A Meta-Analysis on Clinical Outcomes of Ceftolozane versus Piperacillin in Combination with Tazobactam in Patients with Complicated Urinary Tract Infections

Table 1

Characteristics of study.

	Wagenlehner et al., 2015	Kaye et al., 2018	Kaye et al., 2019	Seo et al., 2017	Arakawa et al., 2015	Osornio et al., 1997	Basetti et al., 2020
Methods	Prospective RCT; Double blind; Computer generated randomization; Intention to treat	Prospective RCT; Double blind; Dynamic randomization algorithm and voice/web system; Intention-to-treat analysis	Prospective RCT; Randomization was by ratio 1 : 1; Intention-to-treat analysis	Prospective RCT; Randomization was done at each center; A laboratory center monitored the balance in sample size; Intention-to-treat analysis	Prospective; Longitudinal cohort study; No comparative open-label study	Retrospective multicenter study where patients were treated with piperacillin/tazobactam	Prospective; Longitudinal cohort study; No comparative open-label study
Participants	Inclusion criteria; Number: 398 (group 1), 402 (group 2); Gender (M/F): unknown; Age: >18 years; Clinical symptoms of severe UTI requiring parenteral antibiotic therapy and a positive (, dysuria, flank pain, costovertebral tenderness, nausea, or vomiting) urine culture (pyuria: in unspun urine or ≥10/μL per high power field in spun urine); Exclusion criteria; Cases of allergy, severe underlying disease, renal impairment, pregnancy, urinary tract obstruction, concomitant infection, receipt of any dose prior to trial, intractable urinary tract infection, confirmed fungal urinary tract infection, suspected or confirmed prostatitis or intrarenal abscesses, permanent indwelling bladder catheter, immunocompromised conditions	Inclusion criteria; Number: 233 (group 1), 231 (group 2); Gender (M/F): unknown; Age: >18 years; Clinical symptoms of severe UTI requiring parenteral antibiotic therapy and a positive (, dysuria, flank pain, costovertebral tenderness, nausea, or vomiting) urine culture (pyuria: in unspun urine or ≥10/μL per high power field in spun urine); Exclusion criteria; Cases of allergy, severe underlying disease, renal impairment, pregnancy, urinary tract obstruction	Inclusion criteria; Number: 178 (group 1), 169 (group 2); Gender (M/F): unknown; Age: >18 years; Clinical symptoms of severe UTI requiring parenteral antibiotic therapy and a positive (, dysuria, flank pain, costovertebral tenderness, nausea, or vomiting) urine culture (pyuria: in unspun urine or ≥10/μL per high power field in spun urine); Exclusion criteria; Cases of allergy, severe underlying disease, renal impairment, pregnancy, urinary tract obstruction, nonrenal source of infection, severe sepsis, immunosuppressive medications, uncomplicated UTI	Inclusion criteria; Number: 33 (group 1), 33 (group 2), 6 (group 3); Gender (M/F): 30 F (group 1), 26 F (group 2), 3 F (group 3); Age: >18 years; Hospital-associated UTI; Clinical symptoms of severe UTI requiring parenteral antibiotic therapy and a positive (, dysuria, flank pain, costovertebral tenderness, nausea, or vomiting) urine culture (pyuria: in unspun urine or ≥10/μL per high power field in spun urine); Exclusion criteria; Presence of suspicious or confirmatory infectious foci other than urinary tract infection, any use of antibiotics within seven days prior to recruitment for any reasons, any complicating urinary factors which could not be effectively treated during trial (obstruction, suspected or confirmed prostatitis, epididymitis), indwelling urinary catheters expected to remain in place after therapy has been completed, and need for renal replacement therapy	Inclusion criteria; Number: 115; Males or gender (M/F); cUTI or acute pyelonephritis who need hospitalization and need antibacterial IV therapy; Exclusion criteria; History of recent or recurrent gram-positive organism UTI suggesting colonization, moderate or severe hypersensitivity, or allergic reaction to any beta-lactam antibacterial, receiving probenecid, has received any amount of potentially therapeutic antibacterial therapy after collection of the pretreatment baseline urine culture, complete, permanent obstruction of the urinary tract, confirmed fungal urinary tract infection at time of randomization	Inclusion criteria; Number: 79; Gender (M/F); Data were recorded: age and sex, underlying diseases according to Charlson comorbidity index, type of infection, presence of sepsis or septic shock at the time of the infection, susceptibility pattern of ESBL-E isolates, date of start and end of C/T therapy, source control of infection, when applicable, other antibiotics administered before, concomitant to, and after C/T therapy, reasons for C/T use, dosage(s) of C/T and length of therapy, adverse events (AEs), clinical outcome, and recurrence of infection	Inclusion criteria; Number: 153; Gender (M/F); Data were recorded: age and sex, with clinical and microbiological evidence of UTI caused by microorganism susceptible to piperacillin/tazobactam, have clinical symptoms (, chills, flank pain, dysuria costovertebral tenderness, nausea, or vomiting); Urine culture (pyuria: , peripheral with >5% bands); Exclusion criteria; Patient allergic to beta-lactams or beta-lactamase inhibitors, an FiO2 60% at maintaining aerial hemoglobin oxygen saturation to 90%, septic shock, endoscopic prostatic resection, use of antibiotic within 72 hours, presence of resistance strain, thrombocytopenia, creatinine clearance less than <40 mL/min, peritoneal dialysis, serum concentration of aminotransferase or bilirubin to be twice the normal value
