Download Strategies for Reduction in Duration of Antibiotic Use in Hospitalized

A N T I M I C R O B I A L R E S I S TA N C E
INVITED ARTICLE
George M. Eliopoulos, Section Editor
Strategies for Reduction in Duration of
Antibiotic Use in Hospitalized Patients
Yoshiro Hayashi1,2 and David L. Paterson1,3
1The University of Queensland, Centre for Clinical Research, Brisbane, 2Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital,
Brisbane, and 3Department of Infectious Diseases, Royal Brisbane and Women's Hospital, Brisbane, Australia
There is a global crisis of antibiotic resistance in part because of the collateral damage of antibiotic use.
Reduction in antibiotic consumption is clearly important to minimize this problem. Limiting treatment
duration may be the most clinically palatable means of reducing antibiotic consumption. Antimicrobial
stewardship programs play an important role in this process. Their effectiveness may be increased by drawing
on evidence from randomized controlled trials regarding optimal antibiotic duration. However, in most clinical
scenarios, the recommended duration of therapy in published guidelines is based on expert opinion. Biological
markers, such as procalcitonin, have been shown to reduce antimicrobial consumption with no adverse
outcome in 11 randomized controlled trials. Although procalcitonin may not be the perfect biomarker, the
concept of procalcitonin-guided antibiotic discontinuation after clinical stabilization, in conjunction with
antimicrobial stewardship programs, appears to be ready for introduction into clinical practice.
Infection control plays an important role in preventing
spread of antibiotic-resistant bacteria. However, there
are a number of potential options by which antibiotic
administration can be modified to reduce antibiotic
resistance. In the hospital setting, these include frontend restriction of antibiotic use, whereby prescribers
need prior approval to use certain agents [1]. Antibiotic
cycling and use of combination antibiotic therapy have
been suggested as other options to reduce resistance,
although evidence supporting their use is lacking [1]. At
the 45th Annual Meeting of the Infectious Diseases
Society of America, Louis Rice delivered the Maxwell
Finland Lecture on modalities to reduce antimicrobial
resistance; he concluded that reduction in length of
antibiotic courses was the antibiotic use strategy most
likely to be effective in reducing antibiotic resistance [2].
Received 14 June 2010; accepted 13 January 2011.
Correspondence: David L. Paterson, MD, University of Queensland, Centre for
Clinical Research, Level 8, Bldg 71/918, University of Queensland, Royal Brisbane
and Women's Hospital, Herston, Brisbane, QLD 4029, Australia, (david.antibiotics@
gmail.com).
Clinical Infectious Diseases 2011;52(10):1232–1240
Ó The Author 2011. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
[email protected].
1058-4838/2011/5210-0006$14.00
DOI: 10.1093/cid/cir063
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The proposed mechanism was that shorter courses of
antibiotics reduce selective pressure on bacterial flora
and, therefore, prevent emergence of resistance [2].
The importance of antibiotic stewardship programs
as a modality to improve quality of prescribing and to
reduce duration of antibiotic use has been emphasized
in a number of recent reviews and guidelines [3].
Without external pressures, prescribers may not willingly curtail antibiotic duration or de-escalate their
empirical antibiotic choices. Studies from Europe and
the United States have shown that de-escalation was
only performed in 11%–55% of patients in whom it
would have been appropriate [4–7].
Use of an antibiotic discontinuation policy is a key
potential role of antibiotic stewardship programs. The
feasibility of use of basic clinical, laboratory, and radiologic measures as a means of curtailing antibiotic
duration was established by Singh et al [8]; in their trial,
use of the clinical pulmonary infection score to objectively assess the presence of ventilator-associated pneumonia (VAP) after 3 days of empirical antibiotic therapy
was associated with much shorter antibiotic therapy,
compared with the standard care group (3 days vs 9.8
days). In addition, there was a lower frequency of
development of antimicrobial resistance, with no
difference in mortality and length of intensive care unit
(ICU) stay. However, this study was not performed in the
context of an antibiotic stewardship program and the standard
duration of therapy for VAP in this study was 10–21 days, which
is much longer than the current standard of 7 days.
