Ticarcillin

Cases were identified by data extraction from the Pathology North and Pathology Queensland laboratory information systems (AUSLAB; PJA, Melbourne). Clinical and demographic data on all significant bloodstream infections were prospectively collected as routine surveillance by the infection control and microbiology services. Relapsed cases were retrospectively identified from laboratory data. Outcomes were determined at 28 days post initial positive blood culture for all cases and controls.
In addition to demographic details, clinical variables recorded included source of infection, hospital location, co-morbid conditions, admitting clinical service, acquisition status of infection, initial antibiogram of the blood culture isolate (AmpC de-repressed phenotype), the presence of vascular access devices and the neutrophil count on the day of first positive blood culture. Data on antibiotic use and SAPS II physiology scores [26 (link)] (determined on the day of first positive blood culture) were recorded from clinical chart review. Only antimicrobial agents with Gram-negative activity were recorded, with those used within the first 48 h after initial blood culture defined as empirical use and those prescribed after blood culture results available defined as definitive use. Healthcare acquisition and source designation of the bacteraemia were categorised according to standard definitions [27 –29 ]. Empirical antibiotic therapy was described as appropriate if the isolate was susceptible to at least one agent used. If an agent was used for ≥50% of the definitive treatment duration, this was listed as the primary agent. If a second agent was used either concurrently or sequentially, the patient was described as receiving combination therapy; if combination therapy was used for the majority of the definitive treatment duration the antibiotic choice was determined as ‘other’. For statistical analysis, if the definitive regimen included a carbapenem, quinolone, co-trimoxazole, cefepime or an aminoglycoside to which the isolate was susceptible, the treatment was classified as ‘standard therapy’, if piperacillin-tazobactam or ticarcillin-clavulanate was used and the isolate was susceptible, the treatment was classified as ‘BLBLI’, otherwise the treatment was defined as ‘inappropriate’ (e.g. cephalexin, cephazolin, ceftriaxone, ampicillin/amoxicillin, amoxicillin-clavulanate or no therapy). Standard dosing regimens at participating hospitals for piperacillin-tazobactam are 4.5 g 8-hourly and ticarcillin-clavulanate 3.1 g 6-hourly, with dose adjustment for renal dysfunction according to the Australian Therapeutic Guidelines [30 ]. Patients were classified as being immunosuppressed if they had the following conditions: neutropenia (neutrophil count <0.5 x10⁹/L), haematological / solid organ malignancy or myelodysplastic syndrome, solid organ transplant or if they received any other immunosuppressive drug therapy including prolonged high dose corticosteroids (≥30 mg prednisolone or equivalent daily).

Seventeen clinical isolates of A. baumannii were characterized in this study. Strains were chosen from diverse anatomical origin and from a wide range of disease presentations including urinary tract, respiratory, wound, intra-abdominal infections, and bacteremia. Strains were collected in this pilot study from January of 2010 through August of 2012. Antimicrobial susceptibility to ampicillin-sulbactam (A/S), amikacin (AK), ceftriaxone (CAX), ceftazidime (CAZ), cefotaxime (CFT), ciprofloxacin (CP), cefepime (CPE), gentamicin (GM), levofloxacin (LVX), meropenem (MER), piperacillin (PI), trimethoprim-sulfamethoxazole (T/S), tetracycline (TE), ticarcillin-K clavulanate (TIM), and tobramycin (TO) was determined at the Nashville General Hospital clinical laboratory and values of “susceptible”, “non-susceptible” or “intermediate” per International Organization for Standardization (ISO) 20776–1:2019 guidelines, was determined [18 (link)]. A bacterial strain was considered “susceptible” when it was inhibited in vitro by a concentration of drug that is associated with a high likelihood of therapeutic success. An “intermediate” designation indicated the strain had variable inhibition in vitro, or was inhibited by a concentration of drug that is associated with an uncertain therapeutic effect. And strains were designated resistant or “non-susceptible” to a given antibiotic when the strain was not inhibited in vitro by a concentration of drug that is associated with therapeutic success. Additionally, anatomical site source of culture were retrieved in a de-identified manner from the electronic medical record system. Approval to characterize the de-identified bacterial isolates was provided by the affiliated Meharry Medical College Institutional Review Board (IRB 081204AAH23119). Reference laboratory strains of A. baumannii including 17978 and the 19606 T type strain (ATCC, Manassas, Virginia) from patients with meningitis and urinary tract infection, respectively, were also evaluated for comparison. All bacterial strains were stored as glycerol stock at -80 °C until use. All isolates were grown in Luria-Bertani (LB) broth at 37 °C in room air under shaking conditions overnight at 180 rpm to an optical density of 600 nm (OD₆₀₀) between 0.8–1.0.

High-risk pathogens were defined as multi-drug resistant (MDR) organisms, which were clustered into four classes: methicillin-resistant Staphylococcus aureus (MRSA), extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales, AmpC-overexpressing Enterobacterales, and Pseudomonas aeruginosa resistant to ticarcillin, imipenem, and/or ceftazidime. Carbapenemase-producing Enterobacterales (CPE), as well as carbapenem-resistant and carbapenemase-producing non-fermenting Gram-negative bacteria (NF-GNB) (Acinetobacter baumanii, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia), were considered difficult-to-treat pathogens.
In each center, the patients had a systematic screening for ESBL Enterobacterales at ICU admission and at least once a week [21 (link),22 (link)]. No systematic screening for other MDR organism carriage was performed. A patient was considered colonized if one of these microorganisms was isolated from their screening sample (perirectal area, nose, any screening sample, or any sample performed because of clinical symptoms).

Available data were extracted for all 180 strains from the laboratory software (TD-Synergy TECHNIDATA, Montbonnot-Saint-Martin, France), including the year, origin and type of sampling, hospital ward, and carbapenemase-expressing status. In addition, patient information was retrospectively collected, including the patient gender, age, presence of comorbidities, immune status, whether it was a P. aeruginosa infection or colonization, whether or not death occurred (P. aeruginosa-related or not), and antipseudomonal antibiotic therapy administered during hospitalization (before and after P. aeruginosa identification). According to the European Committee on Antimicrobial Susceptibility Testing (EUCAST), the following drugs were considered active against P. aeruginosa for medical use: antipseudomonal penicillins (ticarcillin, ticarcillin-clavulanic acid, piperacillin, and piperacillin-tazobactam), carbapenems (doripenem, imipenem, imipenem-relebactam, meropenem, and meropenem-vaborbactam), monobactams (aztreonam), 3rd- and 4th-generation cephalosporins (cefepime, cefiderocol, ceftazidime, ceftazidime-avibactam, and ceftolozane-tazobactam), aminoglycosides (amikacin, gentamicin, netilmicin, and tobramycin), fluoroquinolones (levofloxacin, ciprofloxacin), fosfomycin and polymyxins (colistin and polymyxin B)⁴⁹ . The P strain P. aeruginosa acquisition type was also determined: community (i.e., the acquisition occurred before or during the first 48 h of hospitalization) or hospital acquired. The Charlson comorbidity index score was calculated using the available tool at https://www.rdplf.org/calculated^{50 (link)}.