Search Results
The search of PubMed and Science Direct provided 199 citations. Of these, 154 studies were excluded following review of the abstracts, as they did not meet the inclusion criteria. Twenty articles were discarded after reviewing the full article due to the following reasons: non-human (n=2), on non-critically ill (n=10) and children (n=8) subjects. A further four studies were eliminated due to the focus being on pharmacoeconomics and renal replacement therapy.
An additional two studies that met the inclusion criteria were acknowledged through checking references of relevant studies. Twenty-three studies met the described inclusion criteria and were included in the systematic review (13,14,23–32,15,33,34,16–22). The article selection process is illustrated in Figure.1 and selected studies comparing clinical outcome between CI and II of piperacillin are listed in Table.2. Characteristics of included studies comprising of demographic characteristics, C/PI and II dosage, drug regimen treatment results as well as study outcomes and suggestions were extracted from all studies and summarised (Table 2). Out of the twenty-three studies included, only an abstract (and no full article) could be obtained for four of the studies (19,20,25,26).
Definitions
‘Clinical cure’ was defined as ‘the complete resolution of clinical signs and symptoms of infection, with no new signs or symptoms associated with the original infection’ (32,35).
‘Microbiological cure’ was defined as ‘the eradication and presumed eradication of organisms at the infection site’ (35).
‘Adverse events’ were defined as ‘any unexpected medical occurrences in patients administered piperacillin-tazobactam caused by either the drug or dosing regimen being received’ (35).
Study Characteristics
The type of studies included in the systematic review and meta-analysis were RCT’s (n=10), observational cohort studies (n=12; retrospective n=10, prospective n=2) and a Quasi-experimental study (non-randomised trial) (n=1).
Table 2 Characteristics of studies comparing outcomes for continuous versus intermittent infusions of piperacillin-tazobactam
Study
|
Study Design/Patient Population
|
Age (avg)
|
Gender
|
Dosage
|
Clinical Cure n/N (%)
|
Mortality n/N (%)
|
Outcome/Suggestions
|
Grants et al. 2002 (13)
USA
|
Prospective cohort study
98 ICU patients
|
CI - 66
II – 65
|
F - 37
M - 61
|
CI (n=47) – 2.25g LD + 9g DD over 24h CI
II (n=51) – 3.375g every 6h over 30 min II
|
CI- 44/47 (94%)
II- 42/51 (82%)
|
CI- 1/47 (2.1%)
II- 5/51 (9.8%)
|
CI provided equivalent clinical and microbiologic to II. CI is a cost-effective alternative to II. CI is well tolerated resulting in CC.
|
Lau et al.
2006 (14)
USA
|
Randomised control trial
167 patients with gram +/- bacteria
|
CI – NR
II – NR
|
F - NR
M - NR
|
CI (n=81) – 13.5g over 24h CI
II (n=86) - 3.375g every 6hrs over 30 min II
|
CI- 70/81 (86%)
II- 76/86 (88%)
|
CI- 1/130 (0.8%)
II- 3/132 (2.3%)
|
CI are a same and reasonable alternate mode of administration. No differences in bacteriological response by pathogen was noted between CI and II.
|
Rafati et al.
2006 (15)
Iran
|
Randomised control trial
40 Septic, critically ill patients
|
CI - 50.1
II – 48
|
F - 13
M - 27
|
CI (n=20) – 2.25g LD + 9g DD over 24h CI
II (n=20) – 3.375g every 6h over 30 min II
|
CI- 15/20 (75%)
II- 16/20 (70%)
|
CI- 5/20 (25%)
II- 6/20 (30%)
|
Clinical efficacy as a CI is superior to that with II. CI significantly reduces severity of illness resulting in clinical cure.
|
Lodise et al. 2007 (16)
USA
|
Retrospective cohort Study
194 ICU patients with Pa
|
PI - 63.2
II – 63.2
|
F - 75
M - 119
|
PI (n=102) – 3.375g every 8hrs over 4hr PI
II (n=92) - 3.375g every 4-6hrs over 30 min II
|
PI- NR
II- NR
|
PI- 5/41 (12.2%)
II-12/92 (13%)
|
No difference in baseline clinical characteristics were noted between the two dosing regimens, however, mortality rates were significantly lower with PI.