In a more recent evaluation of antimicrobial stewardship in an
ICU by Micek et al [9], antibiotic therapy initiated for clinically
suspected VAP was discontinued if a noninfective etiology for
infiltrate was identified or signs and symptoms suggested active
infection had resolved. In this study, the duration of antibiotics
in the antibiotic discontinuation group was 2 days shorter than
that in the conventional treatment group (mean 6 standard
deviation, 6.0 6 4.9 days vs 8.0 6 5.6 days), with no difference
in occurrence of a secondary episode of VAP, hospital mortality,
and ICU length of stay.
These studies of simple antibiotic discontinuation policies
demonstrate that antibiotic stewardship should be able to reduce
antibiotic use safely, even in critically ill patients. The purpose of
this article is to review 2 additional strategies to encourage
shorter durations of antibiotic use: (1) application of results of
randomized trials of differing antibiotic durations to clinical
practice and (2) use of biomarkers in conjunction with clinical
signs of resolution of infection, to drive discontinuation of antibiotics.
Application of Results of Randomized Trials of
Differing Antibiotic Durations to Clinical
Practice
There are, unfortunately, few randomized controlled trials on
comparative effectiveness of antibiotic regimens of differing
durations (Table 1). This may not be surprising, given the cost
and complexity of organizing randomized trials.
Community-Acquired Pneumonia (CAP)
Current guidelines of the Infectious Diseases Society of America
(IDSA) recommend that patients with CAP should be treated for
a minimum of 5 days [3]. At least 5 randomized controlled trials
(RCTs) have shown that antibiotic treatment for 5 days is as
effective and safe as longer treatment courses [11–13, 15, 17].
Two meta-analyses have also shown the efficacy and safety of
shorter course (#7 days) antimicrobial treatment in CAP [27,
28]. Although trials in these meta-analyses have emphasized
short-course studies with azithromycin (which has a long intracellular half-life) and have not exclusively enrolled hospitalized patients, a recent RCT has even demonstrated that
intravenous amoxicillin for 3 days as treatment for CAP was as
successful as 8 days of antibiotic treatment [16].
The weight of current evidence would suggest that CAP can
be treated for 5 days, perhaps even for as few as 3 days. The
presence of bacteremic Staphylococcus aureus pneumonia, empyema, lung abscess, necrotizing pneumonia, or some specific
agents of infection (for example, Legionella) may mandate longer durations.
Ventilator-Associated Pneumonia (VAP)
Traditionally, VAP was treated for 14–21 days. However, current
IDSA guidelines generally recommend 7 days treatment for
VAP, if a causative organism is other than a nonfermentative
gram-negative bacillus (GNB), such as Pseudomonas aeruginosa
or Acinetobacter species [29]. This is based on a multicenter RCT
by Chastre et al [18] that demonstrated that patients who received appropriate initial empirical therapy of VAP for 8 days
had outcomes similar to those of patients who received therapy
for 15 days. Recommendations for a longer course of treatment
for VAP due to nonfermentative GNB is based on a subgroup
analysis in the study, which showed a greater rate of recurrence
and/or relapse for those with a nonfermentative GNB who were
given 8 days of therapy. In contrast, a recent retrospective
analysis could not find a higher recurrence rate in patients with
VAP caused by nonfermentative GNB who received #8 days of
antibiotic therapy, compared with $ 9 days [30].
Bacterial Meningitis
The duration of antibiotics for bacterial meningitis is based on
tradition and expert opinion rather than on RCTs. The recommended duration of antimicrobial therapy in IDSA guidelines is
7–21 days, depending on the organism (Table 2) [31]. However,
shorter courses have been studied in some settings. One or
2 intramuscular injections of long-acting chloramphenicol (oily
suspension) has been recommended by the World Health Organization for epidemic meningococcal meningitis since 1995.
