Antimicrobial Agents and Chemotherapy-2009-Svetitsky-4069.full
Antimicrobial Agents and Chemotherapy-2009-Svetitsky-4069.full
Antimicrobial Agents and Chemotherapy-2009-Svetitsky-4069.full
10
0066-4804/09/$08.00⫹0 doi:10.1128/AAC.00341-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Vancomycin and teicoplanin are the glycopeptides currently in use for the treatment of infections caused by
Methicillin (meticillin)-resistant Staphylococcus aureus teicoplanin (19, 30, 47). Teicoplanin is not approved for use in
(MRSA) infections are a serious and constantly growing public the United States, while in Europe it is as commonly used as
health concern. The incidence of invasive MRSA infections in vancomycin (2, 3, 69).
the United States was estimated to be 31.8 per 100,000 popu- The comparative clinical efficacies and toxicity profiles of
lation in the general population in 2005, with a fatality rate of vancomycin and teicoplanin are not established. In a previous
6.3/100,000 population (32). The percentage of MRSA isolates review, vancomycin and teicoplanin were found to be equally
among all S. aureus bloodstream isolates in hospitals was 49% efficacious, with teicoplanin causing fewer adverse effects than
in United States hospitals (1998 to 2005), with little variability vancomycin (76). Since then, the findings of more trials com-
in that proportion occurring between regions (68). In Europe, paring vancomycin and teicoplanin have been published. We
the proportions ranged from less than 1% in northern coun- performed a systematic review and meta-analysis of random-
tries to ⬎50% in southern countries (1999 to 2007) (17). Com- ized controlled trials that compared vancomycin to teicoplanin.
munity-acquired MRSA is now of growing concern, reaching The objectives of our review were to compare the efficacy and
rates of more than 80% of all community-acquired S. aureus safety of these glycopeptides.
infections in certain locations in the United States (5, 31, 37).
The first-line treatment of choice for invasive MRSA infec- MATERIALS AND METHODS
tions is a glycopeptide antibiotic (43). Vancomycin (a glyco- Inclusion criteria. We included randomized or quasirandomized controlled
peptide) and teicoplanin (a lipoglycopeptide) are naturally oc- trials that compared systemic treatment with vancomycin versus teicoplanin for
curring substances whose bactericidal activity is mediated suspected or proven infections in adults and children. We included both neutro-
mainly by the inhibition of peptidoglycan synthesis of the bac- penic and nonneutropenic patients. Additional antibiotic treatment was permit-
ted, provided that the same antibiotic and dose or the same rules regarding
terial cell wall. Their spectrum of coverage is similar except for additional antibiotics were applied in both study arms.
VanB vancomycin-resistant enterococci that are susceptible to Outcomes. The primary outcome assessed was all-cause mortality and was
preferentially extracted at day 30. Secondary outcomes included clinical failure,
defined as a nonresolved infection, treatment modification, or death due to the
* Corresponding author. Mailing address: Unit of Infectious Dis- infection; microbiological failure, defined as the persistence or the reappearance
eases, Rabin Medical Center, Beilinson Hospital, Petah-Tikva 49100, of the initiating pathogen during treatment, as defined in the study (after day 3);
Israel. Phone: 972-3-9377512. Fax: 972-3-9377513. E-mail: paulm relapse, defined as the reisolation of the initiating pathogen after the completion
@post.tau.ac.il. of treatment; superinfection, defined as the development of a different infection
䌤
Published ahead of print on 13 July 2009. during treatment or within 1 week of the discontinuation of treatment; resistance
4069
4070 SVETITSKY ET AL. ANTIMICROB. AGENTS CHEMOTHER.
development, defined as the isolation of glycopeptide-resistant gram-positive addressed patients ⬎12 years of age. Patients with renal failure
bacteria; and adverse events, including adverse events requiring the discontinu- were excluded from 17 trials.
ation of treatment, nephrotoxicity (as defined in the study), red man syndrome,
and rash.
Four trials were performed prior to Eli Lilly’s launch of
Search strategy. We searched the Cochrane Register of Controlled Trials, purified vancomycin in 1990 (8, 11, 62, 72), and in one study
PubMed, and LILACS databases. Unpublished trials were sought in the refer- the purified preparation was introduced during the trial (71).
ences of all selected studies; the conference proceedings of the Interscience The standard dosing of teicoplanin for adults was 400 mg/day
Conference on Antimicrobial Agents and Chemotherapy, the European Con-
for adults and 10 to 12 mg/kg of body weight/day for children,
gress of Clinical Microbiology of Infectious Diseases, and the Infectious Diseases
Society of America; trial registries; ongoing trial databases; and personal con- following a loading dose (Table 1); lower doses (200 mg/day)
tacts with the investigators of the trials included. No language or date restrictions were used for adults during the first part of the study in three
were imposed. The last search of all sources was performed in June 2008. The trials (45, 62, 71). The intramuscular administration of teico-
terms “glycopeptides” and “chemical” and the generic and trade names of van- planin was permitted in four trials. Monitoring of serum van-
comycin and teicoplanin were searched for, in combination with the use of the
Cochrane filter for randomized controlled trials in PubMed (28).
comycin and teicoplanin levels was explicitly stated in 12 and
Review methods. Two reviewers (S.S. and M.P.) independently applied the 11 trials, respectively. None of the trials stated the target serum
inclusion criteria and extracted the data. We identified the intention-to-treat level. The serum drug levels achieved during the trial were
FIG. 1. Trial flow. RCTs, randomized controlled trials; CR, catheter related; IVDU, intravenous drug abuse. Three publications described two
Downloaded from http://aac.asm.org/ on October 8, 2020 by guest
trials each (22, 55, 66).
