Effect of Antibiotic Discontinuation Strategies on
Mortality and Infectious Complications in Critically
Ill Septic Patients: A Meta-Analysis and Trial
Sequential Analysis*
Nishkantha Arulkumaran, PhD1; Muska Khpal, FRCA1; Karen Tam, FFICM1;
Downloaded from http://journals.lww.com/ccmjournal by BhDMf5ePHKbH4TTImqenVJua3JJgqHHlFHFCr7V9vuQrsMq+3kyxucRxI7QSlIv0PhdkUcpGhLo= on 04/17/2020
Aravindhan Baheerathan, MRCP1; Carlos Corredor, FFICM2; Mervyn Singer, MD1
Objective: To investigate methods of antibiotic duration minimiza-
tion and their effect on mortality and infectious complications in
critically ill patients.
Data Sources: A systematic search of PubMed, Embase (via Ovid),
clinicaltrials.gov, and the Cochrane Central Register of Controlled
Trials (via Wiley) (CENTRAL, Issue 2, 2015).
Study Selection: Randomized clinical trials comparing strategies
to minimize antibiotic duration (days) for patients with infections
or sepsis in intensive care.
Data Extraction: A systematic review with meta-analyses and trial
sequential analyses of randomized clinical trials. Dichotomous data
are presented as relative risk (95% CIs) and p value, and contin-
uous data are presented as mean difference (CI) and p value.
Data Synthesis: We included 22 randomized clinical trials (6,046
patients). Strategies to minimize antibiotic use included procal-
citonin (14 randomized clinical trials), clinical algorithms (two
randomized clinical trials), and fixed-antibiotic duration (six ran-
domized clinical trials). Procalcitonin (–1.23 [–1.61 to –0.85];
p < 0.001), but not clinical algorithm–guided antibiotic therapy
(–7.41 [–18.18 to 3.37]; p = 0.18), was associated with shorter
duration of antibiotic therapy. The intended reduction in antibiotic
duration ranged from 3 to 7 days in fixed-duration antibiotic therapy
randomized clinical trials. Neither procalcitonin-guided antibiotic
treatment (0.91 [0.82–1.01]; p = 0.09), clinical algorithm–guided
antibiotic treatment (0.67 [0.30–1.54]; p = 0.35), nor fixed-duration
antibiotics (1.21 [0.90–1.63]; p = 0.20) were associated with re-
duction in mortality. Z-curve for trial sequential analyses of mortality
associated with procalcitonin-guided therapy did not reach the
trial sequential monitoring boundaries for benefit, harm, or futility
*See also p. 775.
1
Division of Medicine, Bloomsbury Institute of Intensive Care Medicine,
University College London, London, United Kingdom.
2
Department of Perioperative Medicine, Bart’s Heart Centre, St Bar-
tholomew’s Hospital, London, United Kingdom.
Copyright © 2020 by the Society of Critical Care Medicine and Wolters
Kluwer Health, Inc. All Rights Reserved.
DOI: 10.1097/CCM.0000000000004267
Critical Care Medicine www.ccmjournal.org 757
Copyright © 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
(adjusted CI, 0.72–1.10). Trial sequential analyses for mortality as-
sociated with clinical algorithm and fixed-duration treatment accu-
mulated less than 5% of the required information size. Despite
shorter antibiotic duration, neither procalcitonin-guided therapy
(0.93 [0.84–1.03]; p = 0.15) nor fixed-duration antibiotic therapy
(1.06 [0.74–1.53]; p = 0.75) was associated with treatment failure.
Conclusions: Although the duration of antibiotic therapy is reduced
with procalcitonin-guided therapy or prespecified limited duration,
meta-analysis and trial sequential analyses are inconclusive for
mortality benefit. Data on clinical algorithms to guide antibiotic
cessation are limited. (Crit Care Med 2020; 48:757–764)
Key Words: antibiotics; critical care; sepsis
A
lthough antibiotic therapy plays a fundamental role
in sepsis management, the optimal duration of anti-
biotics in critically ill patients is unknown. Following
source control where possible, a suitable duration is required
for adequate eradication of the infectious microorganism and
minimizing the risk of clinical relapse. Conversely, prolonged
antibiotic use places patients at risk of adverse effects including
secondary infections, Clostridium Difficile diarrhea (1), and
antimicrobial resistance (2).