Nathan et al [36] demonstrated the noninferiority of a single
intramuscular administration of ceftriaxone to single intramuscular administration of oily chloramphenicol in an RCT
with 510 patients with suspected meningococcal meningitis in
Niger. The treatment failure rates for the intention-to-treat
analysis, although evaluated at 72 hours, were only 9% in both
arms. Although this result is not necessarily applicable to the
management of meningococcal meningitis in developed countries, a retrospective analysis and a prospective case series in New
Zealand showed that 3 days treatment with benzyl penicillin for
meningococcal meningitis was very successful [37–39].
Pyelonephritis
The IDSA guidelines for management of pyelonephritis published in 1999 recommended 14 days of treatment for most
situations [35]. This recommendation is based on an RCT
conducted by Stamm et al [21] that demonstrated that 2 weeks
of ampicillin or trimethoprim-sulfamethoxazole (TMP-SMX)
had no difference in clinical cure rate, compared with 6 weeks
of ampicillin or TMP-SMX. Subsequently, a meta-analysis of
4 RCTs compared short-course (7–14 days) with long-course
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Table 1. RCTs on Antimicrobial Duration in Typical Infectious Diseases in Adults, Divided by Year of Publication and Type of Infectiona
Regimen of
shorter course
treatment
Investigator
(year, reference)
Type of
infection
Siegel et al
(1999, [10])
CAP
Cefuroxime 750mg q8h IV,
2d, then cefuroxime axetil
500mg q12 PO, 5d, 7d in total
Cefuroxime 750mg q8h IV,
52
2d, then cefuroxime axetil
500mg q12 PO, 8d, 10d in total
No difference in
clinical cure
Leophonte et al
(2002, [11])
CAP
Ceftriaxone 1g IV qd, 5d
Ceftriaxone 1g IV qd, 10d
244
No difference in
clinical cure
Dunbar et al
(2003, [12])
CAP
Levofloxacin 750mg
IV/PO qd, 5d
Levofloxacin 500mg IV/PO qd,
10d
528
No difference in
clinical cure and
bacteriological
outcome
Dunbar et al
(2004, [13])
CAP
Levofloxacin
atypical
750mg IV/PO qd, 5d
Levofloxacin 500mg IV/PO qd,
10d
149
Leophonte et al
(2004, [14])
CAP
Gemifloxacin
320mg qd, 7d
Amoxicillin/clavulanate
1000/125mg, 10d
320
Noninferiority in
clinical cure and
bacteriological
outcome
No difference in
clinical, bacteriological,
and radiological efficacy
Tellier et al
(2004, [15])
CAP
Telithromycin 800mg
PO qd, 5d
Telithromycin 800mg PO qd, 7d
378
No difference in clinical
cure and bacteriological
outcome
Tellier et al
(2004, [15])
CAP
Telithromycin 800mg
PO qd, 5d or 7d
Clarithromycin 500mg PO bid,
10d
559
No difference in clinical
cure and bacteriological
outcome
El Moussaoui et al CAP
(2006, [16])
Amoxicillin 1g IV q6h, 3d
Amoxicillin 1g IV q6h, 3d, then
amoxicillin 750mg PO q8h, 5d,
8d in total
119
Noninferiority in clinical
and radiological success
File et al
(2007, [17])
CAP
Gemifloxacin 320mg
PO qd, 5d
