Antibiotic stewardship programmes in intensive care units: Why, how, and where are they leading us

Table 1 Non-protocolised antibiotic stewardship programmes

Kollef et al[18]	1997	9351601	Prospective cohort study Follow-up 6 mo	Incidence of VAP Incidence of bloodstream infection and sepsis Duration of mechanical ventilation LOS Mortality	680	Non-protocolised Components Rotating antibiotic schedule	1 Positive study 2 ↓ in resistant Gram negative organisms 3 ↓ in VAP incidence 4 No change to mortality 5 No change to LOS	1 No information on antibiotic usage 2 6 mo follow-up period only
Evans et al[91]	1998	9435330	Prospective observational study Follow-up 1 yr	Antibiotic use Antibiotic cost Cost of hospitalisation Number of adverse events caused by anti-infective agents No. of days of excessive antibiotic dosage LOS Mortality	1681	Non-protocolised Components Computerised decision support tool	1 Positive study 2 ↓ in total antibiotics cost 3 No change in DDD 4 ↓ in susceptibility-mismatch 5 ↓ in allergy-mismatch 6 ↓ of mortality 7 ↓ of LOS from 4.9 d to 2.7 d (4.9 to 8.3 d if overridden)	1 Less patients in post-intervention group 2 Young patients (mean age < 50 yr)
Price et al[84]	1999	10548192	Retrospective observational study Follow-up 1 mo	Antibiotic cost Antibiotic resistance LOS	321	Non-protocolised Components Antibiotic guideline	1 Positive study 2 77% ↓ in antibiotic cost 3 No change to LOS 4 No change to mortality	1 Surgical ICU only 2 1 mo FU follow-up 3 High compliance rate with guideline (95.6%) 4 High baseline APACHEII score (38.0-39.1)
Roger et al[64]	2000	11089498	Retrospective observational study Follow-up 2 mo	Antibiotic use Antibiotic cost	61	Non-protocolised Components ID specialist input	1 Positive study 2 ↓ in duration of treatment from mean 23 d to 13 d 3 ↓ in total antibiotic days from 596 d to 455 d 4 19% ↓ in total antibiotic cost 5 No change to mortality 6 No change to LOS	1 2 mo follow-up period
Fox et al[63]	2001	11712090	Retrospective observational study Follow-up 1 yr	Antibiotic use LOS Days on mechanical ventilation Days with fever No. of cultures performed Antibiotic resistance Antibiotic cost	295	Non-protocolised Components ID specialist input	1 Negative study 2 No change to antibiotic usage 3 57% ↓ in antibiotics cost 4 ↑ infection rate 5 No change in LOS	1 Trauma ICU only 2 Young patients (age < 35 yr)
Mullett et al[90]	2001	11581483	Retrospective observational study Follow-up 6 mo	Antibiotic cost Rate of anti-infective sub-therapeutic and excessive-dose days	1758	Non-protocolised Components Computerised decision support tool	1 Negative study 2 No change to total cost of antibiotics 3 ↓ of excessive dose days and sub-therapeutic days (i.e., dose optimisation)	1 Paediatric ICU only 2 Significantly younger patients in post-intervention group
Dos Santos et al[61]	2003	14552737	Retrospective observational study Follow-up 1 yr	Antibiotic use Antibiotic cost	1473	Non-protocolised Components ID specialist input	1 Positive study 2 ↓ in cephalosporin, carbapenems and vancomycin usage 3 ↑ in penicillin usage 4 ↓ of cost by 37%	1 Limited patient characteristics 2 No information on antibiotic resistance 3 No information on LOS and mortality
Du et al[62]	2003	12682477	Prospective observational study Follow-up 1 yr	Antibiotic use Antibiotic resistance LOS	1205	Non-protocolised Components Antibiotic restriction Senior clinician input	1 Positive study 2 ↓ in 3rd generation cephalosporin usage 3 ↑ in cefepime usage 4 No change to resistance pattern 5 ↓ in LOS from 13.1 d to 9.3 d	1 Significant reduction in APACHEII scores and organ failure % in post-intervention group 2 High baseline Pseudomonas and Acinetobacter rate 3 No information on mortality
