Short-Course Versus Long-Course Systemic Antibiotic ...
Transcript of Short-Course Versus Long-Course Systemic Antibiotic ...
ORIGINAL RESEARCH
Short-Course Versus Long-Course Systemic AntibioticTreatment for Uncomplicated Intravascular Catheter-Related Bloodstream Infections due to Gram-NegativeBacteria, Enterococci or Coagulase-NegativeStaphylococci: A Systematic Review
Severin Muff . Alexis Tabah . Yok-Ai Que . Jean-Francois Timsit .
Leonard Mermel . Stephan Harbarth . Niccolo Buetti
Received: March 29, 2021 / Accepted: May 22, 2021 / Published online: June 25, 2021� The Author(s) 2021
ABSTRACT
Introduction: The optimal duration of systemicantimicrobial treatment for catheter-relatedbloodstream infections (CRBSI) is unknown. In
this systematic review, we aimed to assess theefficacy of short-course treatment for CRBSI dueto Gram-negative bacteria, coagulase-negativestaphylococci and enterococci.Methods: We systematically searched the elec-tronic bibliographic databases MEDLINE,EMBASE and Cochrane Library for studies pub-lished before February 2021. All studies thatinvestigated the duration of adequate systemicantibiotic treatment in adult patients withuncomplicated intravascular catheter infectionsdue to Gram-negative bacteria, coagulase-nega-tive staphylococci or enterococci were eligiblefor inclusion. Studies including concomitanttreatment with antibiotic lock therapy wereexcluded. The primary outcomes were clinicalfailure/cure, mortality and microbiologic-con-firmed relapse.Results: Seven retrospective cohort studies andone case-cohort study met the inclusion crite-ria. No randomized controlled studies metinclusion criteria. The quality of the includedstudies was low (n = 7) to moderate (n = 1). Nosignificant differences were observed regardingmortality and microbiological relapse betweenshort-course and long-course systemic antibi-otic treatment in patients with CRBSI due tocoagulase-negative staphylococci or Gram-neg-ative bacteria. No association was foundbetween mortality and treatment duration inthe two studies assessing enterococcal CRBSI.Conclusion: The limited data available suggeststhat shorter systemic antibiotic treatment
Supplementary Information The online versioncontains supplementary material available at https://doi.org/10.1007/s40121-021-00464-0.
S. Muff � S. Harbarth � N. Buetti (&)Infection Control Program and WHO CollaboratingCentre on Patient Safety, University of GenevaHospitals and Faculty of Medicine, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerlande-mail: [email protected]
A. TabahICU, Faculty of Medicine, Redcliffe Hospital,University of Queensland, Brisbane, QLD, Australia
Y.-A. QueInselpital, Bern University Hospital, University ofBern, Bern, Switzerland
J.-F. TimsitTeam DeSCID, University of Paris, INSERM IAME,U1137, Paris, France
J.-F. TimsitMedical and Infectious Diseases Intensive Care Unit,AP-HP, Bichat-Claude Bernard University Hospital,46 rue Henri Huchard, 75877 Paris Cedex, France
L. MermelDivision of Infectious Diseases, Department ofMedicine, Rhode Island Hospital, Alpert MedicalSchool of Brown University, 593 Eddy St.,Providence, RI, USA
Infect Dis Ther (2021) 10:1591–1605
https://doi.org/10.1007/s40121-021-00464-0
duration may be sufficient for uncomplicatedCRBSI. Further well-designed prospective stud-ies are needed to confirm these findings.Trial Registration Number: CRD42021224946(PROSPERO)
Keywords: Catheter-related bloodstreaminfection; Coagulase-negative staphylococci;CRBSI; Enterococcal; Enterococcus; Gram-negative; Intravascular catheter infection
Key Summary Points
The optimal duration of antibiotic therapyfor intravascular catheter-relatedbloodstream infections is unknown andcurrent recommendations are mainlybased on expert opinions.
The aim of this systematic review was toassess short-course versus long-coursetreatment for catheter-relatedbloodstream infections due to Gram-negative bacteria, enterococci orcoagulase-negative staphylococci.
In the studies assessed, patients withshort-course treatment had similarmortality rates, clinical cure rates andmicrobiological relapse rates as patientswith long-course treatment.
Prospective studies are needed todetermine the optimal antimicrobialtreatment duration for catheter-relatedbloodstream infections.
DIGITAL FEATURES
This article is published with digital features,including a summary slide, to facilitate under-standing of the article. To view digital featuresfor this article go to https://doi.org/10.6084/m9.figshare.14627559.
INTRODUCTION
Intravascular catheters are used for the admin-istration of fluids, blood products and medica-tion, to monitor haemodynamic parametersand for haemodialysis. They are essential for thecare of hospitalized patients, particularly in thecase of critical illness. Unfortunately, intravas-cular catheters are also possible ports of entryfor pathogens into the bloodstream. In 2019,over 18,000 cases of central line associatedbloodstream infections (CLABSI) were reportedin acute care hospitals in the USA [1]. In Europe,36.5% of intensive care unit (ICU)-acquiredbloodstream infections (BSIs) were linked tointravascular catheters and rates of CLABSIranged from 1.7 to 4.8 episodes per 1000catheter days [2]. Catheter-related bloodstreaminfections (CRBSI) were associated with sub-stantial morbidity, increased hospital length ofstay [3, 4], mortality [4, 5] and an estimatedattributable cost of US $45,814 per event [6].According to recently published Centers forDisease Control and Prevention (CDC) data,Gram-negative bacteria (GNB), enterococci andcoagulase-negative staphylococci (CoNS) wereamong the most frequently detected bacterialpathogens associated with such infections [7].