It is imperative to safely minimize duration of antibiotic
exposure, particularly in critically ill patients with sepsis. The
surviving sepsis campaign states that “while substantial con-
sensus on the need for early de-escalation of combination
therapy exists, agreement is lacking on precise criteria for trig-
gering de-escalation” (3). Among the surviving sepsis cam-
paign members, de-escalation of antibiotics is often achieved
by either “clinical progress, infection resolution as indicated
by biomarkers (especially procalcitonin), and a relatively fixed
duration of combination therapy.”
Our objective was to evaluate these different methods used
to guide the cessation of antibiotics in critically ill adults re-
ceiving antibiotics for sepsis. The primary objective was to
assess the all-cause mortality associated with the different
Arulkumaran et al
methods of antibiotic cessation in critically ill patients with
sepsis. Secondary objectives were to ascertain duration of anti-
biotic use, treatment failure, secondary infections, and antimi-
crobial resistance following initiation of antibiotics.
METHODS
This systematic review was registered in International Pro-
spective Register of Systematic Reviews (PROSPERO) database
(PROSPERO registration number: CRD42018091566).
Eligibility Criteria
Inclusion and exclusion criteria were determined a priori. All
randomized clinical trials (RCTs) comparing strategies to min-
imize antibiotic duration for patients with infections or sepsis
in intensive care were considered. The control group was de-
fined as patients who received either “standard care” or who
were assigned to receive a longer course of antibiotics where
fixed-duration antibiotic courses were used. We included RCTs
using different methods to limit antibiotic duration. RCTs
using clinical or biomarker-guided algorithms to initiate (but
not stop) antibiotics were excluded. RCTs involving patients
outside the ICU or pediatric patients (<16 yr) were excluded.
Information Sources and Search Strategy
A systematic search of PubMed, Embase (via Ovid), clinicaltrials.
gov, and the Cochrane Central Register of Controlled Trials (via
Wiley) (CENTRAL, Issue 2, 2015), was conducted. When possible,
we used controlled vocabulary (MeSH) and key words. The search
was constructed on the following Population, Intervention, Con-
trol, Outcome, Study criteria: population (critically ill patients
with sepsis), intervention (method to minimize antibiotic dura-
tion), comparator (standard care or longer duration), outcome
(mortality/recurrence/superinfection/resistant organisms), and
studies (randomized controlled trials) (supplemental data, Sup-
plemental Digital Content 1, http://links.lww.com/CCM/F311).
Full-text articles were considered. Date restrictions were not
applied. The last search update was in December 2018. In addition
to searching electronic databases, research papers and review arti-
cles on the subject were hand-searched for further references. Trial
authors were contacted to clarify missing/unclear information.
Study Selection
Two investigators (M.K., A.B.) independently screened both
titles and abstracts to exclude nonpertinent RCTs. Discrepan-
cies were resolved by a third author (N.A.). Relevant full-text
articles were then retrieved and analyzed for eligibility apply-
ing the predefined inclusion criteria.
Data Extraction and Analysis
Two investigators (M.K., A.B.) independently extracted infor-
mation from selected RCTs using a standardized data collec-
tion form. Data were collected on the following; year of data
collection, country of study, type of study, total number of
participants, type of infection, and method of antibiotic du-
ration optimization. The following data points were collected
for patients in each treatment arm; mortality, actual duration
758 www.ccmjournal.org May 2020 • Volume 48 • Number 5
Copyright © 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
of antibiotics used, treatment failure, frequency of secondary
infection, and frequency of antimicrobial resistance. Where
intention-to-treat and per protocol analysis were both reported,
we elected to use the intention-to-treat data for analysis.
Primary and Secondary Outcomes
The primary outcome was all-cause mortality. Where available,
28- or 30-day mortality was analyzed. Where these data were not
available, hospital mortality was used unless stated otherwise.
Secondary outcomes included duration of antibiotic use, treat-
ment failure, frequency of secondary or infections, and the fre-
quency of antimicrobial resistance. Treatment failure was defined
as the persistence of infection requiring antibiotic treatment
beyond the intended antibiotic duration. Secondary infections
were defined as the subsequent occurrence of an infection at a
site different to the primary infection and by a second organism.
