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REVIEW

C URRENT
OPINION Duration of antibiotic therapy in Gram-negative
infections with a particular focus on multidrug-
resistant pathogens
Sara F. Haddad , Fatima Allaw  and Souha S. Kanj

Purpose of review
Antimicrobial overuse is a major health problem that contributes to antimicrobial resistance (AMR).
Infections with Gram-negative bacilli (GNB) and multidrug-resistant organisms (MDRs) are associated with
high morbidity and mortality, particularly in patients with underlying medical conditions.
Recent findings
Although many recent studies have been published about the novel antibiotics in treating infections
including those due to MDR-GNB, the optimal duration of treatment (DOT) remains inconclusive. Recent
observation has supported that short antibiotic therapy (SAT) decreases AMR and adverse effects. This
narrative review provides an overview of the most recent published studies on the duration of therapy in
the treatment of GNB infections, including hospital-acquired pneumonia (HAP) and ventilator-associated
pneumonia (VAP), intra-abdominal infections (IAIs), bloodstream infections (BSIs) and urinary tract infections
(UTIs), with a particular focus on MDR-GNB.
Summary
Studies showed different outcomes when comparing SAT to long antimicrobial therapy (LAT). No
generalization can be made on all sites of infections and different GNBs. Further studies are needed to
address the optimal DOT in MDR-GNB, as this group is underrepresented in recent studies.
Keywords
bloodstream infections, duration of antibiotic therapy, Gram-negative bacilli, hospital-acquired and ventilator-
associated pneumonia, intra-abdominal infections, multidrug-resistant Gram-negative bacteria, urinary tract
infections

INTRODUCTION mortality and are often seen in patients with comor-

Antimicrobial resistance (AMR) is a major threat
globally and has been made worse by the COVID-
19 pandemic [1]. Historically, antibiotics have been
prescribed for a long duration for infectious diseases
without evidence to support the ideal course of
therapy. The number of 7 to 14 days was arbitrarily
chosen, possibly based on the codified week of
7 days fixed by the Roman emperor Constantine
the Great [2]. It is well established though that
prolonged therapy is a risk factor for AMR [3].
The duration of antibiotic therapy depends on
three major components: the host, the infection
and the drug used. Only recently, studies have
addressed the optimal duration of therapy (DOT).
However, it remains a challenging question notably
for Gram-negative bacilli (GNB) and multidrug-
resistant GNB (MDR-GNB), as infections with these
pathogens are associated with high morbidity and
bidities or in immunocompromised hosts (ICH) [4].
Recent observations have shown that when sup-
ported by evidence, short antimicrobial therapy
(SAT) decreases the emergence of AMR [5] and anti-
biotic-related adverse effects, including Clostridiodes
difficile infection [6]. It also shortens hospital length
Division of Infectious Diseases, American University of Beirut Medical
Center, Beirut , Lebanon
Correspondence to Souha S. Kanj, MD, FACP, FIDSA, FRCP, FES-
CMID, FECMM; Professor of Medicine, Associate Dean for Global
Affairs Head, Division of Infectious Diseases Chairperson, Infection
Control Program; American University of Beirut Medical Center, P.O.
Box 11–0236, Riad El Solh 1107, 2020 Beirut, Lebanon.
Tel: +961 1 350000; fax: +961 1 370814; e-mail: sk11@aub.edu.lb

Both Sara F. Haddad and Fatima Allaw contributed equally to this study.
Curr Opin Infect Dis 2022, 33:000–000
DOI:10.1097/QCO.0000000000000861

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Gram-negative infections

of stay (LOS) and decreases overall healthcare costs

KEY POINTS
 Prolonged antibiotic administration has been associated
with antimicrobial resistance; therefore, the new
paradigm is to treat infections only for as long as it
is necessary.
 When deciding about the duration of treatment of
infections with GNB, one must take into consideration
the site of infection, the patient’s host factors, rapidity
of response to therapy and source control.
 Most studies on the duration of antimicrobial therapy in
Gram-negative infections included mostly
enterobacterales, with an underrepresentation of
nonfermenting organisms and MDR-GNB.
 Results of ongoing RCT will guide proper duration of
therapy in various clinical conditions.
[7]. This review summarizes the evidence regarding
the DOT for GNB in various infections with a focus
on MDR-GNB (Table 1).
HOSPITAL-ACQUIRED AND VENTILATOR-
ASSOCIATED PNEUMONIA
The Infectious Diseases Society of America/Ameri-
can Thoracic Society (IDSA/ATS) [8] and European
[9] guidelines for the management of nosocomial
pneumonia recommend a 7 to 8-day duration. The
efficacy and safety of SAT were first established in a
randomized controlled trial (RCT) by Chastre et al.
[10]. This was further confirmed by other trials and
meta-analyses [11].
Ongoing studies are investigating the possibility
of further shortening the duration to less than
8 days. The REGARD-VAP trial is a multinational

