. was the third bacterial species in the OZAVIE study (n = 47), while data on clinical effectiveness in such infections are scarce. The clinical success rates of 85 % in EZTEAM [7] is within the range of 72.3 % (therapeutic success) and 91.5 % (global success) we reported in OZAVIE.

Nevertheless, CAZ-AVI combination cannot be considered as an interesting treatment option for Acinetobacter spp., and CAZ-AVI should not be used without aztreonam to treat Stenotrophomonas maltophilia infections, as stated in international recommendations [11,12].

Out of the 19 patients with metallo-β-lactamases-producing bacteria, 12 were treated with CAZ-AVI and aztreonam. Since AVI does not inhibit metallo-β-lactamases (class B) [15,16], adding aztreonam to CAZ-AVI may further overcome this resistance [16–20]. The 91.7 % and 66.7 % global and therapeutic success rates we observed for these difficult-to-treat bacteria seem to support the potential clinical interest of such co-administration, as reported by other authors [21,22]. However, the limited sample size and the inability to distinguish the subtypes of metallo-β-lactamases involved, necessary to interpret the data, do not allow to draw any formal conclusion on this subgroup of patients.

Fourteen patients (5.4 %) had bacteria resistant to CAZ-AVI after being treated with CAZ-AVI. Despite the difficulty in distinguishing on-treatment emergence of bacterial resistance from pre-existing resistance, this 5.4 % resistance rate is within the 0 %-21.6 % previously reported [23–27]. The risk of resistance emergence appears higher with Klebsiella
pneumonia producing KPC 2 or 3 [24,28], or in case of prior carbapenems or CAZ-AVI treatment [27], and/or with antibiotic treatments beyond 15 days [23,24]. Considering that i) systematic sampling was not performed in OZAVIE, potentially leading to an underestimation of this risk, and ii) the paucity of alternative antibiotics in cases of resistance, our results suggest robust analysis of susceptibility to CAZ-AVI before and after treatment, particularly in patients at high resistance risk, as recommended [11,12].

## 5. Conclusion

OZAVIE confirms that CAZ-AVI is a reliable option to treat MDR-GNB infections in real-life settings, with clinical success rates ranging from 63.4%, using a stringent definition, to 79% with a broader one, and a good safety profile. The wide variety of clinical and bacterial situations covered is both its strength and its limit, not allowing to draw firm conclusions for each situation. Nonetheless, this study provides additional data, particularly in bone and joint and *P. aeruginosa* or *Enterobacter* spp. infections, for which data remain scarce. It also raises the issue of the ecological impact, which needs to be systematically assessed in further studies. Finally, our study confirms the interest of CAZ-AVI in the therapeutic strategy of patients with MDR-GNB infections and helps better define this strategy.

Contributions of authors

Lionel Piroth contributed to the design of the study, included patients, analyzed the data, and wrote the manuscript.

Virginie Vitrat contributed to the design of the study, included patients, and reviewed the manuscript.

Vincent Le Moing contributed to the design of the study, included patients, and reviewed the manuscript.

Philippe Bret contributed to the design of the study and reviewed the manuscript.

Yves Brault contributed to the design of the study and reviewed the manuscript.

William Greenwood contributed to the design of the study and reviewed the manuscript.

Marie-Charlotte Chopin included patients and reviewed the manuscript.

Eric Vicaut contributed to the design of the study and reviewed the manuscript.

Philippe Montravers contributed to the design of the study, included patients, and reviewed the manuscript.

Pierre Tattevin contributed to the design of the study, included patients, and reviewed the manuscript.

Alexandre Bleibtreu included patients and reviewed the manuscript.

Ethical statement.

OZAVIE was approved by the French ethics committee: "Comité de Protection des Personnes 18.12.102 / SI CNRIPH n° 18.11.14.48352" (National N°: 2021-A00199-32). It was conducted in compliance with national and European laws and regulations.

Data sharing statement

Upon request, and subject to certain criteria, conditions and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines, and

medical devices (1) for indications that have been approved in the US and/or EU or (2) in programs that have been terminated (i.e., development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.

Transparency declarations

Lionel Piroth: contribution to scientific committee for Pfizer.

Virginie Vitrat: conference invitations by Pfizer.

Vincent Le Moing: consulting fees from Pfizer and honoraria for lectures from Advanz Pharma and Pfizer.

Marie-Charlotte Chopin: honoraria for lectures and presentations from Astellas and Pfizer.

Eric Vicaut: none to declare.

Philippe Montravers: consulting fees from Pfizer, MSD, Mundipharma and Viatris and honoraria for lectures and presentations from Menarini, Unyvero, Pfizer, and Viatris.

Pierre Tattevin: contribution to scientific committees for MSD, Shionogi, Advanz Pharma, and Pfizer.

Alexandre Bleibtreu: none to declare.

## Funding

The OZAVIE study was funded by Pfizer, but no payments or honoraria were made to the authors with respect to manuscript preparation.

## Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

## Acknowledgements

We extend our gratitude to the following individuals and groups for their valuable contributions to this research:

- Patients and their families: we express our heartfelt thanks to the patients who participated in this research and their families.

- SPILF Cooperative Group and RENARCI network: their collaboration and support were instrumental in the success of this study.

- Physicians and research teams at participating centers: we acknowledge the dedication and hard work of the physicians, healthcare teams, and research staff at the 41 participating centers (listed in appendix). Their commitment to advancing medical knowledge is commendable.

- Trevor Stanbury (Pro-Pens): we appreciate Trevor Stanbury's medical writing services, which significantly enhanced the quality of this article.

- Hugo Caillou (Excelya): we extend our gratitude to Hugo Caillou for his invaluable assistance throughout this research endeavor.

## Appendix

Centers and principal investigators who took part in the OZAVIE study (alphabetical order)
<table><thead><tr><td>ANGERS</td><td>DUBEE</td><td>Vincent</td></tr></thead><tbody><tr><td>ANNECY</td><td>VITRAT</td><td>Virginie</td></tr><tr><td>AVICENNE</td><td>MÉCHAÎ</td><td>Frédéric</td></tr><tr><td>AVIGNON</td><td>MONTINI</td><td>Florent</td></tr><tr><td>BAYONNE</td><td>VAREIL</td><td>Marc-Olivier</td></tr><tr><td>BEAUJON</td><td>DE LASTOURS</td><td>Victoire</td></tr><tr><td>BICHAT</td><td>LESCURE</td><td>François-Xavier</td></tr><tr><td>BICHAT</td><td>TIMSIT</td><td>Jean-François</td></tr><tr><td>BICHAT</td><td>MONTRAVERS</td><td>Philippe</td></tr><tr><td>BORDEAUX</td><td>NEAU</td><td>Didier</td></tr><tr><td>BREST</td><td>QUESAET</td><td>Luc</td></tr><tr><td>CAEN</td><td>ETHUIN</td><td>Frédéric</td></tr><tr><td>CHAMBERY</td><td>FORESTIER</td><td>Emmanuel</td></tr><tr><td>CLERMONT-FERRAND</td><td>DUPUIS</td><td>Claire</td></tr><tr><td>COCHIN</td><td>CANOUI</td><td>Etienne</td></tr><tr><td>COLMAR</td><td>MARTINOT</td><td>Martin</td></tr><tr><td>DIACONNESSES</td><td>MEYSSONNIER</td><td>Vanina</td></tr><tr><td>DIJON</td><td>PIROTH</td><td>Lionel</td></tr><tr><td>GARCHES</td><td>DINH</td><td>Aurélien</td></tr><tr><td>GRENOBLE</td><td>PAVESE</td><td>Patricia</td></tr><tr><td>KREMLIN-BICETRE</td><td>ESCAUT</td><td>Lélia</td></tr><tr><td>LA PITIE SALPETRIERE</td><td>BLEIBTREU</td><td>Alexandre</td></tr><tr><td>LA ROCHE SUR YON</td><td>GUIMARD</td><td>Thomas</td></tr><tr><td>LILLE</td><td>CHOPIN</td><td>Marie-Charlotte</td></tr><tr><td>LIMOGES</td><td>CYPIERRE</td><td>Anne</td></tr><tr><td>LYON</td><td>FERRY</td><td>Tristan</td></tr><tr><td>MARSEILLE</td><td>FOREL</td><td>Jean-Marie</td></tr><tr><td>MONTPELLIER</td><td>LE MOING</td><td>Vincent</td></tr><tr><td>NANTES</td><td>GABORIT</td><td>Benjamin</td></tr><tr><td>NICE</td><td>DELLAMONICA</td><td>Jean</td></tr><tr><td>PAU</td><td>DESTIZONS</td><td>Audrey</td></tr><tr><td>PERIGUEUX</td><td>ZABBE</td><td>Jean-Benoît</td></tr><tr><td>POITIERS</td><td>LE MOAL</td><td>Gwénaël</td></tr><tr><td>QUIMPER</td><td>TALARMIN</td><td>Jean-Philippe</td></tr><tr><td>SAINT ANTOINE</td><td>SURGERS</td><td>Laure</td></tr><tr><td>SAINT LOUIS</td><td>LAFAURIE</td><td>Matthieu</td></tr><tr><td>ST PRIEST EN JAREZ</td><td>LUTZ</td><td>Marie-France</td></tr><tr><td>STRASBOURG</td><td>SCHNEIDER</td><td>Francis</td></tr><tr><td>TOULOUSE</td><td>MARTIN-BLONDEL</td><td>Guillaume</td></tr><tr><td>TOURCOING</td><td>ALFANDARI</td><td>Serge</td></tr><tr><td>TOURS</td><td>BERNARD</td><td>Louis</td></tr></tbody></table>

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