Gemifloxacin 320mg PO qd, 7d
510
Chastre et al
(2003, [18])
VAP
8d
15 d
401
Non-inferiority in clinical,
bacteriological, and
radiological efficacy
No difference in mortality
and recurrence. Antibiotic-free
days (13.1 vs. 8.7, P,.001)
Sexton et al
(1998, [19])
IE
Ceftriaxone 2g qd 1 gentamicin
3mg/kg qd, 2 weeks
Ceftriaxone 2g qd, 4 weeks
51
No difference in clinical cure
rate and microbiological
eradication
Gleckman et al
(1985, [20])
AP
Gentamicin or Tobramycin
Gentamicin or Tobramycin
1.5–1.75mg/kg q8h IV, 48-72h,
1.5–1.75mg/kg q8h IV, 48-72h,
then TMP-SMX 160/800mg bid
then TMP-SMX 160/800mg
PO, 7-8d, 9-11d in total
bid PO, 18-19d, 20-22d in total
54
No difference in clinical
cure rate
Stamm et al
(1987, [21])
AP
Ampicillin 500mg q6h PO,
2 weeks
Ampicillin 500mg q6h PO,
6 weeks
27
No difference in clinical
cure rate
Stamm et al
(1987, [21])
AP
TMP-SMX 160/800mg q12h
PO, 2 weeks
TMP-SMX 160/800mg q12h
PO, 6 weeks
33
No difference in clinical
cure rate
Jernelius et al
(1988, [22])
AP
Pivampicillin/Pivmecillinam
500/400mg tid PO, 7d
Pivampicillin/Pivmecillinam
500/400mg tid PO, 7d, then
250/200mg tid PO, 14d, 21d
in total
77
Bacteriological success:
28% vs. 69% (P 5 .04)
De Gier et al
(1995, [23])
AP
Fleroxacin 400mg qd, 7d
Fleroxacin 400mg qd, 14d
54
No difference in clinical
cure rate
Talan (2000, [24])
AP
Ciprofloxacin 500mg bid, 7d
TMP-SMX 160/800mg bid, 14d
255
Clinical cure rate:
96% vs. 83% (P 5 .02)
Klausner et al
(2007, [25])
AP
Levofloxacin 750mg qd, 5d
Ciplofloxacin 500mg bid, 10d
192
No difference in
clinical cure and
microbiological eradication
Peterson et al
(2008, [26])
AP
Levofloxacin 750mg qd, 5d
Ciplofloxacin 500mg bid, 10d
1109 Noninferiority in clinical
cure rate and microbiological
eradication
Regimen of comparator
N
Outcome
NOTE. AP, acute pyelonephritis; CAP, community acquired pneumonia; IE, infective endocarditis; TMP-SMX, trimethoprim-sulphamethoxazole; VAP,
ventilator-associated pneumonia.
a
RCTs of CAP in which azithromycin were employed as a treatment regimen were excluded.
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Table 2. Duration of Currently Recommended Antimicrobial Treatment for Typical Infectious Diseases
Recommended duration
of antimicrobial treatment
Type of Infectious Diseases
CAP
HAP, VAP, and HCAP
RCT comparing
different durations
of treatment
Ref
Yes
Yes
[3]
[29]
No
[31]
No
[32]
No
[33]
$ 5 days
Bacteria other than NFGNB
7 days
NFGNB
14 days
Bacterial Meningitis
Neisseria meningitides
7 days
Haemophilus influenza
7 days
Streptococcus pneumonia
10–14 days
Streptococcus agalactiae
Gram-negative bacilli
21 days
21 days
Listeria monocytogenes
21 days
CRBSI
Coagulase-negative Staphylococcus spp.
5–7 days
Staphylococcus aureus
4–6 weeksa
Staphylococcus lugdunensis
4–6 weeksa
Enterococcus spp.
7–14 days
Gram-negative bacilli
Candida spp.