Research to determine the appropriateantibiotic treatment duration is part of theUnited States National Action Plan for Com-bating Antibiotic-Resistant Bacteria 2020–2025[8]. Recent literature derived from randomizedcontrolled trials (RCTs) suggested that short-course treatment for hospital and community-acquired Gram-negative bloodstream infectionsis non-inferior to longer courses of treatment[9, 10]. Similar results were confirmed by tworecent systematic reviews [11, 12]. Nevertheless,little is known about the optimal duration ofantimicrobial treatment for CRBSI. The Infec-tious Disease Society of America (IDSA) andother current guidelines recommended treat-ment durations of 5–14 days for uncomplicatedenterococcal CRBSI, 7–14 days for Gram-nega-tive CRBSI and 5–7 days for CoNS-CRBSI[13–16]. However, these recommendations weremainly based on expert opinions and, to ourknowledge, no recent literature review has been
1592 Infect Dis Ther (2021) 10:1591–1605
performed. Therefore, we conducted a system-atic review with the objective to evaluate if theduration of systemic antibiotic treatment inpatients with uncomplicated CRBSI due toGNB, enterococci, or CoNS influenced the ratesof mortality, clinical cure/failure or microbio-logical relapse.
METHODS
This study was performed according to thePreferred Reporting Items for Systematic reviewsand Meta-Analyses (PRISMA) statements andwas prospectively registered within the inter-national prospective register of systematicreviews (PROSPERO, ID CRD42021224946) on15 December 2020 [17]. This article is based onpreviously conducted studies and does notcontain any new studies with human partici-pants or animals performed by any of theauthors.
Search Strategy, Study Screeningand Selection
We conducted a systematic search of the elec-tronic bibliographic databases MEDLINE(Pubmed, 1949 to date), EMBASE (Elsevier, 1974to date) and the Cochrane Library (includingthe Cochrane Central Register of ControlledTrials). Additionally, we manually searchedthroughout the European Congress of ClinicalMicrobiology and Infectious Diseases (ECCMID2008–2019) and ID-WEEK (2014–2019) confer-ence websites and clinicaltrials.gov to detectgrey literature and unpublished studies. The fullsearch strategies are available in the supple-mentary material. Briefly, the searches wereconstructed with controlled vocabulary termsand keywords describing ‘‘intravascular catheterinfection’’, ‘‘antibiotic therapy’’, ‘‘duration oftherapy’’, ‘‘Gram-negative bacilli’’, ‘‘enterococ-cus’’ and ‘‘coagulase-negative staphylococci’’.The controlled vocabulary terms were adaptedfor each database. We placed no restrictions onlanguage, publication status or publicationperiod. The final search update was performedon 15 February 2021. The results were importedinto a literature management software to
exclude duplicate publications. Then, title andabstract screening and subsequently full-textscreening were performed independently bytwo authors (Severin Muff and Niccolo Buetti),with any disagreement resolved through dis-cussion between the authors. To manage theselection process, we used a web-based screen-ing and data extraction tool [18]. All study typeswith the exception of case reports, letters andcomments were eligible for inclusion.
We included studies that investigated theduration of adequate antibiotic treatment inadult patients with uncomplicated intravascularcatheter infections due to GNB, enterococci orCoNS. Studies assessing treatment duration forother microorganisms (e.g. Staphylococcus aureusor Candida species) were excluded because theynecessitate longer antibiotic treatment dura-tions (i.e. at least 14 days). Of note, Staphylo-coccus lugdunensis was not included amongCoNS since it can cause an aggressive clinicalcourse, and as a consequence, longer treatmentdurations are recommended [15, 16, 19, 20]. Weexcluded studies investigating lock therapieswith systemic antimicrobials because locktherapy may require more prolonged systemicantibiotic courses, and our target populationwas uncomplicated intravascular catheterinfection. Intravascular catheter infections weredefined as uncomplicated if clinical andmicrobiological signs of infections resolvedwithin 72 h after initiation of antibiotic treat-ment and if complications like metastaticinfection, endocarditis or suppurative throm-bophlebitis were absent. Studies includingantimicrobial-coated catheters were excluded.Studies exclusively including paediatric patientswere excluded. Studies with no age restrictionswere included if the majority of the study pop-ulation was adult.
Data Extraction
For evidence synthesis we used a standardizedform to extract data from the included studies.We extracted data on study design, setting,participants, intervention groups (i.e. treatmentduration), catheter removal and outcome
Infect Dis Ther (2021) 10:1591–1605 1593
measurements. Information about risk of biasassessment was extracted with a separate form.