Antimicrobial resistance was defined as the new frequency of
resistant organisms on clinical samples (not screening samples)
following initiation of antibiotics for the primary infection.
Subgroup Analyses
We conducted a subgroup analysis by source of infection (e.g.,
ventilator-associated pneumonia [VAP], intra-abdominal/
surgical).
Risk of Bias of Included RCTs
Methodologic quality of included RCTs was assessed using the
Cochrane Collaboration’s tool for assessing risk of bias (4). The
following domains were assessed for RCTs: random sequence
generation, allocation concealment, blinding of sequence gen-
eration, blinding of participants and personnel, blinding of
outcome assessment, incomplete outcome data, selective re-
porting, and other bias. The risk of bias in each domain was
judged as either low, moderate, high, or unclear.
Statistical Analysis
We combined individual study data for mortality, frequency of
treatment failure, secondary infections, antimicrobial resistance,
and duration of antibiotic use. Mantel-Haenszel models were used
for all dichotomous outcomes, and the mean difference was used
to compare continuous data. A random-effects model was used
to analyze the data. The reference group was taken as the group
randomized to “standard care” or a longer fixed duration of anti-
biotics. The meta-analysis was carried out using review manager
(“RevMan”) for Mac (version 5.1; Cochrane Collaboration, Ox-
ford, United Kingdom). Statistical heterogeneity was assessed using
the I2 methodology. I2 values greater than 50% and greater than
75% were considered to indicate moderate and significant heter-
ogeneity among RCTs, respectively (5). All p values were two-tailed
and considered statistically significant if less than 0.05. Data on di-
chotomous outcomes are presented as relative risk (RR), 95% CIs,
p values, and I2 values, whereas data on continuous outcomes are
presented as mean difference, 95% CIs, p values, and I2 values.
Trial Sequential Analysis
Type I errors due to low sample sizes and repeated test-
ing of significance may result from meta-analyses (6). We
 Review Articles

performed a trial sequential analysis (TSA) using TSA pro-
gram version 0.9.5.10 (Trial Sequential Analysis TSA, Co-
penhagen: Copenhagen Trial Unit, 2016; http://www.ctu.
dk/tsa) to assess the impact of random error and repetitive
testing for the primary outcome (7). Meta-analysis monitor-
ing boundaries (trial sequential monitoring boundaries) and
the required information size (IS) were quantified, alongside
with diversity-adjusted IS (D2) and adjusted 95% CIs. Diver-
sity adjustment was performed according to an overall type
I error of 5% and power of 80%. Required IS was calculated
using a RR reduction of 10%.
RESULTS
investigating the de-escalation from broad- to narrow-spec-
trum antibiotics, but not cessation of antibiotics (13) (Fig. 1).
Study Characteristics
A total of 22 RCTs including 6,046 patients reported mortality
related to different methods of optimizing antibiotic dura-
tion (Supplementary Table 1, Supplemental Digital Content
2, http://links.lww.com/CCM/F312) (14–35). Ten RCTs were
single center, and the other 12 were multicenter. Strategies
to minimize antibiotic use included: 1) biomarker guidance
(procalcitonin) (14 RCTs) (14, 17, 18, 22, 23, 25, 26, 28–34);
2) clinical algorithms (two RCTs) (20, 27); or 3) prespecified
fixed-antibiotic duration (six RCTs) (15, 16, 19, 21, 24, 35).

Included Trials Mortality

The search strategy used in this study produced 5,689 poten- RCTs with procalcitonin-guided antibiotic duration (procal-
tial titles and abstracts from database searches (Fig. 1). After re- citonin arm, 2,371; control arm, 2,373) had a weighted mean
moval of duplicates (n = 625) and screening titles and abstracts, mortality of 21.6%, RCTs using clinical algorithms to minimize
28 articles remained. These articles were screened against in- antibiotic duration (algorithm arm, 98; control arm, 99) had
clusion and exclusion criteria. A total of six prospective RCTs a weighted mean mortality of 22.3%, and the six RCTs using
were excluded as they included RCTs using biomarkers to guide fixed-dose antibiotics (short duration, 549; long duration, 556)
initiation (but not cessation) of antibiotic therapy (four stud- had a weighted mean mortality of 13.6% (Fig. 2; and Supple-
ies) (8–11), lacked mortality data (one study) (12), and an RCT mentary Table 2, Supplemental
Digital Content 3, http://links.
lww.com/CCM/F313).
