β lactam monotherapy versus β lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials
BMJ 2004; 328 doi: https://doi.org/10.1136/bmj.38028.520995.63 (Published 18 March 2004) Cite this as: BMJ 2004;328:668
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In their BMJ paper of March 2004, M. Paul et al. conclude that “In
the treatment of sepsis, the addition of an aminoglycoside to beta-lactams
should be discouraged”. We find this conclusion inaccurate and simplistic
as it is based on an analysis where all beta-lactams are grouped together
irrespective of their clinical and ecological properties. From the list of
studies included in their meta-analysis it is evident that the majority of
patients were recruited from trials where the beta-lactam monotherapy arm
was represented by a very broad-spectrum antibiotic such as a third-
generation cephalosporin or a carbapenem. In many instances the beta-
lactam in the combination regimen was also a very broad-spectrum agent.
The work by Paul et al. consequently demonstrates that there is little to
gain from using an aminoglycoside in addition to a broad-spectrum beta-
lactam in the treatment of sepsis. However, the paper does not determine
the value of aminoglycosides as a means of limiting this indiscriminate
use of broad-spectrum beta-lactams. The Nordic countries have a long
tradition of treating sepsis in immunocompetent patients with a
combination regimen of an aminoglycoside and a more limited-spectrum beta-
lactam such as ampicillin or penicillin G. By this approach, the total
usage of advanced beta-lactams has been limited. It is widely recognized
that there is an association between total usage of broad-spectrum beta-
lactams and the occurrence of antibiotic resistance phenotypes such as
extended spectrum beta-lactamase production in Enterobacteriaceae,
carbapenem resistance in Pseudomonas aeruginosa and glycopeptide
resistance in enteroccocci. These ecological associations cannot be
evaluated in individual trials but are evident from secular trends in
antibiotic usage and antimicrobial resistance among regions and countries.
Unfortunately, it is uncertain whether the favourable situation we
presently enjoy in the Nordic countries in terms of low prevalences of
antibiotic resistance can be re-established in countries where over- and
misuse of broad-spectrum agents has rendered our more conservative
regimens useless. It is nevertheless important to require a high level of
precision when general recommendations are made as in the aforementioned
paper. In our view, a combination regimen of an aminoglycoside and a
narrow-spectrum beta-lactam is clinically appropriate and ecologically
preferrable in the treatment of sepsis when local resistance data indicate
that this approach will be effective. The issue of toxicity of
aminoglycosides is complex as it depends on several parameters related to
both the patient and the treatment regimen. Even if it was not mentioned,
the dosing of aminoglycosides in the included studies were probably three
times daily. It is now well-known that the efficacy of aminoglycosides
depends on Cmax, and it has also been shown that once-daily dosage of
these agents not only has a higher efficacy but also less side-effects in
comparison to three-times daily dosage. The conclusions in the meta-
analysis with regard to aminglycoside toxicity are therefore of little
relevance to modern treatment regimens.
Competing interests:
None declared
Competing interests: No competing interests
Dear Sir,
I would be interested to hear the authors’ response to several issues
of concern with this paper.
Forty-three trials were eventually included. Of the 43 studies
analysed for all-cause mortality, 31 compared beta-lactam X against beta-
lactam Y plus aminoglycoside, e.g. cefoxitin vs. penicillin and
gentamicin. Comparison of outcomes in these groups is therefore
unreliable.
There are 12 studies comparing beta-lactam X against beta-lactam X plus
aminoglycoside. Endocarditis is a specific entity in itself and
appendicitis does not usually meet the criteria for severe sepsis, so
there are eight studies left which could help determine whether the
addition of an aminoglycoside in severe sepsis makes a difference. All
cause mortality is then 71/546 (monotherapy) vs. 67/543 (combination
therapy). This is not going to show a significant difference, however the
numbers analysed are now much smaller and most of these studies do not
appear to have studied once daily aminoglycoside therapy which is
currently thought to provide optimal bactericidal activity with the same
or lower toxicity.(1)
Comment is passed that development of resistance was no less in the
combination therapy groups. A failure to reduce bacterial superinfection
or colonisation rates is cited as evidence of this. In fact these two
parameters have very little to do with concerns about resistance
developing in the pathogen being treated, which is the primary concern.