Intervention and Outcomes
The interventions assessed by this review wereshort-course versus long-course adequateantimicrobial treatment for uncomplicatedintravascular catheter-related infections due toGNB, CoNS or enterococci. Duration of short-and long course treatment was predefined bythe authors of the selected studies. Primaryoutcomes were mortality (in-hospital or day-30mortality), clinical cure/clinical failure andmicrobiologically confirmed relapse. Clinicalcure was defined as resolution of symptomsand/or the significant reduction in inflamma-tory parameters. Clinical failure was defined aspersistence of sign and symptoms of infectionsand/or lack of significant reduction in inflam-matory parameters. We assumed that patientsnot fulfilling the criteria for clinical failure were‘clinically cured’. Microbiological relapse wasdefined as reoccurrence of the same pathogen inat least one blood culture after an initial clinicalresponse to treatment within the follow-upperiod. Secondary outcomes were antibiotic-as-sociated adverse events.
Risk of Bias
To assess the quality (including the risk of bias)of cohort and case–control studies we used theNewcastle–Ottawa scale [21]. The studies wereevaluated by two authors (Severin Muff andNiccolo Buetti) independently; any disagree-ment was resolved through discussion. Scores of0–3, 4–6 and 7–9 were considered as low, mod-erate and high quality, respectively.
Study Synthesis
Since only retrospective observational studieswith high levels of clinical and methodologicalheterogeneity were retrieved, we did not per-form a quantitative synthesis of data and wesummarized our findings in the form of a nar-rative synthesis.
RESULTS
Selection
The review process is summarized in Fig. 1. Oursearch strategy identified 1491 studies, of which236 duplicates were removed. Of the remaining1255 studies, 11 were potentially eligible. Afterfull-text screening, three of 11 studies wereexcluded because of insufficient assessment oftreatment duration (n = 2) and missing assess-ment of intravascular catheter infections(n = 1). Finally, eight studies were included inthe review.
Study Characteristics
The main characteristics of the included studiesare presented in Table 1. Among eight includedstudies, seven were cohort studies [22–28]. Onestudy described a retrospective cohort (i.e.‘‘phase 1’’) and a prospective case-cohort (i.e.‘‘phase 2’’). The cases in the phase 2 were mat-ched with controls of phase 1 and we onlyincluded the results of the case-cohort phase[29]. The total number of included patients was780 with numbers ranging from 44 to 188patients per study. All studies were conductedin tertiary-care hospitals and only hospitalizedpatients were included. All cohort studiesassessed the whole database of their institutionsto identify patients fulfilling the inclusion cri-teria. Adult patients were included in fourstudies [24, 26, 27, 29], whereas four studiesincluded patients of all ages [22, 23, 25, 28].Catheter removal was mandatory for inclusionin five studies [22–24, 27, 29]. No study assessedantibiotic-associated adverse events.
The risk of bias was assessed by the New-castle–Ottawa scale [21] (Table 2). According toour study assessment seven studies [23–29] wereof low methodological quality while one study[22] was of moderate quality.
Gram-Negative Intravascular CatheterInfections
Three studies, including a total of 157 patients,assessed treatment duration for uncomplicated
1594 Infect Dis Ther (2021) 10:1591–1605
intravascular catheter-related infections due toGram-negative bacteria [22, 24, 29]. In all ofthese studies, catheter removal was mandatoryfor inclusion. Two cohort studies compared upto 7 days to more than 7 days of treatment[22, 24]. The differences between the short- andlong-course group for clinical cure, relapse and30-day mortality were not significantly differentin both studies. The case-cohort study com-pared patients receiving at least 14 days withpatients receiving 7 days of antibiotic treatment[29]. No significant differences between thetreatment groups regarding death and relapsewere observed. Clinical cure was notinvestigated.
CoNS Intravascular Catheter Infections
Three cohort studies compared short- versuslong-course treatment for CRBSI due to coagu-lase-negative staphylococci [23, 27, 28]. Treat-ment durations varied from no antibiotictreatment to less than 10 days of treatment inthe short-course groups and from more than3 days to more than 10 days in the long-coursegroups.
The two more recent studies were relativelysimilar: Hebeisen et al. compared no antibiotictreatment with treatment for at least 5 days [27]and San-Juan et al. compared at most 3 days
Fig. 1 Study flow diagram. *Studies did not meet inclusion criteria
Infect Dis Ther (2021) 10:1591–1605 1595
Table
1Studycharacteristics,interventionsandoutcom
es
Reference
Stud
ydesign;stud
yperiod
;coun
try
No.
ofpatients
includ
ed
Setting
Patientscharacteristics
Catheterremoval
Intervention
s
Age
(years),
mean
(–SD
)
Sex(m
ale
gend
erin
%)
Antibioticcourse
bydu
ration
Short-
course
Lon
g-course
Gram-negative
bacteria
Ruiz-
Ruigomez
etal.2
020
[22]
Retrospective
cohort
study;2012–2
018;
Spain
54patients
Tertiary-care
hospital
57.9 (±
15.9)
59.3%
Catheterremoval
mandatory
forinclusion
B7days
[7days
Lee
etal.2
021
[24]
Retrospective
cohort
study;2007–2
016;
SouthKorea
59patients
Twotertiary-
care
hospitals
69(59–
73)a
52.5%
Catheterremoval
mandatory
forinclusion
B7days
[7days
Surapatet
al.
2020
[29]
Case-coho
rtstudy
2016–2
017;
Thailand
44patients
Tertiary-care
hospital
67(18–
81)b
47.8%
Catheterremoval
mandatory
forinclusion
7days
C14
days
Coagulase-negativestaphylococci
Hebeisenet
al.