Compared with the con-
trol group, neither procal-
citonin-guided antibiotic
therapy (RR, 0.91 [0.82–
1.01]; p = 0.09; I2 = 0%),
clinical algorithm–based treat-
ment (RR, 0.60 [0.21–1.70];
p = 0.33; I2 = 53%), nor fixed-
duration antibiotic treatment
(RR, 1.26 [0.88–1.80]; p = 0.19;
I2 = 0%) were associated with
lower mortality. TSA cor-
rection of the 95% CI was
obtained for the procalcito-
nin-guided antibiotic therapy
subgroup. The TSA (CI, 0.72–
1.10) demonstrated that 47%
of the required IS of 10,079
patients had been accrued in
order to detect or reject a 10%
relative risk reduction. The
cumulative z-curve touched
the conventional boundary for
benefit but did not cross the
TSA monitoring boundary for
benefit or harm (Fig. 3). TSA
for the clinical algorithm– and
fixed duration–based sub-
groups accumulated less than
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram. 5% of the required IS, thus
PCT = procalcitonin. they were not reported.
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Arulkumaran et al

Figure 2. Forest plot of mortality in trials using clinical algorithms, fixed duration, or procalcitonin (PCT) as a guide for antibiotic cessation in the ICU. Size
of squares for risk ratio reflects weight of trial in pooled analysis. Horizontal bars represent 95% CIs. df = degrees of freedom, M-H = Mantel-Haenszel.

Duration of Antibiotic Use
Antibiotic duration was reported in all 12 procalcitonin-guided
antibiotic trials and both clinical algorithm trials (Supplemen-
tary Fig. 1, Supplemental Digital Content 4, http://links.lww.
com/CCM/F314; legend, Supplemental Digital Content 10,
http://links.lww.com/CCM/F320). Compared with the control
arm, procalcitonin-guided antibiotic therapy resulted in a shorter
antibiotic duration (–1.23 d [–1.61 to –0.85 d]; p < 0.001; I2 =
92%). Use of clinical algorithms did not demonstrate a reduc-
tion in antibiotic duration (–7.41 d [–18.19 to 3.37 d]; p = 0.18;
I2 = 98%). The intended duration of antibiotics ranged from 2
to 8 days in the treatment arm and 7 to 15 days in the control
arm of the fixed-duration antibiotic RCTs. However, the “actual”
number of days patients received antibiotics in the fixed-duration
RCTs was reported in just one of the five RCTs (15). Treatment
noncompliance was reported in four of the six fixed-duration
RCTs and ranged from 3% to 21% (15, 16, 21, 24).
Clinical Cure/Treatment Failure
Treatment failure at 30 days for all but three (32, 34, 35) of the
procalcitonin RCTs was reported in an individual patient data
meta-analysis investigating the effect of procalcitonin-guided
antibiotic treatment on mortality in acute respiratory infections
in primary care, the emergency department, and ICUs (36).

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 Review Articles

Figure 3. Trial sequential analysis (TSA) of all trials of the effect on mortality of procalcitonin-guided antibiotic duration. Heterogeneity adjusted required
information size (IS) of 10,079 was calculated based on control group proportion of mortality of 22.5%, relative risk reduction of 10%, α of 5%, power of
80% and diversity (D2) of 0%. Four thousand seven hundred forty-four participants were actually accrued, accounting for 47% of the required information
size. Continuous black cumulative z curve touches the conventional boundary for benefit (dotted lines) but does not cross the trials sequential monitor-
ing boundaries (TSMB) of benefit or harm (etched lines). Z curve does not cross the etched line wedge area of futility extending to the right.

Treatment failure was reported in five of the six fixed-duration
RCTs but neither of the clinical algorithm RCTs. There was no
difference in treatment failure among the fixed-duration anti-
biotic RCTs (RR, 1.06 [0.74–1.53]; p = 0.75; I2 = 22%) or pro-
calcitonin-guided antibiotic treatment (RR, 0.93 [0.84–1.03];
p = 0.15; I2 = 0%) (Supplementary Fig. 2, Supplemental Dig-
ital Content 5, http://links.lww.com/CCM/F315; legend, Supple-
mental Digital Content 10, http://links.lww.com/CCM/F320).