Geissler et al[82]	2003	12528022	Retrospective observational study Follow-up 4 yr	Antibiotic use Antibiotic resistance Antibiotic cost	1704	Non-protocolised Components Antibiotic guideline	1 Positive study 2 35% ↓ in antibiotic days 3 37% ↓ in antibiotics cost 4 Significant ↓ in total number of resistant isolates	1 High baseline mortality 2 No data on LOS
Micek et al[81]	2004	15136392	RCT Follow-up 14 mo	Antibiotic use Incidence of VAP LOS Mortality	290	Non-protocolised Components Antibiotic discontinuation policy	1 Positive study 2 ↓ of antibiotic treatment duration 3 No change to LOS 4 No change to mortality	1 Medical ICU only 2 Limited microbiology data
Aubert et al[80]	2005	15620440	Retrospective observational study Follow-up 1 yr	Antibiotic use Microbiological profile and antibiotic resistance	781	Non-protocolised Components Antibiotic restriction	1 Positive study 2 ↓ in fluoroquinolone usage by 75.8% 3 ↓ in usage of aminoglycosides and macrolides 4 ↓ of antibiotic resistance in Pseudomonas 5 No change to mortality 6 No change to LOS	1 No information on antibiotic usage
Sintchenko et al[89]	2005	15802478	Prospective observational study Follow-up 6 mo	Antibiotic use LOS Mortality	5176 patient-days	Non-protocolised Components Computerised decision support tool	1 Positive study 2 Significant ↓ in total DDD from 1925 to 1606, particularly vancomycin and beta-lactam resistant penicillins 3 ↓ of mean LOS from 7.15 to 6.22 d 4 No change to mortality	1 6 mo follow-up period 2 No information on antibiotic resistance
Bochicchio et al[88]	2006	16500251	Randomised pilot study Follow-up 6 mo	Antibiotic decision accuracy	125	Non-protocolised Components Computerised decision support tool	1 Positive study 2 ↑ in decision accuracy (verified by ID specialists)	1 No information on antibiotic usage 2 No information on antibiotic resistance
Brahmi et al[78]	2006a	16944257	Retrospective observational study Follow-up 2 yr	Antibiotic use	727	Non-protocolised Components Antibiotic restriction	1 Positive study 2 Significant ↓ in ceftazidime usage 3 ↓ in tazocin and imipenem resistance 4 ↑ resistance to penicillins	1 High baseline rate of VAP patients (63%-70%) 2 High baseline resistance rate among Pseudomonas (59% to tazocin, 58% to ciprofloxacin, 58% to imipenem, 47% to ceftazidime) 3 No info on mortality and LOS
Thursky et al[87]	2006	16415039	Prospective observational study Follow-up 6 mo	Antibiotic use Antibiotic susceptibility-mismatches Mortality	1060	Non-protocolised Components Computerised decision support tool	1 Positive study 2 ↓ of total DDD from 1670 to 1490 3 ↓ in usage of ceftriaxone, vancomycin and carbapenems 4 ↓ of susceptibility-mismatch 5 No change to mortality	1 6 mo follow-up period 2 High baseline mortality (19%) 3 Fewer isolates in intervention group 4 No information on LOS
Brahmi et al[79]	2006b	17027213	Prospective cohort study Follow-up 2 yr	Antibiotic use Antibiotic resistance	318	Non-protocolised Components Antibiotic guideline	1 Positive study 2 ↓ in duration of treatment from 14.1 to 11.9 d 3 ↓ in antibiotics cost 4 ↓ in LOS from 20.4 to 16.9 d 5 No change to mortality
de Araujo et al[69]	2007	17625777	Retrospective observational study Follow-up 1 yr	LOS Days of parenteral nutrition Requirement for mechanical ventilation Antibiotic use	995	Non-protocolised Components Rotating antibiotic schedule	1 Positive study 2 ↓ in cefepime usage 3 ↑ in tazocin usage 4 No change to LOS
								1 Neonatal ICU only 2 High baseline rates of Pseudomonas and Klebsiella 3 No information on mortality
Ntagiopoulos et al[77]	2007	17629680	Retrospective observational study Follow-up 6 mo	Antibiotic use Antibiotic resistance	147	Non-protocolised Components Antibiotic restriction	1 Positive study 2 ↓ of overall antibiotic usage by 55% 3 ↓ in resistance in Pseudomonas 4 ↑ in resistant strains of Klebsiella and Acinetobacter 5 No change to mortality 6 No change to LOS	1 Male predominance 2 High baseline mortality 3 6 mo follow-up period 4 High baseline ceftazidime and fluoroquinolone resistance 5 90% policy compliance among clinicians