2019
[27]
Retrospective
cohort
study;2008–2
016;
Switzerland
184patients
Tertiary-care
hospital
61(51–
67)a
70%
Catheterremoval
mandatory
forinclusion
0days
[5days
SanJuan
etal.
2019
[23]
Retrospective
cohort
study;2012–2
017;
Spain
79patients
Tertiary-care
hospital
53(±
24.8)
53.2%
Catheterremoval
mandatory
forinclusion
B3days
[3days
Raadet
al.
2009
[28]
Retrospective
cohort
study;2005–2
007;
USA
188patients
University
cancer
center
56(1–8
7)b
62%
Cathetersof
110patients
wereremoved
orexchanged
\10
days
C10
days
Enterococci
Sand
oeet
al.
2002
[25]
Retrospective
cohort
study;1998–2
000;
UK
61patients
Tertiary-care
hospital
63(0.2–8
0)b
57%
48of
61catheterswere
removed
Median5days
(mean
6.4,
range0–
21)
Marschalletal.
2013
[26]
Retrospective
cohort
study;2006;USA
111patients
Tertiary-care
hospital
58.2
±15.3
50.5%
82of
111patientshad
theircathetersremoved
Meanduration
10±
8days
1596 Infect Dis Ther (2021) 10:1591–1605
Table
1continued
Reference
Outcomeby
duration
,no
.of
patients/total
no.of
patients
Add
itional
comment
All-causemortality
Clin
ical
cure
Relapse
Short-course
Lon
g-course
Short-course
Lon
g-course
Short-course
Lon
g-course
Gram-negativebacteria
Ruiz-Ruigomez
etal.2
020[22]
30-day
mortality
3/23
(13%
)
30-day
mortality
1/29
(3%)
18/23(78%
)23/29(79%
)1/23
(4%)
0/29
(0%)
Assessm
entof
outcom
esfor
52of
54
included
patients
Lee
etal.2
021
[24]
30-day
mortality
4/30
(13%
)
30-day
mortality
6/29
(21%
)
22/30(73%
)18/29(62%
)1/30
(3%)
1/29
(3%)
Surapatet
al.
2020
[29]
1/11
(9%)
4/33
(12%
)Not
performed
Not
performed
0/11
(0%)
1/33
(3%)
Wedescribed
onlythe
phase2of
thestudy
Coagulase-negativestaphylococci
Hebeisenet
al.
2019
[27]
Hospitalmortality
6/32
(19%
)
Hospitalmortality
12/140
(9%)
32/32c
(100%)
111/140c
(79%
)0/32
(0%)
8/140(6%)
Assessm
entof
outcom
esfor
172of
184
included
patients
SanJuan
etal.
2019
[23]
30-day
mortality
1/25
(4%)
30-day
mortality
3/54
(6%)
24/25d
(96%
)36/54d
(67%
)3/25
(12%
)10/54(19%
)22.8%
paediatric
patients
Raadet
al.2
009
[28]
Not
performed
Not
performed
38/41(93%
)137/147(93%
)1/32
(3%)
16/121
(13%
)Included
paediatric
patients
Infect Dis Ther (2021) 10:1591–1605 1597
(which included patients with no activeantibiotic treatment) with more than 3 days oftreatment [23]. Catheter removal was manda-tory in these two studies. The number ofpatients with clinical cure was significantlylower in the long-course treatment groups inboth studies. Hebeisen et al. reported that allpatients with short-course treatment (32/32)were clinically cured in contrast to only 79%(111/140) in the long-course group (P = 0.01).San-Juan et al. reported similar results with 96%(24/25) clinically cured patients in the short-course treatment group and only 67% (36/64)clinically cured patients in the long-coursetreatment group (P = 0.07). However, patientsin the long-course groups were significantlymore immunocompromised [27] or moreseverely ill [23]. No significant differences inrelapse or mortality were found. The authorsconcluded that catheter removal may be suffi-cient to treat CoNS-CRBSI in selected patients.
Raad et al. primarily assessed catheter reten-tion versus removal and included only patientswith cancer [28]. The study revealed similarclinical cure and relapse rates for prolongedtherapy (i.e. at least 10 days) and shorter ther-apy durations (i.e. less than 10 days).
Enterococcal Intravascular CatheterInfections
Only two cohort studies investigated entero-coccal CRBSI [25, 26]. Both primarily investi-gated catheter retention versus catheterremoval and/or catheter management. There-fore, patients with catheter retainment wereincluded in both studies. No studies performedan exhaustive comparison between short versusand longer antimicrobial treatment duration.Treatment duration was evaluated using uni-variate analyses. The first study assessed 61enterococcal CRBSIs. Antimicrobial treatmentduration did not impact cure, treatment failureor relapse [25]. Moreover, an analysis of patientstreated by catheter removal plus adequateantibiotic therapy and patients treated bycatheter removal without (adequate) antibiotictherapy did not show statistically significantdifferences for these outcomes. The second
Table
1continued
Reference
Outcomeby
duration
,no
.of
patients/total
no.of
patients
Add
itional
comment
All-causemortality
Clin
ical
cure
Relapse
Short-course
Lon
g-course
Short-course
Lon
g-course
Short-course
Lon
g-course
Enterococci
Sand
oeet
al.