Secondary Infections
The frequency of secondary infections was reported in clin-
ical algorithm RCTs (n = 368) (20, 27), three fixed-duration
RCTs (n = 692) (15, 16, 21), and six procalcitonin-guided RCTs
(n = 3,082) (14, 17, 23, 26, 30, 31) (Supplementary Fig. 3,
Supplemental Digital Content 6, http://links.lww.com/CCM/
F316; legend, Supplemental Digital Content 10, http://links.
lww.com/CCM/F320). No difference was seen in the frequency
of secondary infections between study groups in the clinical
algorithm group (RR, 1.14 [0.84–1.54]; p = 0.40; I2 = 0%),
in the fixed-duration RCTs (RR, 1.26 [0.83–1.92]; p = 0.27;
I2 = 48%), or the procalcitonin-guided RCTs (RR, 1.12 [0.91–
1.38]; p = 0.27; I2 = 15%).
Antimicrobial Resistance
Reporting of the frequency of antimicrobial resistance fol-
lowing initiation of antibiotics was variable. Reported data
included the number of positive isolates from screening sam-
ples, the number of positive isolates from clinical samples, or
the number of patients with any resistant organism isolated.
The majority of RCTs did not provide data on antimicrobial
resistance. We analyzed the number of patients with any re-
sistant organism isolated on clinical samples (excluding
screening samples).
We obtained data from one clinical algorithm study
(n = 74) (27), two fixed-duration RCTs (n = 437) (15, 21), and
none of the procalcitonin-guided antibiotic duration RCTs.
A lower frequency of antimicrobial resistance was seen in the
shorter duration group compared with the control group in
the one clinical algorithm study (odds ratio [OR], 0.26 [0.08–
0.81]; p = 0.02). The fixed-duration RCTs (OR, 1.08 [0.61–
1.90]; p = 0.79; I2 = 27%) did not demonstrate a significant
difference in the frequency of antimicrobial resistance between
the experimental and control groups. In a subgroup analysis
for fixed-duration antibiotics, among patients who developed
recurrent pulmonary infections, multiresistant pathogens
emerged significantly less frequently in those who had received
8 days of antibiotics (42.1% vs 62.3%) (16).
Risk of Bias Assessment
Most RCTs were deemed to have high risk of bias primarily
due to the inability to blind the clinicians to either interven-
tion and/or the outcome. These RCTs were deemed to carry a

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Arulkumaran et al
low risk of bias in the other domains of random sequence gen-
eration, allocation concealment, blinding of sequence gener-
ation, incomplete outcome data, and selective reporting. One
study was deemed to have low risk of bias (19) (Supplemen-
tary Table 3, Supplemental Digital Content 7, http://links.lww.
com/CCM/F317). As all but one RCT were deemed to have ei-
ther high risk of bias, risk of bias assessments was not used in
the data syntheses.
Subgroup Analyses
Six RCTs investigate the duration of antibiotics exclusively
in patients with VAP. Four of the RCTs used fixed-duration
antibiotics (15, 16, 19, 33), one used clinical algorithm (20),
and one used procalcitonin-guided therapy (28). Fixed-dura-
tion antibiotics are not associated with a difference in mor-
tality (RR, 1.20 [0.81–1.78]; p = 0.36; I2 = 0%) compared with
standard care. Neither the study using clinical algorithm nor
the procalcitonin-guided duration of antibiotics demonstrate
a reduction in mortality.
Only two RCTs included patients with an intra-abdominal
source of sepsis (21, 25). One of the two RCTs used fixed-
duration antibiotics and the other used procalcitonin-guided
therapy. One RCT included patients with nosocomial pneu-
monia (27), and another included patients with acute exac-
erbation of chronic obstructive airways disease (32). Other
RCTs include patients with “sepsis” or “bacterial infections”
but without a particular source of infection (Supplementary
Table 4, Supplemental Digital Content 8, http://links.lww.com/
CCM/F318).