|
Roberts et al. 2009 (17)
Austrailia
|
(*) Randomised control trial
16 Critically ill adult patients
|
CI - 30
II – 41
|
F - 5
M - 11
|
CI (n=8) – 4.5g LD + 9g DD over 24h CI
II (n=8) – 4g every 6-8h over 20 min II
|
CI- 8/8 (100%)
II- 8/8 (100%)
|
CI- 0/8 (0%)
II- 0/8 (0%)
|
Administration by CI with initial loading dose achieves superior PD target and CC when compared with conventional II
|
Lorente et al. 2009 (18)
Spain
|
(*) Retrospective cohort study
83 ICU patients suffering VAP
|
CI - 63.2
II – 61.8
|
F - 18
M - 65
|
CI (n=37) – 4.5g LD + 18g DD over 24h CI
II (n=46) – 4g every 6h over 30 min II
|
CI- 33/37 (89.2%)
II- 26/46 (56.2%)
|
CI- 8/37 (21%)
II- 14/46 (30.4%)
|
Higher clinical efficacy achieved by continuous infusion. Higher DD reached target concentration for pathogens with higher MIC’s
|
Li et al.
2010 (19)
China
|
Randomised control trial
66 patients with severe pneumonia
|
PI – NR
II – NR
|
F - NR
M - NR
|
CI (n=28) - 4.5g every 8 hrs over 8hr CI
II (n=31)- 4.5g every 8hrs over 30 min II
|
CI- 24/32 (75%)
II- 17/34 (50%)
|
CI- NR
II- NR
|
Results obtained from the study suggest clinical advantages of CI compared with II administration in patients suffering with severe pneumonia.
|
Rose et al.
2011 (36)
USA
|
Retrospective cohort study
90 ICU patients
|
PI - 58.4
II – 60.4
|
F - 13
M - 77
|
PI (n=54) – 3.375g every 8-12 hrs over 4hr PI
II (n=36) - 3.375g every 8-12 hrs over 30 min II
|
PI- NR
II- NR
|
CI- NR
II- NR
|
PI reduced: (1) days of therapy in ICU, (2) time spent on ventilator, (3) length of ICU and hospital stay and, (4) mortality.
|
Ye et al.
2011 (20)
China
|
Randomised control trial
66 ICU patients, gram (–) bacteria
|
PI – NR
II – NR
|
F - NR
M - NR
|
PI (n=35) - 4.5g every 8hrs over a 3h PI
II (n=31) – 4.5g every 8hrs over 30 min II
|
PI- 24/35 (68.6%)
II- 13/31 (41.9%)
|
PI- 8/35 (22.9%)
II- 8/31 (25.8%)
|
Prolonged infusion is superior to traditional regimens and should be recommended as empirical therapy for gram (-) bacteria
|
Yost et al.
2011 (21)
USA
|
Retrospective cohort study
270 ICU patients with Pa
|
PI - 65
II – 62
|
F - 129
M - 141
|
PI (n=186) - 3.375g every 8 hrs over 4hr PI
II (n=84) - dose not recorded, 30 min II
|
PI- 171/186 (90.3%)
II- 67/84 (79.8%)
|
PI- 18/186 (9.7%)
II- 17/84 (20.2%)
|
Pharmacodynamic dosing via PI’s of piperacillin-tazobactam demonstrated positive outcome compared with II. PRT need to further verify findings.
|
Fahmi et al. 2012 (22)
|
Quasi experimental study
61 ICU patients with VAP
|
PI – NR
II – NR
|
F - NR
M - NR
|
PI (n=31) – 3.375g every 8hrs over a 4h PI
II (n=30) - 3.375g every 6hr over 30 min II
|
PI- NR
II- NR
|
PI- NR
II- NR
|
No significant difference in clinical outcome of PI and II. Suggest administration by PI or II according to MIC of organism.
|
Pereira et al. 2012 (23)
Portugal
|
Retrospective cohort study
346 ICU patients
|
CI – NR
II – NR
|
F - NR
M - NR
|
CI (n= 173) – Majority 18g DD, every 8hr
II (n=173) – Majority 18g DD, 30 min II
|
CI- 124/173 (71.7%)
II- 124/173 (71.7%)
|
CI- 49/173 (28.3%)
II- 49/173 (28.3%)
|
Clinical efficacy of piperacillin-tazobactam dosing was independent of the mode of administration. CI is not associated with a decrease in mortality.
|
Lee et al.