2002
[25]
Durationof
antimicrobialtherapywas
notassociated
withmortality
Durationof
antimicrobialwas
not
associated
withclinicalcure
Durationof
antimicrobialtherapywas
notassociated
withmicrobiological
relapse
14%
paediatric
patients
Marschallet
al.
2013
[26]
Noassociationbetweenmortality
andtreatm
entduration
foun
d
Not
performed
Not
performed
aMedian(interquartilerange)
bMedian(range)
cStatistically
significant
difference
(pvalue=0.01)
dMarginally
statisticsignificant
difference
(pvalue=0.07).Allotherdifferencesin
outcom
esbetweenshort-andlong-coursegroups
werenotstatistically
significant
SDstandard
deviation,
USA
UnitedStates
ofAmerica,UK
UnitedKingdom
1598 Infect Dis Ther (2021) 10:1591–1605
Table2
Qualityassessment
Coh
ortstud
ies
Ruiz-
Ruigomez
etal.2020
[22]
Lee
etal.
2021
[24]
Hebeisen
etal.
2019
[27]
San-
Juan
etal.
2019
[23]
Raad
etal.
2009
[28]
Sand
oeet
al.
2002
[25]
Marschall
etal.2
013
[26]
Case-coho
rtstud
ies
Surapat
etal.
2020
[29]
Totalscore
42
32
32
23
Selection
Representativenessof
the
exposedcohort
––
––
––
–Selection
Adequacyof
case
defin
ition
–
Selectionof
thenon-
exposedcohort
**
*–
*–
–Representativeness
ofthecases
–
Ascertainmentof
exposure
––
––
––
–Selectionof
controls
–
Dem
onstration
that
outcom
eof
interest
was
notpresentat
startof
study
**
**
**
*Definition
of
controls
*
Com
parability
––
––
––
–Com
parability
*–
Outcomes
Assessm
entof
outcom
e–
––
––
––
Exposure
Ascertainmentof
exposure
–
Was
follow-uplong
enough
foroutcom
es
tooccur?
*–
**
**
*Samemethodof
ascertainm
ent
forcasesand
controls
*
Adequacyof
followup
of
cohorts
*–
––
––
–Non-responserate
–
*The
studyhasmet
thecriteriaforthisdomainof
theNew
castle–O
ttaw
ascale
–The
studyhasnotmet
thecriteriaforthisdomainof
theNew
castle–O
ttaw
ascale
Infect Dis Ther (2021) 10:1591–1605 1599
study included 111 enterococcal CRBSIs and didnot find an association between the treatmentduration and mortality [26].
DISCUSSION
Over the last 2 decades, a substantial reductionin CLABSI rates has been achieved owing to thedevelopment and implementation of effectiveprevention measures [30]. Our systematicreview identified only eight observationalstudies which assessed treatment duration forGram-negative, CoNS and enterococcal CRBSI.Interestingly, no RCT that compared short-course versus long-course antibiotic treatmentdurations for intravascular catheter infectionswas retrieved. High-quality research on themanagement of intravascular catheter infec-tions is scarce and guidelines rely on expertopinion. The few studies addressing the topicincluded a very limited number of patients and,probably because of the retrospective nature ofthese studies, short- and long-course groupswere not well balanced. Notwithstanding, theydid not identify significant differences in mor-tality or relapse rates between short- and long-course treatment groups.
Optimizing use of antibiotics is an essentialstep in fighting against antibiotic resistance [8].Our results revealed that unadjusted outcomesfor short-course treatment (i.e. 7 days) andlonger courses of treatment were similar amonguncomplicated Gram-negative CRBSI[22, 24, 29]. Our findings were supported by tworecent RCTs on treatment of uncomplicatedGram-negative bacteraemia including catheter-related urinary tract infection, which demon-strated similar outcomes for short- and long-course antibiotic therapy [9, 10]. In light ofthese considerations, a treatment duration of7 days after source control (i.e. catheterremoval) is a reasonable recommendation forGram-negative CRBSI.
CoNS, traditionally considered typical skincommensals, have emerged as common causesof nosocomial infections [31]. Internationalguidelines recommended a treatment durationof 5–7 days for CoNS-CRBSI [14–16]. The treat-ment durations were shorter than those
recommended (i.e. 0 days and less than 3 days)in two of the studies we included in this review[14–16, 23, 27]. Relapse and mortality rates inthe study groups without treatment or withshort treatment duration were low. Curiously,the clinical cure rate was significantly lower inthe long-course groups [23, 27]; however,patients in the long-course groups were morepredisposed to an unfavourable course (i.e.immunosuppressed, haematological cancer,higher Pitt bacteraemia score). Overall, a veryshort-course (i.e. at most 3 days) of antibiotictreatment should be therefore considered forCoNS-CRBSI. The risk of unfavourable clinicalcourses in patients with severe underliningconditions is most likely considerably higherand they therefore may need longer antibiotictherapy durations.
Little is known about the optimal durationof treatment for enterococcal intravascularcatheter infections. The lack of associationbetween treatment duration and mortality, aswell as clinical cure and microbiological relapsein one study [25], implied that longer treatmentdid not improve outcomes and short treatmentduration may be considered for some patientswith this infection. However, RCTs assessingthe optimal treatment duration are needed todevelop well-founded recommendations.