Combination therapy is not intended to prevent subsequent infection with
other organisms, or colonisation with resistant organisms, but is rather
to reduce the risk that the organism being treated will develop resistance
itself. Only nine of 64 studies looked at resistance in pre treatment
isolates and only six out of 64 carried out surveillance cultures. From
this information it seems hard to draw definite conclusions about the
effects of an additional aminoglycoside on the development of resistance.
The issue of beta-lactam therapy, with or without an aminoglycoside,
for Pseudomonas aeruginosa infection is certainly not resolved. The author
admits that “only few patients with documented P. aeruginosa infections
could be evaluated”. In addition they state “The quality of included
studies was poor overall”. Therefore, I find the conclusion that “In the
treatment of sepsis the addition of an aminoglycoside to beta-lactams
should be discouraged” rather difficult to accept.
Perhaps targeted research in specific groups of septic patients,
treated with a particular beta-lactam (with or without a specific
aminoglycoside) would help to clarify the position. From the evidence
supplied, I feel the case that “ beta-lactam - aminoglycoside combination
therapy does not improve clinical outcomes in patients with severe
infections” remains unproved.
References.
1. Freeman CD, Nicolau DP, Belliveau PP, Nightingale CH. Once-daily
dosing of aminoglycosides: review and recommendations for clinical
practice. J Antimicrob Chemother. 1997 Jun;39(6):677-86.
Competing interests:
None declared
Competing interests: No competing interests
Dear Sir,
In their review and meta-analysis, Paul et al. conclude that the
addition of an aminoglycoside to beta-lactam therapy for sepsis in
immunocompetent patients should be discouraged (1). Case-fatality ratios
remain unchanged with the addition of an aminoglycoside whereas
nephrotoxicity was much more common. In subgroup analysis regarding
patients with P. aeruginosa infections their conclusions remain identical.
Nonetheless, the authors state that relatively few patients could be
included and reference is made to a prospective, observational study of
200 consecutive patients with P. aeruginosa bacteraemia, conducted between
1982 and 1986 (2). In this study, Hilf et al. found that combination
therapy was significantly better than monotherapy in improving outcome.
The difference in mortality between patients receiving combination therapy
(27%) and monotherapy (47%) was significant. With reference to this study,
others (3) have also emphasized that “combining an antipseudomonal beta-
lactam with an aminoglycoside or ciprofloxacin is likely to obtain a much
better outcome than monotherapy”.
It is important to realize that in this very influential study 186 of 200
patients received antipseudomonal therapy. 143 Patients received
combination therapy, which usually consisted of piperacillin or
ticarcillin combined with tobramycin or gentamycin. Of 43 remaining
patients, 37 received an aminoglycoside alone and only six received an
antipseudomonal beta-lactam. The inferior nature of monotherapy in this
study thus might represent the inferiority of aminoglycoside monotherapy
alone and is therefore not in contradiction to the finding of Paul et al.
that the addition of aminoglycosides should also be questioned for severe
P. aeruginosa infections. Further studies are really needed to answer the
important question of the value of combination therapy in severe P.
aeruginosa infections.
References
1. Paul M, Benuri-Silbiger I, Soares-Weiser K, Leibovici L. Beta
lactam monotherapy versus beta lactam-aminoglycoside combination therapy
for sepsis in immunocompetent patients: systematic review and meta-
analysis of randomised trials. BMJ 2004; 328: 668-72.
2. Hilf M, Yu VL, Sharp J, Zuravleff JJ, Korvick JA, Muder RR.
Antibiotic therapy for Pseudomonas aeruginosa bacteremia: outcome
correlations in a prospective study of 200 patients. Am J Med.1989; 87:
540-6. See also comment in: Am J Med 1991 Jan; 90: 135.
3. Chastre J, Fagon JY. Ventilator-associated pneumonia. Am J Respir
Crit Care Med 2002;165: 867-903.