7–14 days
14 days after the first negative BC
Native valve endocarditis
Viridans Group and S. bovis (MIC: ..12, #0.5lg/mL)
4 weeks
Viridans Group and S. bovis (MIC: #.12lg/mL)
14 days
MSSA (uncomplicated right-sided)
14 days
MRSA
6 weeks
Prosthetic valve endocarditis
Viridans Group and S. bovis (MIC: #.12lg/mL)
MSSA and MRSA
6 weeks
$6 weeks
Complicated intra-abdominal infection
4–7 days
No
[34]
Pyelonephritis
14 days
Yes
[35]
NOTE. BC, blood culture; CAP, community-acquired pneumonia; HAP, hospital-acquired pneumonia; HCAP, health care–associated pneumonia; CRBSI,
catheter-associated bloodstream infection; Ref, reference; VAP, ventilator-associated pneumonia.
a
Patients can be considered for a shorter duration of antimicrobial therapy (ie, a minimum of 14 days of therapy) if the patient is not diabetic; if the patient is not
immunosuppressed (ie, not receiving systemic steroids or other immunosuppressive drugs, such as those used for transplantation, and is nonneutropenic); if the
infected catheter is removed; if the patient has no prosthetic intravascular device (eg, pacemaker or recently placed vascular graft); if there is no evidence of
endocarditis or suppurative thrombophlebitis on TEE and ultrasound, respectively; if fever and bacteremia resolve within 72 hours after initiation of appropriate
antimicrobial therapy; and if there is no evidence of metastatic infection on physical examination.
(14-42 days) antibiotic therapy in acute pyelonephritis in adults
[40]. No statistically significant differences were found between
the short- and long-course treatment of acute pyelonephritis in
terms of clinical success, bacteriologic efficacy, relapse, and adverse events.
In the past 10 years, several RCTs evaluating short courses
(#7 days) of fluoroquinolones have been conducted [23–26].
Talan et al [24] demonstrated that 7 days of treatment with
ciprofloxacin more successfully treated pyelonephritis than did
14 days of treatment with TMP/SMX. Two other RCTs showed
that 5 days of treatment with levofloxacin (750 mg once daily)
was as efficacious as 10 days of treatment with ciprofloxacin
(500 mg twice daily) [25, 26].
Infective Endocarditis (IE)
Recommended antimicrobial treatment durations for IE are
variable (2 weeks to $8 weeks) and depend on the causative
organism, minimum inhibitory concentrations of antibiotics
against the causative organism, and whether native or prosthetic
valves are involved (Table 2). A 2-week treatment course is
limited to only 2 situations [33]. The first is treatment of uncomplicated native valve endocarditis caused by highly penicillin-susceptible viridians group streptococci and Streptococcus
bovis with penicillin G or ceftriaxone plus gentamicin. This is
based on an RCT by Sexton et al [19] that demonstrated that
ceftriaxone plus gentamicin for 2 weeks was equivalent to ceftriaxone for 4 weeks and some case series that showed high cure
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rates (94%–100%) for short-duration regimens [41–43]. The
second situation is the treatment of uncomplicated native valve
right-sided endocarditis caused by oxacillin-susceptible S. aureus
with nafcillin or oxacillin plus gentamicin. This regimen is
supported by several clinical trials including RCTs, none of
which were planned to compare treatment durations [44–48].
Historically, short-course (#20 days) treatments for IE were
associated with higher relapse rates. Although these studies had
a number of methodological flaws, the overall contribution of
prolonged antibiotic duration for endocarditis to development
of resistance seems limited. However, further study of shortened
durations of intravenously administered antibiotic courses for
IE may be warranted for the economic and social gains that may
be achieved.
Complicated Intra-abdominal Infections
Current IDSA guidelines recommend use of antibiotics in the
treatment of complicated intra-abdominal infections for 4–7
days unless it is difficult to achieve adequate source control [34].
A retrospective analysis of 929 patients with intra-abdominal
infection that was performed by Hendrick et al [30] showed that
an antibiotic treatment duration #7 days was associated with
the same mortality rate and a lower recurrence rate than longer
antibiotic courses. On the basis of this result, a multicenter RCT
has commenced to evaluate short-course (3–5 days) antimicrobial treatment for intra-abdominal infections, compared
with antimicrobial treatment for up to 2 days after normalization of white blood cell count, temperature, and gastrointestinal
function (NCT00657566).