2012 (24)
USA
|
Retrospective cohort study
148 ICU patients
|
PI – 64
II – 69.6
|
F - 64
M - 84
|
PI (n=68) – 3.375g every 8hrs over 4hr PI
II (n=80)- 2.25g every 6hr over 30 min II
|
PI- 55/68 (81%)
II- 50/80 (62%)
|
PI- 13/68 (19.1%)
II- 30/80 (37.5%)
|
Results suggest improved 30-day mortality in ICU patients treated via PI vs CI. Clinical benefits of PI at lower MIC’s are less substantial compared with more RO.
|
Waxier et al. 2012 (25)
-
|
Retrospective cohort study
400 ICU patients
|
PI – NR
II – NR
|
F - NR
M - NR
|
PI (n=200) - dose not recorded, over 4hr PI
II (n=200) - dose not recorded, over 30 min II
|
PI- NR
II- NR
|
PI- NR
II- NR
|
PI patients received fewer doses and demonstrated decreased morbidity and mortality; results however are not SS so larger prospective studies are needed.
|
Lu et al.
2013 (26)
China
|
Randomized control trial
50 patients with HAP
|
PI – NR
II – NR
|
F - NR
M - NR
|
PI (n=25) - 4.5g every 6hrs over a 3h PI
II (n=25) - 4.5g every 6hrs over 30 min II
|
PI- 22/25 (88%)
II- 20/25 (80%)
|
PI- NR
II- NR
|
PI’s of piperacillin-tazobactam for gram negative bacteria with high MIC values, like HAP, provide stable plasma concentration and curative clinical effect.
|
Cutro et al.
2014 (27)
USA
|
Retrospective cohort study
843 patients suffering from sepsis
|
PI – NR
II – NR
|
F - NR
M - NR
|
PI (n=662) – 2.25-3.375g every 6-12h over 4h PI
II (n=181) – 2.25-4.5g every 8-12h over 30 min II
|
PI- 540/662 (81.6%)
II- 145/181 (80.1%)
|
PI- 72/662 (10.9%)
II- 25/181 (13.8%)
|
No significant difference between the two dosing regimens was observed in terms of mortality or clinical cure however PI resulted in shorter duration of therapy.
|
Jamal et al.
2015 (28)
Malaysia
|
(*) Randomised control trial
16 ICU patients
|
CI - 44
II – 62.5
|
F - 4
M - 12
|
CI (n=8) - 2.25g LD + 9g DD over 24h CI
II (n=8) – 2.25g every 6hr over 30 min II
|
CI- 6/8 (75%)
II- 6/8 (75%)
|
CI- 0/8 (0%)
II- 0/8 (0%)
|
CI is advantageous in the presence of more resistant pathogens as it allows achievement of rapid and consistent piperacillin-tazobactam concentrations.
|
Abdul et al.
2016 (33)
Malaysia
|
(*) Randomised control trial
85 ICU patients
|
CI - 54
II – 56
|
F - 27
M - 58
|
CI (n=38) – dose not recorded
II (n=47) – dose not recorded
|
CI- 22/38 (58%)
II- 15/47 (32%)
|
CI- 7/38 (18.4%)
II- 20/47 (42.6)
|
Results showed that CI piperacillin-tazobactam demonstrated higher clinical cure rates and better PK/PD target attainment compared to II.
|
Schmees et al. 2016 (31)
USA
|
Retrospective cohort study
113 ICU patients
|
PI - 68
II – 59.4
|
F - 47
M - 66
|
PI (n=61) – 3.375-4.5g every 8-12h
II (n=52) – dose not recorded
|
PI-31/61 (50.8%)
II-22/52 (42.3%)
|
PI-9/61 (14.8%)
II-11/52 (21.1%)
|
Mortality rates and length of hospital stay were significantly lower in PI patients. PI improves patient outcomes while maintaining patient safety.
|
Cortina et al. 2016 (29)
Spain
|
Randomised control trial
78 Patients with suspected Pa
|
CI - 64.3
II – 63.8
|
F - 32
M - 46
|
CI (n=40) – 2.25g LD + 8g DD over 24h CI
II (n=38) – 4.5g every 8h over 30 min II
|
CI- 20/40 (50%)
II- 18/38 (47.4%)
|
CI- 0/40 (0%)
II- 1/38 (2.6%)
|
No SS difference in efficacy between CI & II. Data indicates better performance of II than CI. II cure rates almost doubled CI.