Competing interests:
None declared
Competing interests: No competing interests
Paul et al make a laudable attempt to synthesise the data on the use
of beta-lactam/aminogylocoside combination therapy for sepsis.
Unfortunately their primary research question lacks the necessary focus to
usefully inform UK clinical infection practice, which is increasingly
burdened by bacterial resistance to beta-lactams. The important question
in the UK is whether the addition of gentamicin to a beta-lactam in a
patient with suspected severe Gram positive (e.g. staphylococcal
endocarditis) or Gram negative (e.g. intra-abdominal infection) sepsis is
better, worse or equal to monotherapy or ‘upgrading’ to other agents such
as carbapenems and glycopeptides. This question cannot be answered by a
systematic review in which only 20 (31%) of the 64 studies included used
gentamicin, the most commonly prescribed aminoglycoside in the UK. Are all
aminoglycosides equal? The studies also use a wide range of beta-lactam
agents, many of which are not used in the UK, and there is considerable
inter- and intra-study variation in the types of infection treated.
No data is presented about the aminoglycoside dosing and monitoring
regimens used in the studies and what proportion of patients were in the
sub-therapeutic, therapeutic and toxic ranges. This data may not have been
reported in the original studies, but it is clearly an important
consideration given the potential impact on outcomes. Although the study
found a higher rate of nephrotoxicity in aminoglycoside treated patients,
it is interesting that discontinuation was similar in both groups.
The importance of this systematic review lies not in the results or
conclusions, which are clearly flawed, but in the reminder it will give
clinicians to ask: Does this patient really need an aminoglycoside and is
the risk-benefit ratio favorable? Until more specific data is available,
however, clinicians in the UK should still consider using adequately
monitored gentamicin in patients with severe sepsis and according to local
bacterial epidemiology.
Competing interests:
None declared
Competing interests: No competing interests
A case for antibiotic combination therapy against pseudomonas
infection remains
Editor – The key message from the systematic review and meta-analysis
by Paul et al is that B lactam – aminoglycoside combination therapy does
not improve clinical outcome in critically-ill patients. However, only
2,530 (33%) of the patients studied after 1991 appear to have warranted
intensive care and only 1,576 (20%) patients were stated to have a
nosocomial infection. Also only one quoted study involving critically-ill
patients appears to have been a randomised and blinded trial.
Furthermore, the authors admit that few patients with Pseudomonas
aeruginosa infections could be evaluated.1
These are significant weaknesses in the study. P.aeruginosa
accounted for 14% of all nosocomial infections reported through the
National Nosocomial Infection Surveillance reporting system and ranked
second amongst Gram-negative pathogens.2 The frequency of P.aeruginosa
infection, especially ventilator-associated pneumonia (VAP) is
particularly high in critical care units (CCUs).3 Such infections are
often difficult to cure and associated with high mortality rates.4
As the choice of effective anti-pseudomonal antibiotics is relatively
limited, empirical combination therapy is often used in clinical practice
due to the emerging problem of Gram-negative antimicrobial resistance and
the need to “get it right first time”. As well as in-vitro synergy,
better clinical outcome has been demonstrated with combination therapy.5
Though many of the studies quoted by Paul were from the 1970s and 1980s
when single agent cephalosporin therapy was used,1 many CCUs would now
avoid third-generation cephalosporins due to the spread of extended-
spectrum beta-lactamases and the risk of Clostridium difficile colitis.
Hence, an alternative approach is the use of carapenem B lactam
monotherapy as front line treatment for the critically-ill. However, the
development of imipenem-resistant P.aeruginosa during therapy is well
recognised and has been reported between 14% and 55% of VAP patients.
There is also an associated increase in cross-resistance to other anti-
pseudomonal antibiotics and drug costs.4
With only limited available data, B lactam-aminoglycoside combination
therapy against P.aeruginosa remains a valid therapeutic option and should
continue to be included in the British National Formulary. Specific
antibiotic choices should be based on local resistance patterns and
therapeutic algorithms. Antibiotic resistance, fungal super-infection and
aminoglycoside toxicity can all be minimised by short course therapy and a
de-escalation strategy if a causative agent is identified. It would have
been therefore helpful if Paul’s influential review had been linked to an
editorial overview of a complicated clinical issue.