Post Hoc Analyses
Based on reviewer’s recommendations, we conducted a post
hoc analyses of mortality at 21 days, 28 or 30 days, 3 months,
or in-hospital (Supplementary Fig. 4, Supplemental Digital
Content 9, http://links.lww.com/CCM/F319; legend, Supple-
mental Digital Content 10, http://links.lww.com/CCM/F320).
Among the procalcitonin-guided therapy RCTs, five studies re-
ported mortality outcomes at more than one time point (14,
22, 23, 26, 28). Eight studies reported 28- to 31-day mortality
(14, 17, 22, 23, 28, 31, 34, 35), eight studies reported in-hospital
mortality (18, 22, 23, 25, 26, 28–30), and three studies reported
3-month mortality (14, 26, 32). There is a reduction in 28- to
31-day mortality associated with procalcitonin-guided antibi-
otic therapy (RR, 0.88 [0.78–0.99]; p = 0.03; I2 = 0%) but not
in-hospital mortality (RR, 0.93 [0.73–1.18]; p = 0.53; I2 = 0%)
or 3-month mortality (RR, 1.03 [0.90–1.19]; p = 0.64; I2 = 0).
Among fixed-duration antibiotic studies, there were four
studies that reported 28- to 31-day mortality (16, 19, 21, 33).
These studies did not demonstrate any mortality benefit as-
sociated with fixed-duration antibiotics (RR, 1.20 [0.88–1.64];
p = 0.26; I2 = 0%). One study reported 21-day mortality, and
the other study reported in-hospital mortality; neither of
which demonstrated a mortality benefit. Of the two studies
using clinical algorithms, one study reported 28- to 30-day
mortality and the other study reported in-hospital mortality;
neither of which demonstrated a mortality benefit.
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DISCUSSION
This is the first meta-analysis with TSA to compare different strat-
egies to minimize antibiotic duration in the ICU. Although mor-
tality is a relevant clinical outcome, other clinical outcomes are
equally relevant although not always reported. This includes du-
ration of antibiotic use, all-cause mortality, treatment failure, sec-
ondary infections, and antimicrobial resistance (AMR). Although
a number of other meta-analyses on the use of procalcitonin in
ICU have been published, none have investigated all pertinent
clinical outcomes. Additionally, we have performed a TSA on the
effect of antibiotic discontinuation strategies on mortality.
Procalcitonin-guided therapy or prespecified limited dura-
tion is effective in reducing the number of days of antibiotic
exposure. The benefit on mortality with procalcitonin-guided
therapy or prespecified limited duration remains unclear based
on the current level of evidence. Irrespective of the method
used to de-escalate antibiotics, it is reassuring that a shorter
duration of antibiotic use is not associated with any difference
in mortality, treatment failure, or secondary infections. Based
on the TSAs, additional RCTs are required before data are con-
clusive. Data on clinical algorithm–guided antibiotic cessation
are limited.
Unlike fixed-duration antibiotic treatment, procalcitonin-
guided and clinical algorithm–guided antibiotic treatment is
underpinned by individual patient illness trajectory and their
response to treatment allowing the duration of antibiotics to
be personalized. Previous meta-analyses investigating the use
of procalcitonin to guide antibiotic duration have conflicting
results on mortality (36–42). It has been suggested that only
procalcitonin-guided cessation of antibiotics (but not initia-
tion, or initiation and cessation) is associated with a shorter
duration of antibiotic use and lower mortality (39). However,
RCTs investigating procalcitonin-guided initiation of antibi-
otics are from small numbers. We have included RCTs inves-
tigating procalcitonin-guided initiation of antibiotics in this
meta-analysis, as long as procalcitonin-guided algorithms were
used to discontinue antibiotics (30, 31).
Fixed durations of antibiotics may potentially provide an
objective method to reduce antibiotic exposure. Although we
have not demonstrated any mortality benefit with fixed-dura-
tion antibiotics in the heterogeneous populations studied, it
may be beneficial under specific conditions, such as hospital-
acquired pneumonia in critically ill adults not due to ferment-
ing and nonfermenting Gram-negative bacteria (43).
Another complication of prolonged antibiotic use includes
secondary infection. Antibiotics themselves are associated with
immune cell dysfunction, and they may contribute to post-
sepsis immunosuppression (44). Eight procalcitonin RCTs
report secondary infections with no difference between pro-
calcitonin-guided antibiotic cessation and the control group.