|
Winstead et al. 2016 (30)
USA
|
Retrospective cohort study
181 patients, gram (-) bacteria
|
PI - 65.1
II – 68.2
|
F - 99
M - 82
|
PI (n=86) – 4.5g LD + 3.375g every 6h over 3h PI
II (n=95) - 4.5g every 8hrs over 30 min II
|
PI- NR
II- NR
|
PI- 7/86 (8.1%)
II- 6/95 (6.3%)
|
No SS difference in the primary outcome of mortality and length of hospital stay, however, 30-day hospital re-admission was significantly reduced in PI patients.
|
Bao et al
2017 (32)
China
|
Randomised control trial
50 patients with HAP
|
PI - 69.75
II – 67.04
|
F - 21
M - 29
|
PI (n=25) – 4.5g every 6h over a 3h PI
II (n=25) – 4.5g every 6h over 30 min II
|
PI- 22/25 (88%)
II- 20/25 (80%)
|
PI- 0/25 (0%)
II- 0/25 (0%)
|
Dosing regimen had no impact on adequacy of treatment and that PI is as effective as II. PI is potentially a more cost-effective alternative to II.
|
Fan et al
2017 (34)
China
|
Prospective cohort study
367 ICU patients
|
PI - 69
II – 70
|
F - 120
M - 247
|
PI (n=182) - 4.5g every 8-12h over 4h PI
II (n=185) - 4.5g every 8-12h over 30 min II
|
PI- NR
II- NR
|
PI- 21/182 (11.5%)
II- 29/185 (15.6%)
|
No significant difference between the two dosing regimens in terms of mortality rate and length of hospital stay
|
ICU= intensive care unit; CI= continuous infusion; II= intermittent infusion; PI= prolonged infusion; F= female; M= male; MIC= minimal inhibition concentration; LD= loading dose; DD= daily dose; VAP= ventilator-associated pneumonia; PD= pharmacodynamic; CC= clinical cure; Pa= pseudomonas aeruginosa; SS=statistically significant; PRT=prospective randomised trials; RO=resistant organisms; HAP=hospital acquired pneumonia; NR= not recorded; (*)= studies that reported SOFA score.
|
Study Quality
The quality of the majority of RCT’s included was moderate to high (Table 3). According to the Jadad scale, seven out of ten RCT’s (70%) obtained a score of three and above. The studies by Ye (20) and Lu (26) had a score of one and two respectively due to retrieval of only the abstract (full text unavailable). Rafati (15) received a score of two as the article did not describe randomisation method and study was not blinded. All observational studies assessed using the Newcastle Ottawa Scale scored eight or nine stars and recognised as being of high quality (Table 4).
Table 3 Quality assessment of randomised control trials in meta-analysis based on the Jadad Scale
Quality assessment of RCT’s
|
Lau
(14)
|
Rafati (15)
|
Robert
(17)
|
Li
(19)
|
Ye
(20)
|
Lu
(26)
|
Jamal (28)
|
Abdul (33)
|
Cotrina (29)
|
Bao (32)
|
|
2006
|
2006
|
2009
|
2010
|
2011
|
2013
|
2015
|
2016
|
2016
|
2017
|
(1) Described as randomised
|
1
|
1
|
1
|
1
|
1
|
1
|
1
|
1
|
1
|
1
|
(2) Described as double blind
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
1
|
0
|
(3) Description of withdrawals
|
1
|
1
|
1
|
1
|
0
|
1
|
1
|
1
|
1
|
1
|
(4) Randomisation method described
|
1
|
0
|
1
|
1
|
0
|
0
|
1
|
1
|
1
|
1
|
(5) Double blinding method described
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
1
|
0
|
Score (-/5)
|
3/5
|
2/5
|
3/5
|
3/5
|
1/5
|
2/5
|
3/5
|
3/5
|
5/5
|
3/5
|
|
|
|
|
|
|
|
|
|
|
|
RCT’s = Randomised Control Trials
Randomisation:
Up to two points are given: (1) described as randomised (yes = 1) (no = 0) and (4) randomisation method described (yes = 1) (no = 0)
Double blinding:
Up to two points are given: (2) described as double blind (yes = 1) (no = 0) and (5) double blinding method described (yes = 1) (no = 0)
Reports of withdrawals and dropouts:
Up to one point is given: (3) Description of withdrawals (yes = 1) (no = 0)
|
Table 4 Quality assessment of observational studies based on the Newcastle-Ottawa Scale