Richard PD Cooke Consultant Microbiologist
Ged Dempsey Consultant Anaesthetist
Rachel A Sen Consultant Microbiologist
Christopher Whitehead Consultant Anaesthetist
University Hospital Aintree, Liverpool L7 7AL
1. Paul M, Benuri-Silbiger 1, Soares-Weiser K, Leibovici L, B lactam
monotherapy versus B lactam-aminoglycoside therapy for sepsis for
immunocompetant patients: a systematic review and meta-analysis of
randomised trials. BMJ 2004;328: 668-672
2. National Nosocomial Infection Surveillance (NNIS) System report,
data summary from October 1996 – April 1998 Issued June 1998. Am J
Infect Control 1998; 26:522-533
3. Hanberger H, Garcia-Rodriguez JA, Gobernado M et al. Antibiotic
susceptibility among aerobic gram-negative bacilli in intensive care units
in 5 European countries. JAMA 1999;281:67-71.
4. Javier A, Pujol M. Nosocomial antibiotic resistance in GNB at the
ICUs. Clin Pulm Med 2004;11:71-83.
5. Chestre J, Fagon JY. Ventilator-associated pneumonia. Am J Resp
Crit Care Med 2002;165:867-903.
Competing interests:
None declared
Competing interests: No competing interests
Sir, in their review and meta-analysis, Paul et al recommend that
addition of an aminoglycoside to beta-lactams should be discouraged as the
fatality remains unchanged, while the risk for adverse events is increased
when compared to beta-lactam monotherapy (1). The authors also point out
current evidence that suggests that aminoglycoside monotherapy may be
inadequate for infections outside the urinary tract. Might aminoglycosides
become obsolete? I for one would need to have further evidence before
ceasing to use these agents.
The trials analysed by Paul et al, were performed between the years
1968 and 2001. In the late 1980s and early 1990s several studies were
published that demonstrated the advantages of a single daily dose of an
aminoglycoside compared to the then convention of divided doses twice or
three times a day (2, 3, 4, 5, 6, 7). These trials showed either equal or
superior therapeutic benefits and also in most cases reduced or similar
levels of toxicity. Many hospitals now favour this approach above the
conventional divided dosing regimens. In their study, Paul et al do not
discuss whether there were any differences in fatality or toxicity in the
trials where single dosing of aminoglycosides combined with beta-lactams
were employed compared to twice or thrice daily dosing in combination with
beta-lactams, but instead pool these different approaches together and
then compare them to beta-lactam monotherapy. Furthermore, I am concerned
that they also do not differentiate between the various aminoglycosides.
Not all organisms are susceptible to all aminoglycosides. An example would
be Pseudomonas aeruginosa which commonly can be resistant to gentamicin
but susceptible to amikacin. Resistance may therefore be the cause of
bacteriological and treatment failure. Until these further analyses of the
trial data are forthcoming I would caution against ceasing to use
aminoglycosides in combination with beta-lactams.
References
1. Paul M, Benuri-Silbiger I, Soares-Weiser K, Leibovici L. Beta-
lactam monotherapy versus beta-lactam-aminoglycoside combination therapy
for sepsis in immunocompetent patients: systematic review and meta-
analysis of randomised trials. BMJ 2004; 328: 668-72.
2. Sturm AW. Netilmicin in the treatment of gram-negative bacteremia;
single daily versus multiple daily dosage. J Infect Dis 1989; 159: 931-37.
3. ter Braak EW, de Vries PJ, Bouter KP, van der Vegt SG, Dorrenstein
GC, Nortier JW et al. Once-daily dosing regimen for aminoglycoside plus
beta-lactam combination therapy for serious bacterial infections;
comparative trial with netilmicin and ceftriaxone. Am J med 1990; 89: 58-
66.