Interventions	Treatment group 1; Ceftolozane/tazobactam 1.5 g every 8 hours IV for 7 days; Treatment group 2; Levofloxacin 750 mg once daily IV for 7 days	Treatment group 1; Meropenem vaborbactam 4 g in 250 mL normal saline IV administer over 3 hours every 8 hours followed by 100 mL saline over 30 minutes every 8 hours; Treatment group 2; Piperacillin-tazobactam 4.5 g in 250 mL normal saline IV administer over 30 minutes every 8 hours Levofloxacin 500 mg once daily for 10 days after 15 doses of piperacillin-tazobactam, if clinically indicated; Cointervention; Both groups received levofloxacin 500 mg oral once daily after 15 doses of each intervention	Treatment group 1; Fosfomycin 6 g IV administered every 8 hours for 7 to 14 days; Treatment group 2; Piperacillin-tazobactam 4.5 g IV administered every 8 hours for 7 to 14 days	Treatment group 1; Piperacillin/tazobactam 4.5 g q 6 hours for 10-14 days; Treatment group 2; Ertapenem 1 g, IV q 24 hours for 10-14 days; Treatment group 3; Cefepime 2 g, IV q 12 hours for 10-14 days	Treatment group; 1.5 g (ceftolozane 1 g/tazobactam 0.5 g) administered as an intravenous (IV) infusion every 8 hours for 7 days	Treatment group; Piperacillin-tazobactam 4.5 g IV administered every 8 hours for 10 to 14 days	Treatment group; Ceftolozane 1 g/tazobactam 0.5 g administered as intravenous infusion every 8 hours
Outcomes	Clinical and microbiological eradication outcomes at test of cure visit in the mMITT population (test of cure visit 7 days after the completion of study drug administration); Clinical and microbiological eradication outcomes at test of cure visit in the microbiological evaluation population (test of cure visit 7 days after the completion of study drug administration)	(1) Proportion of participants in the microbiological modified intent-to-treat (m-MITT) population who achieved overall success at the end of intravenous treatment visit (time frame: EOIVT (days 5-14)); (2) Proportion of participants in the m-MITT population who achieved a microbiologic outcome of eradication at the test of cure visit (time frame: test of cure (TOC) (days 15-23)); Proportion of participants in the microbiological evaluable (ME) population who achieved a microbiologic outcome of eradication at the TOC visit (time frame: TOC (days 15-23))	(1) Number of patients with an overall success (time frame: TOC visit (day 19)); (2) Number of patients with a response of clinical cure in various protocol populations (time frame: TOC visit (day 19)); (3) Number of patients with a response of microbiologic eradication (time frame: TOC visit (day 19))	(1) Clinical improvement rate (time frame: 3-5 days after treatment); (2) Microbiological eradication rate (time frame: 10-14 days after treatment)	(1) Percentage of participants with microbiological response (eradication, persistence, or indeterminate) at test of cure (TOC) (time frame: up to 14 days after the first dose of study drug (up to 14 days)); (2) Percentage of participants with adverse events (AEs) (time frame: from time of the first dose of study drug until the end of follow-up (up to 42 days)); (3) Percentage of participants discontinuing study drug due to AEs [time frame: Up to 7 days after the first dose of study drug (up to 7 days)]	(1) Clinical failure was defined as either lack of clinical response or recurrence or attributable mortality due to ESBL-E infection; (2) Clinical failure was confirmed by (a) 30-day mortality, (b) ongoing fever after 5 days of therapy, (c) persistence of leukocytosis after 5 days of therapy, and (d) presence, after 5 days of therapy, of clinical signs of infection that could not be attributed to causes other than ESBL-E infection	(1) Patients treated with piperacillin/tazobactam are said to be cured if the patient was asymptomatic without any evidence of active infection at the end of treatment (time frame: 5-9 days after treatment for early evaluation and 4-6 weeks after termination of therapy); (2) Improvement of a posttherapy evaluation but without complete resolution of symptoms; (3) Relapse, initial improvement during first 3-4 days of treatment followed by deterioration during therapy or at the posttreatment evaluation (5-9 days)
Notes	Of 1083 patients who met the inclusion criteria, 800 were enrolled (16 received no study drug); Two hundred sixty-eight patients were excluded after randomization because urine culture was negative; Thirty-one (group 1) and forty-two (group 2) were lost to follow-up; Three in each group were without cUTI diagnosis; Seven (group 1) and five (group 2) received nonstudy antibiotic; Four (group 1) and nine (group 2) did not adhere to study treatment; Three (group 1) and one (group 2) catheter not removed by the end of treatment	Of 585 patients who met the inclusion criteria, 550 were enrolled (23 did not met inclusion and exclusion criteria, 7 withdrew consent, and 5 other reasons); Five patients were excluded after randomization because they did not receive study drug; Thirty-one (group 1) and forty-two (group 2) were lost to follow-up; Twenty-three (group 1) and thirty-eight (group 2) discontinued treatment; Fourteen (group 1) and twenty-three (group 2) discontinued study; Eighty (group 1) and ninety-one (group 2) no baseline pathogens	Of 465 patients who met the inclusion criteria, 464 were enrolled (1 did not get the study drug); Twelve (group 1) and two (group 2) did not complete the study; Fourteen (group 1) and nine (group 2) discontinued the study	(1) If any participant receiving randomized drug dropped out, the drug was given to the next participant; (2) Recruitment in group 3 was stopped after 6 participants due to high risk of therapy failure	Out of 115 patients who met the inclusion criteria, 112 completed the study (1 withdrew consent while 2 physician decided)	No dropouts were there as it was a retrospective study	Out of 79 patients, 61 patients were included in clinical and bacteriological evaluation. 6 were excluded due to abnormal baseline aminotransferase, 3 were excluded due to inappropriate drug regimen, 1 was excluded due to the presence of resistant pathogen, 2 were excluded due to the previous antibiotic use