Study
|
Selection
|
Comparability
|
Outcome
|
Score
|
|
A
|
B
|
C
|
D
|
E
|
F
|
G
|
H
|
|
Grant 2002 (13) (p)
|
*
|
*
|
*
|
*
|
**
|
*
|
*
|
*
|
9*
|
Lodise 2007 (16) (R)
|
*
|
*
|
*
|
*
|
**
|
*
|
*
|
*
|
9*
|
Lorente 2009 (18) (R)
|
*
|
*
|
*
|
*
|
**
|
*
|
*
|
*
|
9*
|
Rose 2011 (36) (R)
|
*
|
*
|
*
|
*
|
**
|
*
|
*
|
*
|
9*
|
Yost 2011 (21) (R)
|
*
|
*
|
*
|
*
|
*
|
*
|
*
|
*
|
8*
|
Pereira 2012 (23) (R)
|
*
|
*
|
*
|
*
|
**
|
*
|
*
|
*
|
9*
|
Lee 2012 (24) (R)
|
*
|
*
|
*
|
*
|
**
|
-
|
*
|
*
|
8*
|
Waxier 2012 (25) (R)
|
*
|
*
|
*
|
*
|
**
|
-
|
*
|
*
|
8*
|
Cutro 2014 (27) (R)
|
*
|
*
|
*
|
*
|
*
|
*
|
*
|
*
|
8*
|
Schmees 2016 (31) (R)
|
*
|
*
|
*
|
*
|
**
|
-
|
*
|
*
|
8*
|
Winstead 2016 (30) (R)
|
*
|
*
|
*
|
*
|
**
|
-
|
*
|
*
|
8*
|
Fan 2017 (34) (P)
|
*
|
*
|
*
|
*
|
**
|
-
|
*
|
*
|
8*
|
(P) = prospective cohort study and (R) = retrospective cohort study
Selection:
A: representation of the exposed cohort (yes = *) (no= -), B: selection of non-exposed cohort (yes = *) (no= -), C: ascertainment of exposure (yes = *) (no= -), D: demonstration that outcome of interest was not present at start of study (yes = *) (no= -)
Comparability:
E: comparability of cohorts on the basis of the design or analysis [controls for: age, sex and marital status (yes = *) (no= -) and for other factors (yes = *) (no= -)]
Outcome:
F: assessment of outcome (yes = *) (no= -), G: was follow up long enough for outcome to occur (yes = *) (no= -) and H: adequacy of follow up of cohorts (yes = *) (no= -).
|
Meta-Analysis of Included Studies
Clinical Cure
Seventeen of the included studies reported clinical cure rates (Table 2) (6,13,26–29,31–33,14,15,18–21,23,24). Patients that received C/PI had a statistically significantly higher clinical cure rate compared to those who received treatment via II (2535 patients; OR 1.56, 95% C.I 1.28-1.90, P = 0 .0001; Figure 2). No significant heterogeneity was found among the studies (I2 = 41%, P = 0.04). The symmetrical funnel plot obtained indicates the absence of publication bias (Figure 3).
Despite methodological differences among selected studies, patients receiving C/PI displayed higher clinical cure rates compared with patients receiving II; overall, clinical cure rate was 79.62% and 69.26% for C/PI and II respectively. Pooling results from the 17 studies that reported clinical cure showed that the odds of clinical cure was higher in patients receiving C/PI. The pooled OR shows that C/PI piperacillin-tazobactam was 1.56 (95% C.I 1.28-1.90, P = 0 .0001), indicating clinical cure rates are 34% higher than in II with the true population effect between 72% and 10%.
Mortality
Eighteen of the included studies reported patient mortality rates (Table 2) (13,14,28–34,37,15–18,20,21,24,27). Statistically significantly fewer mortality rates were found among patients receiving C/PI compared with patients receiving conventional II (3100 patients; OR 0.68, 95% C.I 0.55-0.84, P = 0 .0003; Figure 4). No significant heterogeneity was found among the studies (I2 = 0%, P = 0.56). The symmetrical funnel plot obtained indicates the low possibility of publication bias (Figure 5).
Results obtained from meta-analysis suggested that C/PI piperacillin-tazobactam resulted in significantly lower mortality rates. Overall, ICU mortality rate was 12.46% and 18.13% for C/PI and II respectively. Combining results from 18 studies that reported mortality, the pooled OR shows that C/PI piperacillin-tazobactam was 0.68 (95% C.I 0.55-0.84), indicating lower mortality rates compared with conventional II. This was statistically significant (P = 0.0003) with the true population effect between 84% and 55%.