4. Nordstrom L, Ringberg H, Cronberg S, Tjernstrom O, Walder M. Dose
administration of an aminoglycoside in a single daily dose affect its
efficacy and toxicity. J Antimicrob Chemother 1990; 25: 159-73.
5. deVries PJ, Verkooyen RP, Leguit P, Verbrugh HA. Prospective
randomized study of once-daily versus thrice-daily netilmicin regimens in
patients with intraabdominal infections. Eur J Clin Microbiol Infect Dis
1990; 9: 161-68.
6. Prins JM, Buller HR, Kuijper EJ, Tange RA, Speelman P. Once versus
thrice daily gentamicin in patients with severe infection. Lancet 1993;
341: 335-39.
7. Nicolau DP, Freeman CD, Bellineau PD, Nightingale CH, Ross JW,
Quintiliani R. Experience with a once-daily aminoglycoside program
administered to 2184 adult patients. Antimicrob Agents Chemother 1995; 39:
650-55.
Competing interests:
None declared
Competing interests: No competing interests
Sir,
I read with deep interest this week's paper by Mical Paul et al.
Although clinical research involving children is indeed scarce when
compared with adult-based data, I find the usual practice among non-
pediatric review groups to exclude pediatric data an unwelcomed choice
leading to delayed or postponed application of adult-based evidence to
pediatric patients.
Beyond the neonatal and infant periods, children can probably, now and
then, be considered little adults from standpoints such as the one of this
paper. The limited number of children included in that systematic review
will be used as a placating argument to dismiss further discussion by
pediatric colleagues unwilling to face Mical Paul's conclusions. A
subgroup of pediatric data would have help some of us corner some of them.
Competing interests:
I am a pediatric intensivist.
Competing interests: No competing interests
As already said last year [1], it is perhaps regrettable that Paul et
al.'s statistical analysis did not distinguish patients with septic shock,
or severe sepsis, from other patients at lower risk of adverse outcome.
Reference:
[1] http://bmj.bmjjournals.com/cgi/eletters/326/7399/1111#33591
Competing interests:
None declared
Competing interests: No competing interests
Dear Sir,
The present review included studies on non-neutropenic, immunocompetent
patients. There is a mistake in 'This week in the BMJ'. We have reviewed
the same question in neutropenic patients in a former article (1).
Reference
Paul M, Soares-Weiser K, Leibovici L. Beta-lactam versus beta-lactam-
aminoglycoside combination therapy for fever with neutropaenia:
systematic review and meta-analysis. BMJ. 2003; 24;326:1111-5.
Competing interests:
None declared
Competing interests: No competing interests
Is combination therapy with betalactam plus aminoglycoside (AGL) improving the outcome of nosocomial meningitis in children? (letter)
Sir, recently a paper was published in Br Med J from Paul et al. (1),
presenting a metanalysis of the role of the combination of aminoglycosides
with betalactams in the therapy of sepsis. The conclusion of metanalysis
of 52 studies was that addition of an aminoglycoside did not improve the
outcome in bacteremia/sepsis, but increased the toxicity of the treatment.
We assessed all children with nosocomial meningitis (NM) treated with
combination therapy (20) in a national antimicrobial survey within 12
years and compared them to the 137 cases of NM, concerning risk factors
and outcome. AMP + gentamicin or cefotaxim/ceftazidime with netilmicin
have been considered to be state of the art therapies in both nosocomial
meningitis and endocarditis.(2)
An EORTC study supported the use of amikacin for the first days of sepsis
due to multiresistant organisms such as ESBL-producing enterobacteriaceae,
VAN-resistant enterococci.(3) Methicillin-resistant streptococci often
require combination of at least two available effective antibiotics.
However metanalysis included in to the model all abovementioned cases
apart from endocarditis and meningitis.
In our retrospective analysis we considered as combination therapy an
addition of aminoglycoside to either betalactam or glycopeptide or
clindamycin for at least 5 days. In this letter therefore we would like
to show what was the prognosis of cases treated with combination therapy.