Skin and Soft-Tissue Infection
A randomized study has compared 5 with 10 days of antibiotics
in patients with uncomplicated cellulitis [49]. However, only
a minority of these patients were hospitalized [49]. We are not
aware of studies evaluating different treatment durations for
complicated skin and soft-tissue infection, although there is
a trend toward shorter durations in RCTs evaluating new antibiotics for this indication.
Catheter-Related Bloodstream Infection
For uncomplicated catheter-related bloodstream infection, recommended durations of antibiotic therapy by IDSA guidelines
are shown in Table 2. There are no randomized trials of differing
durations of therapy for catheter-related bloodstream infection,
with recommendations being based on retrospective case series
and expert opinion.
Conditions in Which No Randomized Trials Have Been Performed
The duration of antibiotic therapy for conditions, such as
bloodstream infection, aspiration pneumonia, septic arthritis,
and osteomyelitis, in hospitalized patients have not yet been
assessed in randomized trials. Although recommendations of
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treatment duration for other conditions are sometimes indicated for certain defined organisms, there is a lack of literature
regarding treatment duration for culture-negative infections.
Conclusions
A number of studies have been recently undertaken that have
compared shorter durations of antibiotics than have been typically been used in the past. The extent to which knowledge of
the efficacy of shortened durations of antibiotics for common
infections has been translated into changes in clinical practice is
almost completely unknown. Deviation of patient characteristics
from those included in RCTs is likely to be common in clinical
practice and may encourage physicians to use more prolonged
antibiotic courses. Furthermore, uncertainty regarding the
meaning of subgroup analyses (eg, relapse rates of nonfermentative GNBs in VAP) may further hamper extension of
RCT results in clinical practice. Regardless, controlled investigation of shorter antibiotic treatment durations should be
encouraged by the National Institutes of Health. On the basis of
published RCTs, shorter treatment durations seem just as likely
as more prolonged, traditional regimens to cure most common
bacterial infections.
Use of Biomarkers
Biomarkers, such as C-reactive protein (CRP) or procalcitonin,
have been increasingly studied as an aid to the clinical decision to
commence or discontinue antibiotics. Although biomarkers have
been used to aid the decision to commence antibiotic therapy, our
discussion emphasizes those studies examining use of procalcitonin in making the decision to discontinue antibiotic therapy.
Serum procalcitonin levels increase dramatically within 2–4
hours after onset of systemic inflammation, persist as long as the
inflammatory process continues, and normalize with recovery
[50]. The biological half-life of procalcitonin is 22–26 hours
[51]. Procalcitonin levels are increased in moderate-to-severe
bacterial infections but remain at comparatively low levels in
viral infections and nonspecific inflammatory diseases [52].
In the past decade, a large number of observational studies on
procalcitonin as a serum marker of bacterial infections have
been conducted [53–56]. Subsequently, procalcitonin has been
investigated for the purpose of limiting antibiotic use in RCTs in
2 major patient categories: patients with respiratory tract infection in the community and critically ill patients in the ICU.
Eleven RCTs on procalcitonin-guided antimicrobial treatment
have been published thus far, and all have shown significant
reduction of antimicrobial consumption in those whose treatment is guided by procalcitonin, compared with those treated
conventionally (Table 3).