However, ICU-acquired infections may only contribute mod-
estly to overall mortality (45).
Many RCTs postulate that the benefit in reducing antibiotic
exposure may translate to reduced antimicrobial resistance.
The frequency of multidrug resistance in hospital-acquired
bloodstream infections in ICUs is as high as 35%, even in

high-income European countries where most of these RCTs
were conducted (46). However, reporting of antimicrobial re-
sistance in the RCTs included within this meta-analysis was
sparse. Reporting of antimicrobial resistance was, in itself, not
straightforward, with differing clinical implications between
routine surveillance and clinical samples. Furthermore, distin-
guishing colonization from infection is often vexatious.
Different RCTs have used different procalcitonin-guided or
clinical algorithms (with different procalcitonin cut-off values),
with a variable number of protocol violations. Furthermore,
the duration in the control arm of the procalcitonin studies
is variable, which may result in differences in outcomes. The
duration of follow-up is variable, which may further confound
the difference in results. Data on both short- and long-term
outcomes would be valuable, particularly long-term data on
secondary infections and AMR rates. The patient populations,
their underlying diagnoses and illness severity, and manage-
ment have not been factored into this study. Some types of in-
fection may well require differing durations of therapy and this
could influence outcome. The RCTs looking at fixed duration
of antibiotics are mostly limited to patients with VAP, whereas
this forms only a minority of procalcitonin-guided antibiotic
RCTs.
Data on secondary infections and relapse rates are incom-
plete, and data on antimicrobial resistance are even more lim-
ited. Different RCTs are likely to have used different thresholds
and criteria for the diagnosis of treatment failure and sec-
ondary complications. In order to ascertain complete data on
treatment failure in the procalcitonin RCTs, we used data from
the published individual patient data meta-analysis rather than
from individual RCTs (where data are not always reported)
(36). There were only two trials studying the utility of clinical
algorithms in guiding antibiotic cessation, limiting any inter-
pretation of these data.
Additionally, there are differences in the proportion of
patients who may have had antibiotics prior to trial enrolment,
whereas the types and number of antibiotics used subsequent
to trial enrolment may also vary. It was not possible to control
for the variability in antibiotic type or dosing between RCTs
in the pooled analysis; even though we had intended to do this
when writing the protocol. Although performing a TSA was
not prespecified in the initial protocol, on final data analysis,
we performed TSAs for completeness.
Information gained from this analysis should help in the
design of further high-quality RCTs which focus on specific
clinical cohorts and treatment algorithms, with data collected
on treatment failure rates, secondary infections, and the de-
velopment of antimicrobial resistance. Data on clinical algo-
rithms to guide antibiotic cessation are limited and require
further attention.
In conclusion, earlier cessation of antibiotics, when guided
by procalcitonin or prespecified limited duration, is associated
with shorter duration of antibiotic use. Although the duration
of antibiotic therapy is reduced with procalcitonin-guided
therapy or prespecified limited duration, the benefit on mor-
tality remains unclear. The shorter duration of antibiotic use
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Review Articles
is safe with no increase in mortality or the frequency of treat-
ment failure, or secondary infections.
Mr. Arulkumaran contributed in study conception and drafting the article.
Ms. Khpal and Mr. Baheerathan contributed in literature search and data
extraction. Ms. Khpal contributed in assessment of bias. Mr. Arulkumaran
and Mr. Corredor contributed in statistics. Mr. Arulkumaran and Dr. Singer
contributed in finalizing article.
Supplemental digital content is available for this article. Direct URL cita-
tions appear in the printed text and are provided in the HTML and PDF
versions of this article on the journal’s website (http://journals.lww.com/
ccmjournal).
Mr. Arulkumaran and Ms. Khpal acknowledge the National Institute of
Health Research for salary funding.
Dr. Singer’s institution received funding from Bayer and Innovate UK, and
he received funding from Shionogi. The remaining authors have disclosed
that they do not have any potential conflicts of interest.
Address requests for reprints to: Nishkantha Arulkumaran, PhD, Division
of Medicine, Bloomsbury Institute of Intensive Care Medicine, University
College London, Gower Street, London, WC1E 6BT, United Kingdom.
E-mail: nisharulkumaran@doctors.org.uk
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