Table 1 shows risk factors and outcome in those treated with combination
therapy (defined above) or monotherapy (meropenem, 3.-4. generation
cephalosporine, vancomycin, chloramphenicol, ciprofloxacin,
cotrimoxazole). There was no major difference in risk factors. More
patients with Ps. aeruginosa (20% vs 7%; P<_0.045 received="received" combination="combination" therapy.="therapy." also="also" more="more" acinetobacter="acinetobacter" baumanii="baumanii" nm="nm" of="of" betalactam="betalactam" cephalosporin="cephalosporin" or="or" meropenem="meropenem" plus="plus" aminoglycoside="aminoglycoside" than="than" monotherapy="monotherapy" _35="_35" vs="vs" _7.5="_7.5" p0.01.="p0.01." p="p"/>Concerning outcome, there was no difference in attributable mortality (25%
vs 14%; NS) neither in the number of sequels (14% vs 10%). Therefore, we
have not been able to document a benefit of combination of aminoglycosides
to betalactam or carbapenem in nosocomial meningitis. This was similar to
the cases of sepsis, where survival of patients did not improve with
combination therapy. Combination therapy did not increase the chance of
appropriateness of the therapy. 30% of those on combination therapy were
considered as inappropriately treated in comparison to 2.8% of those on
monotherapy (P<_0.01. p="p"/>References:
1. Paul M, Benuri-Silbiger I, Soares-Weiser K, Leibovici L: Adding
aminoglycoside to betalactam does not improve results. BMJ. 2004; 328:
668
2. Leibovici L, Shraga I, Drucker M, Konigsberger H, Samra Z, Pitlik S
D: The benefit of appropriate empirical antibiotic treatment in patients
with bloodstream infection. J Inf Med 1998; 244: 397-386
3. EORTC. Ceftazidime combined with a short or long course of amikacin for
empirical therapy of gram-negative bacteremia in cancer patients with
granulocytopenia. The EORTC International Antimicrobial Therapy
Cooperative Group. N Engl J Med 1987; 317: 1692-8
Address: Prof. Vladimir Krcmery, MD, FACP, FRCP
St. Elisabeth Cancer Institute, Heydukova 10, 812 50 Bratislava
vladimir.krcmery@szu.sk
Competing interests:
None declared
Competing interests: Table 1: Outcome in combination therapy versus monotherapyCombination therapy (A) Monotherapy (B) p A vs B1. Underlying disease VLBN/prematurity 1 (5) 35 (24.5) 0.04Neoplasia 3 (15) 22 (16) NSDiabetes, cystic fibrosis 4 (20) 14 (10) NSPerinatal pathology (hydrocephalus) 3 (15) 15 (11) NS2. Type of surgery Trauma 5 (25) 17 (13) NSTumor resection 4 (20) 13 (9) NSVP-S insertion, change, drainage 3 (15) 61 (47) 0.04Spinal puncture, evacuation absces hemat. 2 (10) 6 (4.7) NSDecompressive craniotomy, ventriculostomy 6 (30) 13 (9) NSHemorrhage punction/derivation 6 (30) 11 (8) NSCongenital malformation operation 1 (5) 20 (14) NS3. Microbiology Positive blood cultures 2 (10) 39 (26) NSMultiple positive CSF cultures 2 (10) 23 (17) NSCandida 0 12 (8) NSCoagulasa negative staphylococci – SE 5 (15) SE rid 68 (49) NSS.hominis, S.warneri, S.xylosus, S.hemolyticus, S.cohni 1 (5) Non SE CONS 9 (7) NSEnterobacteriaceae 1 (5) 22 (16) NSStreptococci (SP, S.virid, S.agalactiae) 2 (10) 8 (6) NSEnterococci 0 9 (7) NSS.aureus 0 12 (8) NSAcinetobacter 7 (35) 10 (7.5) 0.01Pseudomonas 4 (20) 9 (7) 0.0454. Outcome/ sequels Died of infection 5 (25) 19 (14) NSCured no sequels 14 (70) 100 (72) NSNeurological sequels 1 (5) 20 (14) NSInappropriate therapy (in vitro resist.) 6 (30) 4 (2.8) 0.01VLBN – neonates with very low birth weight