Table 1. Suggested duration of therapy for infections with Gram-negative pathogens including those with multidrug resistance

Recommended antibiotic
Site of infection duration (days) Comments

HAP/VAP
Enterobacterales 7--8 Ongoing trials about shortening the duration for less than 8 days: - REGARD-VAP
trial: noninferiority and superiority of SAT (up to 7 days) versus LAT
- DATE trial: 4 versus 8-day treatment for early VAP, completed in early 2022 with
pending results
Pseudomonas aeruginosa 8--14 Prolonged duration associated with lower risk of relapse
IAI
With source control 4--15 Duration varies depending on adequate source control, underlying host factors and
type of organisms;
ICU patients might require longer duration
Ongoing trial:- EXTEND trial: comparing 28 days of antibiotics to standard of care
BSI
Enterobacterales 7 Longer in complicated bacteraemia
Pseudomonas aeruginosa 10--14 Depending on host factors and source of the bacteraemia (primary versus
secondary);
3 weeks might be required for complicated infections
Catheter-related BSI 7 Catheter should be removed
UTI
Afebrile cystitis in women 3--5 If fosfomycin is used two doses separated by 3 days
Afebrile cystitis in men 7 If ciprofloxacin or trimethoprim/sulfamethoxazole is used, otherwise longer
duration might be required
Pyelonephritis due to 7 Including UTI with secondary BSI and ESBL producing Enterobacterales
Enterobacterales
Pyelonephritis due to 14 Might need to extend to 3 weeks if slow response
Pseudomonas aeruginosa
Prostatitis 14 Shorter courses associated with higher relapse
Catheter-associated UTI 3--7 Duration depends on the initial response;
3-day treatment course for women younger than 65 years whose catheters have
been removed

BSI, bloodstream infections; ESBL, extended-spectrum beta-lactamases; GNB, Gram-negative bacilli; HAP/VAP, hospital-acquired or ventilation-associated
pneumonia; IAI, intra-abdominal infections; LAT, long antibiotic treatment; NF-GNB: nonfermenting Gram-negative bacilli; SAT, short antibiotic treatment; UTI,
urinary tract infection.