Current guidelines and expert statementsrecommended treatment durations of 7–14 daysfor Gram-negative CRBSI, 5–7 days for CoNSand 5–14 days for enterococcal CRBSI[13, 14, 16, 19, 20, 32] (Table 3). As the treat-ment duration depends on several factors (e.g.host, causative pathogen, complications andthe type of catheter), the decision on how longto treat a patient should be individualized.Further research to determine the optimum foreach patient is urgently needed. In the interim,we discourage prolonged therapy for uncom-plicated Gram-negative CRBSI (i.e. longer than7 days) and we recommend considering veryshort treatment for uncomplicated CoNS-CRBSIafter catheter removal. Longer antibiotic treat-ment durations may be needed for more com-promised patients. Optimal duration oftreatment for uncomplicated enterococcalCRBSI remains an unresolved issue and a treat-ment of 7–14 days appears to be reasonable [33].
1600 Infect Dis Ther (2021) 10:1591–1605
Table3
Summaryof
recommendation
sandexpertopinions
First
author
Journal
Year
Setting
Recom
mendedtreatm
entdu
ration
Whenprolon
gedtherapy?
Gram-negative
CRBSI/C
LABSI
Coagulase-
negative
staphylococcal
CRBSI/
CLABSI
Enterococcal
CRBSI/
CLABSI
German
guidelines
Boll
Ann Hem
atol
2021
Oncology
Pseudomonas
and
Stenotrophom
onas:
C2weeks
5–7days
after
defervescence
5–7days
after
defervescence
Com
plications
(end
ocarditis,
osteom
yelitis)
French
recommendation
s
Tim
sit
Ann In
tensive
Care
2020
ICU
Enterobacteriaceae,
Pseudomonas
aeruginosa,
Acinetobacter
baum
annii:7days
7days
7days
Rem
otecomplications
Expertstatem
ent
Buetti
Semin
Respir
CritC
are
Med
2019
ICU
Enterobacteriaceae:
(5–)
7days
Pseudomonas
aeruginosa,
Acinetobacter
baum
annii:7days
(5–)
7days
(5–)
7days
Persistent
CRBSI,com
plicated
courses(i.e.another
vascular
line
infection,
metastaticabscess,
septicthrombophlebitisor
endocarditis)
Spain
recommendation
s
Chaves
Med Intensiva
2018
ICU
C7days
5–7days
7–14
days
ForCoN
S:10–1
4daysforpatients
withintravasculardevices,
biom
edicaldevicesor
persistent
markersof
inflammationafter
catheter
removal
Internationalexpert
consensus
statem
ent
Tim
sit
Intensive
Care
Med
2018
ICU
7–14
days
5–7days
7–14
days
Persistent
bacteraemia,
complications
relatedto
bacteraemia(i.e.suppurative
thrombophlebitis,endocarditis,
osteomyelitis,m
etastatic
infection)
Infect Dis Ther (2021) 10:1591–1605 1601
Table3
continued
First
author
Journal
Year
Setting
Recom
mendedtreatm
entdu
ration
Whenprolon
gedtherapy?
Gram-negative
CRBSI/C
LABSI
Coagulase-
negative
staphylococcal
CRBSI/
CLABSI
Enterococcal
CRBSI/
CLABSI
Expertstatem
ent
Rupp
InfectDis
Clin
North
Am
2018
All catheters
Pseudomonas
or
MDRGNB:
10–1
4days
Other
GNB:
7–14
days
5–7days
7–14
days
Com
plicated
CRBSI
(i.e.
suppurativethrombophlebitis,
persistent
bacteraemia,
osteom
yelitis,infective
endocarditis)
IDSA
guidelines
(USA
)
Mermel
Clin
Infect
Dis
2009
All catheters
7–14
days
5–7days
or
undercertain
circum
stances
observation
without
antibiotics
7–14
days
Com
plicated
CRBSI
(i.e.
suppurativethrombophlebitis,
osteom
yelitis,infective
endocarditis)
ICUintensivecare
unit,C
RBSI
catheter-related
bloodstream
infection,
CLABSI
centrallineassociated
bloodstream
infection,
USA
UnitedStates,IDSA
Infectious
DiseasesSocietyof
America,GNBGram-negativebacteria,M
DRmultidrug-resistant.
1602 Infect Dis Ther (2021) 10:1591–1605
Our systematic review has several limita-tions. We did not perform a quantitative syn-thesis because of the heterogeneity and lowquality of the studies. We modified our designcompared to the published protocol by includ-ing studies which did not exclude paediatricpatients but studies exclusively including pae-diatric patients were excluded. Paediatric rep-resented a limited part of the included patientsand recommendations for this specific popula-tion cannot be provided. Moreover, our out-come definition of clinical failure/cure wasmodified. Studies of enterococcal CRBSI did notperform a comparison between short- and long-course treatment. As a consequence, an exactevaluation of treatment duration was not pos-sible. We did not include studies using antimi-crobial lock therapy which is recommended inguidelines and in use clinically at some insti-tutions. We did not differentiate studiesinvolving different central venous catheters(e.g. short-term catheters versus long-termcatheters such as tunnelled or implantedcatheter or those used exclusively for dialysis).We did not differentiate Gram-negative infec-tions on the basis of the pathogen involved (e.g.outcomes of CRBSI due to Pseudomonas spp.versus Klebsiella spp). Finally, we included onlyuncomplicated CRBSI and therefore no conclu-sion can be drawn on complicated intravascularcatheter infections.