Ding et al[76]	2008	18493864	Retrospective observational study Follow-up 2 yr	Antibiotic use Rate of bacterial resistance	900	Non-protocolised Components Antibiotic guideline Staff education	1 Positive study 2 ↓ in usage of 3rd generation cephalosporin 3 ↑ in usage of beta-lactams 4 ↓ in antibiotics cost 5 No change to LOS	1 Paediatric ICU only 2 High baseline antibiotic utilisation (98.7% patients were on antibiotics) 3 High baseline resistance rate (> 60% to cefepime, for E coli and Klebsiella; > 20% to cefepime and imipenem, for Pseudomonas) 4 No information on mortality
Peto et al[60]	2008	19011742	Retrospective observational study Follow-up 2 yr	Antibiotic use Incidence of sepsis LOS Mortality	3403	Non-protocolised Components Senior clinician input	1 Positive study 2 ↓ of mean DDD from 162.9 to 101.3. 3 No change to LOS 4 No change to mortality	1 Surgical ICU only with > 60% neurological patients 2 Low baseline resistance rate 3 Increased patient turnover since intervention
Marra et al[59]	2009	18986735	Retrospective observational study Follow-up 10 mo	Antibiotic resistance	360	Non-protocolised Components ID specialist input	1 Positive study 2 ↓ of total DDD by 12.1% 3 ↓ of resistant strains of Pseudomonas, Klebsiella and Acinetobacter	1 High baseline resistance rate 2 Limited patient characteristics 3 Unknown sample size 4 No information on mortality and LOS
Meyer et al[74]	2010	19904488	Retrospective observational study Follow-up 3 yr	Mortality Antibiotic use	11887	Non-protocolised Components Antibiotic prophylaxis	1 Positive study 2 15% ↓ in total antibiotic usage primarily cefuroxime and co-trimoxazole 3 Sustained ↓ to antibiotic usage 4 No change to LOS 5 No change to mortality	1 Surgical ICU only 2 Limited resistance data
Yong et al[86]	2010	20215130	Retrospective observational study Follow-up 4.5 yr	Antibiotic susceptibilities of Pseudomonas, Klebsiella, Acinetobacter and Enterobacteriaceae	13295	Non-protocolised Components Computerised decision support tool	1 Positive study 2 No change to Abx usage 3 ↑ susceptibility to imipenem for Pseudomonas, Acinetobacter and Enterobacter 4 ↑ susceptibility to gentamicin for Pseudomonas and Enterobacter 5 No change to LOS	1 Limited patient characteristics 2 No information on mortality
Sharma et al[75]	2010	21206622	Retrospective observational study Follow-up 4 mo	Antibiotic use Antibiotic resistance	177	Non-protocolised Components Antibiotic restriction	1 Negative study 2 ↓ of carbapenem usage 3 ↑ in beta-lactam usage	1 Medical ICU only 2 No information on overall antibiotic usage 3 4 mo follow-up period 4 No pre-intervention arm 5 Male predominance 6 High baseline Acinetobacter isolates 7 High baseline resistance rate
Raymond et al[68]	2011	11395583	Prospective cohort study Follow-up 1 yr	Mortality Duration of treatment Antibiotic cost LOS	1456	Non-protocolised Components Rotating antibiotic schedule	1 Positive study 2 ↓ in infection rate by 25% 3 ↓ in infections caused by resistant organisms 4 ↓ in usage of aminoglycosides, vancomycin and antifungals 5 ↑ in usage of clindamycin 6 ↓ in mortality from 38.1% to 15.5% 7 No change to LOS	1 No information on overall antibiotic usage 2 High baseline mortality rate
Dortch et al[67]	2011	21091186	Retrospective observational study Follow-up 8 yr	Incidence of infection caused by MDR organisms Antibiotic use	20846	Non-protocolised Components Antibiotic guidelines Antibiotic prophylaxis Rotating antibiotic schedules	1 Positive study 2 Significant ↓ of total broad spectrum antibiotic usage 3 ↓ in total infection rate 4 ↓ in MDR Pseudomonas, Acinetobacter and Enterobacter isolates	1 Surgical ICU only 2 High baseline respiratory infection rate 3 High baseline Enterobacter infection rate 4 Concomitant infection control policy