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QCO 350602
multicentre study, which aims to demonstrate clin-
ical noninferiority and superiority of SAT (up to
7 days) versus long antibiotic treatment (LAT)
[12]. Another study, the DATE trial (Duration of
Antibiotic Treatment for Early VAP), was completed
in early 2022 with pending results. It investigated a
regimen of 4 versus 8-day treatment for early VAP
[13].
However, although evidence is mounting to
support SAT in GNB HAP/VAP, the DOT for non-
fermenting GNB has not been clearly established. In
the initial trial of Chastre et al. [10], patients with
VAP due to NF-GNB (33%) had statistically higher
infection recurrence with SAT but no other differ-
ences in outcomes including the duration of
mechanical ventilation and 28-day mortality. How-
ever, fewer MDR organisms were identified among
patients treated for 8 compared with 15 days [10]. In
a study by Kollef et al., the 28-day mortality was
reported as significantly greater in the subgroup of
patients with Pseudomonas aeruginosa VAP (PA-VAP)
treated with SAT [14]. A Cochrane systematic review
published in 2015 showed that a SAT of 7 to 8-day
compared with 10 to 15-day reduced recurrence of
VAP due to MDRO without adversely affecting mor-
tality and recurrence. However, for cases of VAP due
to NF-GNB, recurrence was greater after SAT, though
mortality outcomes were not significantly different
[11].
Although based on moderate-quality evidence,
the most recent IDSA/ATS guidelines for HAP/VAP
in 2016 recommend a 7-day antibiotic course for all
GNB HAP/VAP, including NF-GNB [8].
Recent studies aimed to provide more robust
evidence. The iDIAPASON RCT published this year
compared 8 to 15 days in confirmed PA-VAP. The
primary outcome was a composite endpoint com-
bining mortality and PA-VAP recurrence occurring
during the ICU stay until day 90. There was no
difference in the mortality between SAT and LAT;
however, patients in the 8-day group were twice as
likely to have a PA-VAP recurrence. As for the sec-
ondary outcomes, both groups had a similar median
duration of mechanical ventilation, duration of ICU
stay and a similar proportion of MDR pathogens
&&
acquisition during ICU stay [15 ]. However, this
study included only 33% of the patients initially
planned, a factor that may limit the power of
the study.
Moreover, there are no rigorous data addressing
the optimal DOT of VAP due to other NF-GNB such
as Stenotrophomonas spp., Acinetobacter spp., nor for
the carbapenem-resistant Enterobacterales (CRE),
which are common organisms in HAP/VAP. More
research is needed before definitive conclusions can
be drawn. For now, 7–8 days seem to be the
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Duration of antibiotic therapy for GNB Haddad et al.
recommended regimen for GNB HAP/VAP; how-
ever, the optimal duration for P. aeruginosa pneumo-
nia is still uncertain. We believe that a longer course
of therapy should be favoured especially in patients
who have underlying comorbidities, bacteraemia,
slow response to therapy or a multidrug-resistant
strain. Further research is needed before drawing
any definitive conclusions.
INTRA-ABDOMINAL INFECTIONS
The cornerstone of effective IAI management is
adequate source control (ASC) and appropriate anti-
microbial therapy, the optimal duration of which
remains uncertain. The STOP-IT trial, which com-
pared 4 versus 8 days of antibiotics after ASC,
showed no difference in the composite primary
endpoint of surgical-site infection (SSI), recurrent
IAI or death, although longer durations significantly
reduced the time until relapse. It is worth noting
though that there are some limitations to the study,
as the rate of nonadherence to the protocol was
high, including 18% of patients in the experimental
group, and the original calculated sample size to
assert equivalence between groups was not achieved
[16].
In a recent retrospective analysis comparing 4
versus 6 days of antibiotics after ASC, no difference
was noted in ICU and hospital LOS, SSI, intra-
abdominal abscesses or death between the two
groups [17]. Another retrospective single-centre
study revealed no significant difference in the rate
of clinical cure between SAT (=7 days) and LAT
(>7 days), as well as the ICU and hospital LOS, 28-
day all-cause mortality rate and 30-day readmission
rate [18].
However, the DURAPOP trial, which only
included patients with IAI admitted to the ICU,
compared 8 with 15 days of antibiotics and found
no difference in terms of ICU and hospital LOS,
emergence of MDR bacteria [except for a slight
increase in the number of MDR P. aeruginosa after
the 15-day course (59 versus 21%)] [19] or reopera-
tion rate between the two groups, but a higher rate
of subsequent need for drainage in patients with
the SAT.
The different studied patient populations and
the variations in the measurement of outcomes in
some of the IAIs studies may lead to biased and
misleading results, questioning the validity of the
reported data supporting SAT.
In fact, a new randomized controlled unblinded
feasibility trial on 31 patients (the CABI trial)
showed that 23.5% of patients in the SAT arm
(10 days) had a relapse of IAI compared with none
in the LAT arm (28 days), suggesting the importance
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Gram-negative infections
to increase recruitment in a full trial to have solid
&
data [20 ]. Due to concerns of unacceptably high