Christ-Crain et al [57] first demonstrated that procalcitoninguided antimicrobial initiation was an effective strategy to limit
Table 3. Published RCTs of Procalcitonin (PCT)–Guided Antimicrobial Treatment in Adults
Primary
investigator
(year)
Journal
[reference]
Type of
infection
Country
(institution)
PCT assay
method
N
PCT used PCT used for
for initiation discontinuation
of antibiotics of antibiotics
Antibiotic
use
Clinical
outcome
Christ-Crain Lancet [57]
(2004)
LRTI
Switzerland
(University
Hospital,
Basel)
Kryptor
243
Yes
No
-47%
Unchanged
prescription
Christ-Crain Am J Respir
(2006)
Crit Care
Med [58]
CAP
Switzerland
(University
Hospital,
Basel)
Kryptor
302
Yes
Yes
-7.1
days
Stolz (2007) Chest [59]
COPD
exacerbation
Switzerland
(University
Hospital,
Basel)
Kryptor
226
Yes
No
-32%
Unchanged
prescription
Briel (2008) Arch Intern
Med [60]
Mild RTI at GP
Switzerland
Kryptor
(50 GPs
coordinated
by University
Hospital,
Basel)
458
Yes
Yes
-72%
Unchanged
prescription
Nobre (2008) Am J Respir
Crit Care
Med [61]
Severe
Switzerland
Sepsis/Septic
(University
Shock in medical Hospital,
ICU
Geneva)
Kryptor
79
No
Yes
-3.5 days
-2days
LOS in ICU
Unchanged
Schroeder
(2009)
Langenbecks
Sepsis
Germany
Arch Surg [62] (post-abdominal
(West
surgery)
Coast
Hospital)
LIA
27
No
Yes
-1.7 days
Unchanged
Hochreiter
(2009)
Critical
Care [63]
LIA
110
No
Yes
-2.0 days
Unchanged
-2.3 days
LOS
Sepsis in
surgical ICU
Germany
(West
Coast
Hospital)
Kristoffersen Clin Microbiol
(2009)
Infect [64]
LRTI
Demmark
Kryptor
(3 hospitals)
223
Yes
No
-1.7 days
Stolz
(2009)
Eur Resp
J [65]
VAP in ICU
Switzerland
Kryptor
and
USA (7 ICUs)
101
No
Yes
13.5
Unchanged
days
‘‘antibioticfree
days alive’’
28 days
after VAP
onset
Schuetz
(2009)
JAMA [66]
LRTI
Kryptor
1359
Yes
Yes
-3.0 days
Unchanged
Bouadma
(2010)
Lancet [67]
Kryptor
621
Yes
Yes
12.7 days
antibioticfree
days
Unchanged
Switzerland
(6 tertiary
hospitals)
All suspected
France
infections in ICU (8 ICUs)
NOTE. CAP, community-acquired pneumonia; COPD, chronic obstructive pulmonary disease; GP, general practitioner; LOS, length of stay; LRTI, lower
respiratory tract infection; PCT, procalcitonin; RTI, respiratory tract infection. Previously published in German in Anaethesist 2008; 57: 571–577.
antibiotic use in patients with lower respiratory tract infection.
In 3 subsequent RCTs by these investigators, a similar advantage
of procalcitonin-guided antimicrobial initiation and/or discontinuation was observed in hospitalized patients with
CAP [58], acute respiratory tract infection in a primary care
setting [60], and acute exacerbation of chronic obstructive
pulmonary disease [59]. Indeed, in the RCT studying
CAP, patients with procalcitonin-guided antimicrobial
initiation and discontinuation received 7 days fewer antibiotics,
compared with those treated conventionally [57]. The safety of
procalcitonin-guided antibiotic initiation and discontinuation
in patients with lower respiratory tract infection (CAP 68.1%,
exacerbation of COPD 16.8%, and acute bronchitis 11.1%) in
emergency departments of tertiary care hospitals was demonstrated as a primary outcome in a multicenter RCT (ProHOSP
trial). In this large study, the mean duration of antibiotics in the
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procalcitonin group was 3 days shorter than that in those
managed conventionally (5.7 days vs 8.7 days) [66].
In critically ill patients, if clinicians have a suspicion of bacterial infectious diseases, it is unrealistic to expect that antibiotics will be withheld, regardless of the level of procalcitonin.
Therefore, an alternative approach—procalcitonin-guided antibiotic discontinuation after clinical stabilization—has been
evaluated in 5 RCTs in critically ill patients [59, 61–63, 67].
Although definitions in these studies have varied, each has
shown a reduction in antibiotic duration.