CONCLUSION
Our review suggests that shorter antibioticduration for uncomplicated intravascularcatheter infections due to CoNS and Gram-negative bacilli can be implemented when theinfected catheter was removed. However, well-designed studies are urgently needed to confirmthis recommendation.
ACKNOWLEDGEMENTS
Funding. Niccolo Buetti is currently receiv-ing a Mobility grant from the Swiss NationalScience Foundation (Grant No.
P4P4PM_194449). The Journal’s Rapid ServiceFee was funded by Swiss National ScienceFoundation.
Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.
Authors’ Contributions. Niccolo Buetti andSeverin Muff contributed to the study concep-tion and design. Niccolo Buetti and SeverinMuff were responsible for the literature searchand the data collection. All authors analysedand interpreted the data. Niccolo Buetti andSeverin Muff were the major contributors inwriting the manuscript. Alexis Tabah, Yok-AiQue, Jean-Francois Timsit, Leonard Mermel andStephan Harbarth critically revised the manu-script. All authors read and approved the finalmanuscript.
Disclosures. Severin Muff, Alexis Tabah,Yok-Ai Que, Stephan Harbarth, Niccolo Buettihave disclosed that they do not have conflict ofinterest. Jean-Francois Timsit received fees forlectures from 3M, MSD, Pfizer, and Biomerieux.Jean-Francois Timsit received research grantsfrom Astellas, 3M, MSD, and Pfizer. Jean-Fran-cois Timsit participated in advisory boards of3M, MSD, Bayer Pharma, Nabriva, and Pfizer.Leonard Mermel has served as a consultant forCitius Pharmaceuticals, Marvao Medical, Leo-nard-Meron Biosciences, Destiny Pharma, andNobio unrelated to the submitted work.
Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any new studies withhuman participants or animals performed byany of the authors.
Data Availability. The datasets generatedduring and/or analysed during the currentstudy are available from the correspondingauthor on reasonable request. Preliminary datawere submitted (abstract) to the ICPIC confer-ence (Geneva, September 2021).
Infect Dis Ther (2021) 10:1591–1605 1603
Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.
REFERENCES
1. Centers for Disease Control and Prevention. Centralline-associated bloodstream infections: A.R. &Patient Safety Portal. 2019. https://arpsp.cdc.gov/profile/infections/CLABSI. Accessed 11 Jan 2021.
2. European Centre for Disease Prevention and Con-trol. Healthcare-associated infections in intensivecare units - Annual Epidemiological Report for2017. ECDC; 2019 Oct. https://www.ecdc.europa.eu/sites/default/files/documents/AER_for_2017-HAI.pdf.
3. Dimick JB, Pelz RK, Consunji R, Swoboda SM,Hendrix CW, Lipsett PA. Increased resource useassociated with catheter-related bloodstream infec-tion in the surgical intensive care unit. Arch Surg.2001;136:229.
4. Olaechea PM, Palomar M, Alvarez-Lerma F, et al.Morbidity and mortality associated with primaryand catheter-related bloodstream infections incritically ill patients. Rev Esp Quimioter. 2013;26:21–9.
5. Ziegler MJ, Pellegrini DC, Safdar N.Attributable mortality of central line associatedbloodstream infection: systematic review and meta-analysis. Infection. 2015;43:29–36.
6. Zimlichman E, Henderson D, Tamir O, et al. Healthcare-associated infections: a meta-analysis of costs
and financial impact on the US health care system.JAMA Intern Med. 2013;173:2039–46.
7. Novosad SA, Fike L, Dudeck MA, et al. Pathogenscausing central-line-associated bloodstream infec-tions in acute-care hospitals-United States,2011–2017. Infect Control Hosp Epidemiol.2020;41:313–9.
8. The Task Force for Combating Antibiotic-ResistantBacteria. National Action Plan for CombatingAntibiotic-Resistant Bacteria, 2020–2025. 2020.https://aspe.hhs.gov/pdf-report/carb-plan-2020-2025. Accessed 7 Jan 2021.
9. von Dach E, Albrich WC, Brunel A-S, et al. Effect ofC-reactive protein-guided antibiotic treatmentduration, 7-day treatment, or 14-day treatment on30-day clinical failure rate in patients withuncomplicated Gram-negative bacteremia: a ran-domized clinical trial. JAMA. 2020;323:2160.
10. Yahav D, Franceschini E, Koppel F, et al. Sevenversus 14 days of antibiotic therapy for uncompli-cated Gram-negative bacteremia: a noninferiorityrandomized controlled trial. Clin Infect Dis.2019;69:1091–8.
11. Tansarli GS, Andreatos N, Pliakos EE, Mylonakis E.A systematic review and meta-analysis of antibiotictreatment duration for bacteremia due to Enter-obacteriaceae. Antimicrob Agents Chemother.2019;63:e02495-e2518.
12. Li X, Liu C, Mao Z, Li Q, Qi S, Zhou F. Short-courseversus long-course antibiotic treatment in patientswith uncomplicated gram-negative bacteremia: asystematic review and meta-analysis. J Clin PharmTher. 2021;46:173–80.