rates of relapse, a current multicentre, open-label
RCT in the UK aims to compare a fixed duration of
28 days of antibiotics to the standard duration (typ-
ically 7–18 days) based on clinical outcomes, cost-
effectiveness and quality of life assessed over
180 days of follow-up [21].
Thus, short treatment regimens must be used
prudently in IAI with close monitoring, until more
robust data are provided. Underlying host factors
and ASC are essential in guiding decisions. Future
trials must measure standardized and clinically
meaningful outcomes, which would enable clini-
cians to make better decisions on patient care and
result in improved antimicrobial prescribing [22].
BLOODSTREAM INFECTIONS
Historically, BSIs have been treated for at least
14 days regardless of the isolated pathogens. On
the basis of the most recent guidance by IDSA, there
is no need to prolong the DOT for a resistant patho-
gen compared with the susceptible ones [23]. A
recent systematic review and meta-analysis found
no significant difference between SAT and LAT in
the treatment of uncomplicated GN-BSI on 30-day
and 90-day mortality, recurrent bacteraemia or
&
resistance development [24 ]. Moreover, in an
observational prospective cohort study in adults
with uncomplicated GNB bacteraemia, a treatment
course of less than 10 days was not associated with
an increased risk of 30-day mortality and a 90-day
recurrence rate. Twelve percent and 4% of the
patients in the SAT group had E. coli extended
spectrum beta lactamase (ESBL) and Klebsiella sp.
CRE, respectively [25]. This was also observed in
another study wherein the rate of ESBL E. coli was
29.3% in the SAT group (less than 10 days), and SAT
was not identified as an independent risk factor for
all-cause mortality or relapse of GNB bacteraemia
within 90 days of treatment after adjusting for mul-
tiple factors [26]. In an RCT including 504 patients
from three Swiss hospitals, 504 patients were
randomized to C-reactive protein (CRP)-guided
duration, a 7 and a 14-day duration of antibiotics
for GN-BSI. There was no difference in clinical out-
&&
comes on day 30 between the three groups [27 ].
One should be careful in using CRP-guided therapy,
as its elevation is not solely related to infection-
related inflammation.
It is difficult to generalize the findings of the
studies on MDR-GNB BSI to P. aeruginosa BSI, as the
latter tends to occur in patients with underlying
medical conditions, and the sources of infections
are usually different than for Enterobacterales. In a
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10-year retrospective study from Korea, patients
with uncomplicated P. aeruginosa BSI (including
MDR) who received SAT had no significant differ-
ence in the risk of recurrence or 30-day mortality
&&
compared with the LAT group [28 ]. ICH including
those on chemotherapy were included in the study.
However, almost all patients had ASC, and patients
with complicated infections defined as persistent
bacteraemia after 3 days and the presence of meta-
static foci of infection were excluded. Also, analysis
based on AMR genotyping of P. aeruginosa was not
done. RCTs are needed to draw stronger conclusions
about MDR P. aeruginosa.
As for catheter-related BSI (CR-BSI), although
IDSA recommends that GNB get treated for 7–
14 days [29], data from the literature support that
SAT (7 days) may be as effective as LAT (>7 days)
& &
when the central line is removed [30 ,31 ].
Finally, for patients with BSI in the setting of
febrile neutropenia, there remains uncertainty about
the conditions required for antibiotics discontinua-
tion [32,33]. In an interventional single-centre study
wherein the 4th European conference on infections
in leukaemia (ECIL-4) recommendations [34] were
implemented, antibiotics exposure was reduced to
7 days and there was no increase in infectious com-
&&
plications [35 ]. The SHORTEN trial is an ongoing
phase 4 RCT to prove that SAT is favoured over LAT in
patients with Enterobacterales bacteraemia. How-
ever, patients postchemotherapy and patients with
CRE were excluded from this trial [36].
SAT for MDR-GNB BSI has not yet been imple-
mented in clinical practice, as they are underrepre-
sented in studies. More RCTs are needed, and
decisions on the optimal duration should be guided
by the response to therapy, ASC and underlying
host factors.
URINARY TRACT INFECTIONS
Guidelines for the DOT in pyelonephritis have not
been updated and recommend a variable duration
according to the drug, and the presence of obstruc-
tion or abscesses [37]. As for resistant GNB, a retro-
spective single-centre observational study about
ESBL-producing Enterobacterales UTI including bac-
teraemia showed that there was no significant differ-
ence in 30-day mortality between patients who
received a 7 and more than 7 days of antibiotic
&&
therapy [38 ]. Hence, there is a tendency towards
not extending the DOT for pyelonephritis even if it
is associated with bacteraemia or MDR pathogens.
A recent RCT showed that in afebrile men with
suspected UTI, a 7-day course of ciprofloxacin or
trimethoprim/sulfamethoxazole was noninferior to
&&
a 14-day course [39 ].
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QCO 350602
An ongoing multicentre RCT - the Shortened
Antibiotic Treatment of 5 Days in Gram-negative
Bacteremia (GNB5) - aims to assess the efficacy and
safety of shortening antibiotics course to 5 com-
pared with 7 or more days for patients presenting