Microbiological Cure
Seven of the included studies reported microbiological cure rates (13,14,19,20,23,27,33). Lau et al (14) found no statistically significant difference between the dosing regimens however, higher microbiological success was seen in patients receiving II. In contrast, Abdul-Aziz et al (33) found C/PI piperacillin-tazobactam had significantly higher microbiological cure rates compared with II. Pooling of the outcomes of seven studies that reported microbiological cure rates showed that patients receiving C/PI had significantly higher microbiological success rates (920 patients; OR 1.52, 95% C.I 1.10-2.11, P = 0.01; Figure 6). No significant heterogeneity was found among studies (I2 = 0 %, P = 0.48). The symmetrical funnel plot obtained demonstrates the absence of publication bias (Figure 7).
The pooled OR shows that C/PI piperacillin-tazobactam was 1.52 (95% C.I 1.10-2.11), indicating C/PI piperacillin-tazobactam achieved higher microbiological cure rates compared to conventional II. Overall, microbiological cure rates were 74.83% and 61.89% for C/PI and II respectively. This was statistically significant (P = 0.01).
Adverse Events
Six of the included studies reported adverse events (13,14,31–34). Participants enrolled in three of these studies experienced adverse event (14,31,32). Lau et al’s (14), Bao et al (32) and Schmees et al (31) observed treatment-related adverse events in patients receiving both C/PI and II; CI: 16.9% vs II:13.6%, CI: 47.5% vs II:53.8%, CI: 76% vs II:92%, respectively. Boa (32) reported serious adverse events in 9 patients (PI:5 vs II:4), including renal failure, Tachycardia and confusion.
The average occurrence of adverse events was 13.3% for C/PI and 13.4% for II, respectively. Participants in the other three studies did not experience adverse events (13,33,34). Data obtained from studies showed no significant difference between the two infusion strategies (935 patients; OR 0.85, 95% C.I 0.50-1.42, P = 0.53; Figure 8). No significant heterogeneity was found among studies (I2 = 25 %, P = 0.26).
Although adverse events were not observed in the study by Grants et al (13), dosing and administrative errors arose where one patient was administered 13.5g piperacillin-tazobactam dose over a 30 minute II rather than a 24-hour CI. Cortina et al (29) reported that the most common side effects experienced by patients were gastrointestinal and allergic reactions but the number of patients that experienced these was not reported. The meta-analysis demonstrated that no adverse events that are directly associated to the dosing regimens occurred. C/PI resulted in a lower percentage of adverse events however, the difference between the two groups did not reach statistical significance (935 patients; OR 0.85, 95% C.I 0.50-1.42, P = 0.53; Figure 8).
Length of Hospital Stay
Fifteen of the included studies reported length of hospital stay (13,14,31,33,34,36,38,15,16,18,23,24,26,29,30). Pooling of studies showed that patients receiving C/PI had a significantly shorter length of hospital stay (2101 patients; Mean Difference -1.27, 95% C.I -2.45—0.08, P = 0.04; Figure 9) The meta-analysis suggests there is a significant reduction in the length of hospital stay in patients receiving C/PI compared to those receiving II. Moderate heterogeneity among studies evaluating ‘length of hospital stay’ (I2= 65%, P = 0.0003) was observed. This is likely due to clinical heterogeneity in the design and outcomes of the included studies. The length of hospital stay was an independent risk factor for mortality, however the influence of mortality on the length of hospital stay could not be evaluated.
Emergence of Resistance
Data regarding the emergence of resistance was reported in four of the included studies (13,14,17,18). Two resistant pathogens were isolated in one study (13) however, resistant strains were not isolated in three studies (14,17,18) following the initiation of piperacillin-tazobactam treatment. Three studies reported that no resistant pathogen was isolated following the initiation of piperacillin-tazobactam treatment. In the study conducted by Grant et al (13), two resistant strains were isolated from patients receiving CI piperacillin-tazobactam.
Risk of Bias
The majority of RCT’s and prospective studies assessed were judged to have a low risk of bias for random sequence generation, allocation concealment, incomplete outcome data, selective reporting and other biases. However, evaluations of blinding of participants and personnel parameter was judged to have a high or unclear risk of bias (Figure 10).