Nobre et al [61] conducted an RCT in patients in a medical
ICU and showed a 4-day reduction in the duration of antimicrobial treatment in the group whose antibiotic duration was
guided by the procalcitonin results, compared with the conventionally treated group. The median duration of antibiotic
therapy was 6 days in those whose antibiotic discontinuation
was guided by the procalcitonin results, compared with 10 days
in the conventionally treated group. In addition, a 2-day shorter
stay in the ICU was observed in the procalcitonin group in this
study. There was no difference in mortality or recurrence of
primary infection between the 2 groups. A significant reduction
of the duration of antimicrobial treatment in critically ill patients with no adverse clinical outcome has also been demonstrated in 2 RCTs in surgical ICUs by a German group [62, 63].
Stolz et al [65] demonstrated that procalcitonin-guided antibiotic discontinuation in patients with VAP increased the number
of ‘‘antibiotic-free days alive’’ 28 days after VAP onset (13 days
vs 9.5 days); this translated to a reduction in the overall duration
of antibiotic therapy of 27% in the procalcitonin group. Again,
there was no adverse impact on length of hospital stay or
mortality rate. The safety of procalcitonin-guided antibiotic
initiation and discontinuation in critically ill patients was also
demonstrated in a 621-patient study, in which 28- and 60-day
mortality was not affected [67]. In this study, patients in the
procalcitonin group had significantly more days without antibiotics at 28 days after enrollment than patients in the control
group (14.3 days vs 11.6 days).
a number of infection types has never been studied. Fourth,
cutoff values of procalcitonin levels to discourage or encourage
antibiotic use are variable among studies even in the same patient category. Fifth, daily measurement of procalcitonin level,
which is done in some RCTs, seems to be wasteful and potentially expensive. The cost-effectiveness of a procalcitonin-guided
strategy needs to be fully evaluated. Finally, although antibiotic
use has been reduced, a corresponding reduction in isolation of
antibiotic-resistant organisms has not yet been demonstrated.
SUMMARY
Each of the strategies for reducing duration of antibiotic courses
that we have evaluated carries potential problems. Even antibiotic stewardship, which we believe should be the cornerstone of
interventions to reduce antibiotic use, requires considerable
human resources and a significant budget for implementation
(especially if computer-assisted resources are used). The culture
of an institution may be a major determinant of the success of an
antibiotic stewardship program and this may be difficult to alter
quickly. Application of results of RCTs into practice is clearly
necessary, but availability of funding to perform clinically relevant studies is limited.
The global issue of antimicrobial resistance has already placed
us in a critical situation in which antibiotic consumption needs
to be aggressively reduced beyond our current levels. An integration of biomarker-guided antibiotic duration into antibiotic stewardship programs appears to be essential. The concept
of procalcitonin-guided antibiotic discontinuation after clinical
stabilization is more likely to be clinically acceptable than is
reliance on procalcitonin measurement alone. The evidence is
mounting that we need to more aggressively intervene in reducing duration of antibiotic therapy in our hospitals.
Acknowledgments
Potential conflicts of interest. D. P. has received research support for
other projects or has appeared on advisory boards for Merck, AstraZeneca,
Cubist, Pfizer, Novartis, and Leo Pharmaceuticals. Y. H.: no conflicts.
Conclusions
Although the results of RCTs examining procalcitonin as a guide
to cessation of antibiotics in the hospital setting appear to be
very promising, there are a number of concerns that need to be
raised. First, the intensity of antibiotic stewardship programs at
institutions where those studies were conducted is unclear. It is
possible that unnecessary antibiotic use could have been reduced
by antibiotic stewardship activities without monitoring procalcitonin. Second, there seems to be a considerable geographical publication bias, with all published studies being
performed in Europe. Indeed, 5 of 6 RCTs in the management of
respiratory tract infection were conducted by the same Swiss
group. Third, the use of procalcitonin in the management of
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