13. Boll B, Schalk E, Buchheidt D, et al. Central venouscatheter-related infections in hematology andoncology: 2020 updated guidelines on diagnosis,management, and prevention by the InfectiousDiseases Working Party (AGIHO) of the GermanSociety of Hematology and Medical Oncology(DGHO). Ann Hematol. 2021;100:239–59.
14. Timsit J-F, Baleine J, Bernard L, et al. Expert con-sensus-based clinical practice guidelines manage-ment of intravascular catheters in the intensive careunit. Ann Intensive Care. 2020;10:118.
15. Mermel LA, Allon M, Bouza E, et al. Clinical prac-tice guidelines for the diagnosis and managementof intravascular catheter-related infection: 2009update by the Infectious Diseases Society of Amer-ica. Clin Infect Dis. 2009;49:1–45.
16. Chaves F, Garnacho-Montero J, Del Pozo JL, et al.Diagnosis and treatment of catheter-related blood-stream infection: clinical guidelines of the Spanish
1604 Infect Dis Ther (2021) 10:1591–1605
Society of Infectious Diseases and Clinical Micro-biology and (SEIMC) and the Spanish Society ofSpanish Society of Intensive and Critical CareMedicine and Coronary Units (SEMICYUC). MedIntens. 2018;42:5–36.
17. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMAGroup. Preferred reporting items for systematicreviews and meta-analyses: the PRISMA statement.PLoS Med. 2009;6:e1000097.
18. Ouzzani M, Hammady H, Fedorowicz Z, Elma-garmid A. Rayyan—a web and mobile app for sys-tematic reviews. Syst Rev. 2016;5:210.
19. Rupp ME, Karnatak R. Intravascular catheter-relatedbloodstream infections. Infect Dis Clin N Am.2018;32:765–87.
20. Buetti N, Timsit J-F. Management and prevention ofcentral venous catheter-related infections in theICU. Semin Respir Crit Care Med. 2019;40:508–23.
21. Wells G, Shea B, O’Connell D, et al. The New-castle–Ottawa Scale (NOS) for assessing the qualityof non-randomized studies in meta-analysis. 2000.http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 19 Jan 2021.
22. Ruiz-Ruigomez M, Fernandez-Ruiz M, San-Juan R,et al. Impact of duration of antibiotic therapy incentral venous catheter-related bloodstream infec-tion due to Gram-negative bacilli. J AntimicrobChemother. 2020;75:3049–55.
23. San-Juan R, Martınez-Redondo I, Fernandez-Ruiz M,et al. A short course of antibiotic treatment is safeafter catheter withdrawal in catheter-relatedbloodstream infections due to coagulase-negativestaphylococci. Eur J Clin Microbiol Infect Dis.2019;38:977–83.
24. Lee Y-M, Moon C, Park K-H. Is short-term antibiotictherapy safe in patients with central venous cathe-ter-related Gram-negative bacteraemia? J Antimi-crob Chemother. 2021;76:539–41.
25. Sandoe JAT, Witherden IR, Au-Yeung H-KC, Kite P,Kerr KG, Wilcox MH. Enterococcal intravascularcatheter-related bloodstream infection:
management and outcome of 61 consecutive cases.J Antimicrob Chemother. 2002;50:577–82.
26. Marschall J, Piccirillo ML, Fraser VJ, Doherty JA,Warren DK. Catheter removal versus retention inthe management of catheter-associated enterococ-cal bloodstream infections. Can J Infect Dis MedMicrobiol. 2013;24:e83–7.
27. Hebeisen UP, Atkinson A, Marschall J, Buetti N.Catheter-related bloodstream infections with coag-ulase-negative staphylococci: are antibiotics neces-sary if the catheter is removed? Antimicrob ResistInfect Control. 2019;8:21.
28. Raad I, Kassar R, Ghannam D, Chaftari AM,Hachem R, Jiang Y. Management of the catheter indocumented catheter-related coagulase-negativestaphylococcal bacteremia: remove or retain? ClinInfect Dis. 2009;49:1187–94.
29. Surapat B, Montakantikul P, Malathum K, Kiert-iburanakul S, Santanirand P, Chindavijak B.Microbial epidemiology and risk factors for relapsein Gram-negative bacteria catheter-related blood-stream infection with a pilot prospective study inpatients with catheter removal receiving short-du-ration of antibiotic therapy. BMC Infect Dis.2020;20:604.
30. Centers for Disease Control and Prevention.National and State Associated Infections ProgressReport. Centers for Disease Control and Prevention.2016. https://www.cdc.gov/HAI/pdfs/progress-report/hai-progress-report.pdf.
31. Heilmann C, Ziebuhr W, Becker K. Are coagulase-negative staphylococci virulent? Clin MicrobiolInfect. 2019;25:1071–80.
32. Timsit J-F, Rupp M, Bouza E, et al. A state of the artreview on optimal practices to prevent, recognize,and manage complications associated withintravascular devices in the critically ill. IntensiveCare Med. 2018;44:742–59.
33. Muff S, Hebeisen U, Timsit J-F, Mermel L, HarbarthS, Buetti N. Treatment duration of enterococcalintravascular catheter-related infections. ClinMicrobiol Infect. 2020;S1198-743X:30717-5.
Infect Dis Ther (2021) 10:1591–1605 1605