Slain et al[57]	2011	21687626	Retrospective observational study Follow-up 7 yr	Antibiotic use Antibiotic resistance	N/A	Non-protocolised Components Prospective audits Antibiotic restriction Staff education Antibiotic guidelines Rotating antibiotic schedules	1 Positive study 2. Overall ↓ of DDD 3 Fluctuations due to resistance and change in protocols 4 ↑ in resistance to ciprofloxacin, tazocin, cefepime	1 Pseudomonas infections only 2 Limited patient characteristics 3 No information on mortality or LOS
Chiu et al[73]	2011	21085051	Prospective observational study Follow-up 1 yr	Antibiotic use	190	Non-protocolised Components Antibiotic guideline	1 Negative study 2 No change to overall antibiotic usage 3 ↓of vancomycin usage	1 Neonatal ICU only 2 Limited patient characteristics 3 Limited resistance data 4 No information on mortality and LOS
Sarraf-Yazdi et al[66]	2012	22445457	Retrospective observational study Follow-up 9 yr	Antibiotic use Antibiotic resistance	321	Non-protocolised Components Rotating antibiotic schedules	1 Positive study 2 No change in total antibiotic usage 3 ↓ in prescribed dosage of target antibiotics 4 ↓ in resistance against ceftazidime and tazocin	1 No LOS or mortality data 2 Limited patient characteristics
Sistanizad et al[72]	2013	24250656	Prospective cohort study Follow-up 9 mo	Antibiotic use Susceptibility of P. aeruginosa, A. baumanni, K. pneumonia and E. coli	N/A	Non-protocolised Components Antibiotic restriction	1 Positive study 2. 60% ↓ in imipenem use 3 ↑ in carbapenem sensitivity for Klebsiella and Pseudomonas	1 No mortality and LOS data 2 Limited patient characteristic data
Rimavi et al[58]	2013	23873275	Prospective cohort study Follow-up 3 mo	Antimicrobial use Treatment duration APACHEII score LOS Mechanical ventilation days Mortality rate	246	Non-protocolised Components ID specialist input	1 Positive study 2 Significant ↓ in overall antibiotic usage 3 ↓ of LOS 4 No change to mortality	1 Medical ICU only 2 Follow-up period of only 3 mo 3 Limited resistance data
Bauer et al[71]	2013	23571547	Retrospective cohort study Follow-up N/A	Duration of mechanical ventilation LOS Mortality	1433	Non-protocolised Components Intermittent vs extended dosing regimen of cefipime	1 Positive study 2. ↓ of mortality from 20% to 3% 3 ↓ of LOS 4 ↓ of antibiotic cost per patient by $23183 in extended dosing group	1 Pseudomonas infection only 2 No information on antibiotic resistance 3 No follow-up
Ramsamy et al[65]	2013	23725954	Retrospective observational study Follow-up 1 yr	Antibiotic use Antibiotic resistance	227	Non-protocolised Components Antibiotic restriction	1 Negative study 2 6.5% inappropriate broad- spectrum antibiotic usage	1 Trauma ICU 2 No pre-intervention arm 3 Limited patient characteristics 4 No information on mortality and LOS
Apisarnthanarak et al[98]	2014	24485368	Retrospective observational study Follow-up 1 yr	Rate of XDR Acinetobacter baumanni acquisition rate per 1000 patient days Rate of Acinetobacter baumanni infection or colonisation	1365	Not specified	1 Positive study 2 Significant ↓ in XDR Acinetobacter baumanni infection or colonisation rates	1 Type of ASP not specified 2 No information on antibiotic usage 3 Concomitant infection control policy (Use of disinfectant-detergent; Enhanced isolation; Active surveillance cultures for all ICU patients)

LOS: Length of stay; VAP: Ventilator-associated pneumonia; ICU: Intensive care units; ASP: Antibiotic stewardship programme; DDD: Defined daily dose; RCT: Randomised Controlled Trial; APACHEII: Acute Physiology and Chronic Health Evaluation II.