with BSI from UTI. However, in this trial, ICH, and
those with NF-GNB are excluded [40].
Finally, IDSA guidelines recommend a course of
7–14 days for the treatment of catheter-associated
UTI (CA-UTI) according to the initial response and a
3-day treatment course for women younger than
65 years whose catheters have been removed [41].
There are no RCTs to support shortening the dura-
tion of CA-UTI treatment, but a retrospective obser-
vational study showed that a SAT of 3–5 days in
trauma ICU patients had an acceptable clinical suc-
cess rate compared with the LAT [42]. Thus, a SAT is
attractive to minimize the emergence of bacterial
resistance particularly, as the catheters might
remain colonized with organisms.
OPTIMAL DURATION OF THERAPY FOR
MULTIDRUG-RESISTANT GRAM-NEGATIVE
BACTERIA
The optimal DOT remains a debate when dealing with
MDR-GNB, and the evidence behind it is scarce, as
most studies focus on the choice rather than the DOT.
Moreover, studies focusing on novel antibiotics with
activity against MDR-GNB had an objective to com-
pare these drugs to the standard of care or to the best
available therapy, but with a heterogeneous total
DOT from 5 to 21 days according to the clinical
&&
trial, site of infection and clinical response [43 ].
Novel antibiotics, including ceftazidime-avibactam,
ceftolozane-tazobactam, imipenem-cilastatin-rele-
bactam, meropenem-vaborbactam and cefiderocol,
have been found to be noninferior to the comparators
&&
in HAP/VAP, IAI and UTI [43 ]. These drugs are a
welcome addition to the armamentarium in clinical
practice. However, no firm recommendations can be
drawn from these trials on the optimal DOT.
An ongoing trial is investigating a 7 compared
with a 14-day course regimen for drug-resistant
Acinetobacter baumannii HAP/VAP [44]. Another trial
aims to compare antimicrobial discontinuation in
MDR-GNB HAP/VAP based on a daily assessment as
compared to the fixed duration set by guidelines
[45]. Results of these studies will hopefully lead to
conclusive results to guide future practice.
SPECIAL SCENARIOS WHEREIN A
LONGER DURATION OF THERAPY MIGHT
BE NEEDED
Patients’ host factors might play an important role
in the decision-making regarding the DOT, as the
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Duration of antibiotic therapy for GNB Haddad et al.
safety of shortening the DOT in certain high-risk
groups is still uncertain.
Immunodeficiency
There is limited evidence on the optimal DOT for
GNB infections in ICH. The lack of adequate innate
and adaptive defense mechanisms alters clinical
outcomes of infections, which may hinder the gen-
eralizability of the earlier discussed study results.
Moreover, ICH have a wide range of conditions
including malignant and nonmalignant conditions.
For these reasons, most studies on treatment dura-
tion exclude or under-represent ICH.
The management of GNB infections in this pop-
ulation is extremely challenging, as prolonged expo-
sure to antimicrobial agents puts patients at risk for
infections with resistant pathogens, whereas SAT
may lead to worse outcomes.
Two retrospective studies in 2018 included ICH
&&
but reported contradictory results: Fabre et al. [46 ]
included a majority of ICH (65%) with P. aeruginosa
BSI and showed no difference in outcomes between
shorter (7–11 days) and LAT. In contrast, Giannella
et al. [26] who investigated treatment duration for E.
coli BSI included 20% ICH with a higher cumulative
risk of relapse for SAT. Prospective studies with
larger populations and a focus on MDR pathogens
are needed to determine the optimal DOT in ICH.
For now, a patient-centred approach, including the
isolated pathogen, the level of immunosuppression
and the rapidity of response to therapy, shall guide
the DOT in these patients.
Absence of adequate source control
ASC is a fundamental prerequisite to SAT. Whether
removal of catheters or other foreign bodies or
draining of abscesses, a multidisciplinary approach
with collaboration with intensivists, surgeons and
interventional radiologists is highly recommended.
However, this is not always possible. In these prob-
lematic situations, short antibiotic regimens shall
not be considered, as this is not supported by evi-
dence and may lead to negative outcomes.
CONCLUSION
The DOT in GNB deserves considerable attention, as
limiting antibiotic exposure remains a cornerstone of
proper antimicrobial stewardship in the fight against
AMR. In recent years, a strong trend towards SAT has
been discussed, as studies proved its efficacy and
safety in certain infections. Data on SAT for treatment
of infections due to GNB are limited and are summar-
ized in this review. Whereas some studies showed
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Gram-negative infections
similar outcomes, others showed worse outcomes in
defined situations. Care must be taken not to extrap-
olate results from sites and pathogens to others. Fur-
ther robust studies are needed in the future to address
the optimal DOT in various sites of infection includ-
ing for MDR-GNB and in ICH. Until such data become
available, a patient-centred approach and precision
medicine are recommended taking into considera-
tion many factors, including the isolated bacteria, the
host, the drug used, source control and the rapidity of
the response.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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