Table 2 Protocol-based antibiotic stewardship programmes

Ref.	Year	Pubmed ID	Study type	Outcome	No. of patients	Type of ASP	Major findings	Limitations/Confounding factors
Singh et al[54]	2000	10934078	RCT Follow-up N/A	1 LOS 2 Mortality 3 Proportion of patients with resolution of pulmonary infiltrate	81	Clinical Pulmonary Infection Score-based De-escalation	1 Positive study 2 ↓ in total antibiotic days from 9.8 to 3 d 3 ↓ of antibiotics cost by $381 per patient 4 ↓ in LOS from 14.7 to 9.4 d mean 5 Significant ↓ in total antibiotic resistance 6 No change to mortality	1 79% surgical patients 2 Mean APACHEII score of 42.7 in intervention group 3 Unknown follow-up period
Nobre et al[47]	2008	18096708	Single-centred RCT	1 Antiiotic Antibiotic use 2 28-d mortality 3 LOS 4 Incidence of clinical cure 5 Recurrence of infection 6 Incidence of nosocomial superinfection	79	PCT-based De-escalation	1 Positive study 2 ↓ in duration of treatment from median 9.5 to 6 d 3 ↓ in ICU LOS from 5 to 3 d 4 ↓ in hospital LOS 21 to 14 d 5 No change to mortality	1 Small study 2 Sepsis patients only 6 Infections by Pseudomonas, Acinetobacter etc. were excluded 7 Patients with chronic infections were excluded 8 Immunocompromised patients were excluded 9 Patients on antibiotics at time of admission were excluded
Hochreiter et al[48]	2009	19493352	Single-centred RCT	1 Antibiotic use 2 LOS 3 Mortality	110	PCT-based De-escalation	1 Positive study 2 ↓ in duration of treatment from median 7.9 to 5.9 d 3 ↓ in LOS from median 17.7 to 15.5 d 4 No change to mortality	1 Patients on antibiotics at time of admission were excluded 2 Sepsis patients only
Schroeder et al[49]	2009	19034493	Single-centred RCT	1 Antibiotic use 2 LOS 3 Mortality	27	PCT-based De-escalation	1 Positive study 2 ↓ in duration of treatment from 8.3 to 6.6 d 3 ↓ in antibiotic cost by 17.8% 4 No change to LOS 5 No change to mortality	1 Sepsis patients only
Stolz et al[55]	2009	19797133	Multi-centred RCT	1 No. of days without antibiotics at 28 d 2 Number of days without mechanical ventilation 3 ICU mortality 4 LOS 5 Incidence of VAP	101	PCT-based De-escalation	1 Positive study 2 27% ↓ in duration of treatment 3 No change to mortality 4 No change to LOS	1 VAP patients only
Bouadma et al[50]	2010	20097417	Multi-centred RCT (PRORATA trial)	1 28-d and 60-d mortality 2 Number of days without antibiotics at 28 d 3 Incidence of recurrence of infection or superinfection 4 Days of unassisted breathing 5 LOS 6 Antibiotic use 7 Incidence of MDR organisms	630	PCT-based Escalation/De-escalation	1 Positive study 2 ↓ in duration of treatment from 13.3 to 10.3 d 3 No change to mortality 4 No change to LOS	1 Patients on antibiotics on admission were excluded 2 Patients with chronic infection were excluded 3 Immunocompromised patients were excluded 4 90% medical patients 5 Close to 50% respiratory/CVS failure, and > 30% CNS failure 6 70% pulmonary infection site 7 53% did not adhere to algorithm in PCT group
Jensen et al[51]	2011	21572328	Multi-centred RCT (PASS trial)	1 28-d mortality	1200	PCT-based Treatment escalation	1 Negative study 2 Significant ↑ in duration of tretment (Median: from 4 to 6 d), especially for tazocin and meropenem 3 ↑ in LOS from median 5 to 6 d 4 No change to mortality	1 Low resistance and antibiotic usage units 2 Incomplete adherence to PCT algorithm
Layios et al[52]	2012	22809906	Single-centred RCT	1 Antibiotic use 2 Accuracy of infectious diagnosis 3 Diagnostic concordance between intensive care unit physician and ID specialist	510	VAP -based Escalation	1 Negative study 2 No change in duration of antibiotic treatment 3 No change in DDD 4 No change to LOS 5 No change in mortality	1 41% surgery and trauma patients
Annane et al[53]	2013	23418298	Multi-centred RCT	1 Proportion of patients on antibiotics at day 5	62	PCT-based Escalation	1 Negative study 2 Premature termination	1 Poor clinician compliance with algorithm 2 Patients on antibiotics at time of admission were excluded

LOS: Length of stay; VAP: Ventilator-associated pneumonia; ICU: Intensive care units; ASP: Antibiotic stewardship programme; DDD: Defined daily dose; RCT: Randomised Controlled Trial; APACHEII: Acute Physiology and Chronic Health Evaluation II; PCT: Procalcitonin; CVS: Cardiovascular system; CNS: Central Nervous system; XDR: Extensively Drug-Resistant.