initiated for a suspected or a proven infection with gram- 95% CI, 0.26 to 1.72; 5 trials and 73 patients), and bacteremia
positive bacteria, with higher doses of teicoplanin, and with (RR, 0.95; 95% CI, 0.73 to 1.24; 15 trials and718 patients).
adequate allocation concealment and double blinding (Table The microbiological failure rates were not significantly dif-
2). A modified intention-to-treat analysis, with the assumption ferent for teicoplanin treatment and vancomycin treatment
of treatment failure for all dropouts (excluding studies in which (RR, 1.24; 95% CI, 0.93 to 1.65; 12 trials and 716 patients). No
the number randomized was unclear), yielded an RR of 0.94 significant differences in the rates of relapse (RR, 0.61; 95%
(95% CI, 0.84 to 1.05; 17 trials and 1,679 patients). Clinical CI, 0.29 to 1.30; 8 trials and 330 patients) and superinfection
failure could also be assessed in the subgroups of patients with (RR, 1.02; 95% CI, 0.77 to 1.37; 10 trials and 1,083 patients)
documented S. aureus infections (RR, 0.97; 95% CI, 0.63 to were found. None of the trials reported quantitatively on the
1.51; 13 trials and 289 patients), MRSA infections (RR, 0.67; changes in the glycopeptide MICs for persisting gram-positive
TABLE 1. Characteristics of included trials
4072
Akan, 2008 (1) 1 g two times for adults, 400 mg two times (three Febrile neutropenia, with solid Adults and children Unknown A Open
10 mg/kg four times doses) and then 400 malignancies; empirical over age 2
for children (97) mg once for adults; 10 first-line treatment
mg/kg two times (three
doses) and then 10 mg/
kg once for children
aged 2–16 yr (93)
Auperin et al., 10 mg/kg four times (34) 10 mg/kg two times (three Febrile neutropenia with solid Children; median age, 8 Unknown A Open
SVETITSKY ET AL.
episode only
Nucci et al., 1998 40 mg/kg/day divided 6 mg/kg two times (three Febrile neutropenia, T, median, 31 (range, 1 A Open Patients randomized more
(46) into four doses a day doses) and then 6 mg/kg hematological malignancies; 13–71); V, median, than once; no. of
(53) once (53) empirical first-line 37 (range, 12–72) patients randomized to
treatment each arm reported;
clinical failure and
adverse events reported
per episode
Pham Dang et al., Target drug levels 400 mg two times for 36 h, Postorthopedic surgery bone T, mean, 62 ⫾ 17; V, 70 A Open
2001 (48) between 20 and 30 followed by 400 mg infections caused mainly by mean, 64 ⫾ 23
mg/liter (15) once; target levels, ⱖ10 MRSA
mg/liter (15)
Rolston et al., 15 mg/kg two times 6 mg/kg two times (three Catheter-related or other T, mean, 50 (range, 19– 2 A TB
1999 (51) (122) doses) and then 6 mg/kg vascular access-related GP 80); V, mean, 50
once (118) bacteremia (range, 17–83)
Sidi et al., 2000 40 mg/kg in three 10 mg/kg two times (three Febrile neutropenia with GP Children; T, mean, 8 Unknown C Open Patients randomized more
(60) divided doses a day doses) and then 10 mg/ bacteremia (range, 2–14); V, than once; no. of
(21) kg once (24) mean, 8.5 (range, patients randomized
2.5–15) reported; clinical failure
reported per episode
only
Smith et al., 1989 1 g two times (35) For first 11 episodes, 400 Febrile neutropenic patients T, mean, 40 (range, 17– Unknown A Open Patients randomized more
(62) mg once (one dose) and with hematological 77); V, mean, 45 than once; no. of
then 200 mg once; for malignancy and catheter- (range, 26–78) patients randomized to
subsequent episodes, associated GP infections each arm not reported;
800 mg once (one dose) results reported per
and then 400 mg once episode
(37)
Van der Auwera 1 g two times (37) 400 mg once (three doses) Cancer patients without T, median, 59 (range, 5 A Open
et al., 1991 (71) and then 200 mg once neutropenia with 35–78); V, median,
and 400 mg once (37) documented GP infection 62 (range, 25–75)
Van Laethem et 1 g two times (10) 400 mg once (12) Documented MRSA infections T, mean, 56 (range, 23– 100 B Open Patients randomized more
al., 1988 (72) 85); V, mean, 69 than once; no. of
(range, 44–86) patients randomized and
evaluated for each
outcome reported
Vazquez et al., Variable, according to 400 mg two (three doses) Febrile neutropenic patients T, mean, 51; V, mean, Unknown A/B Open Patients randomized more
1999 (73) nomogram (38) and then 400 mg once with hematological 47 than once; no. of
(38) malignancies; empirical patients randomized to
second-line treatment each arm not reported;
results reported per
episode
Zhao et al., 2003 1 g two times (34) 400 mg two times and then Documented GP infections T, mean, 41.9 ⫾ 16; V, 20 B Open
(77) 400 mg once (36) mean, 40.6 ⫾ 14.2
a
GP, gram-positive organism; HIV, human immunodeficiency virus; ICU, intensive care unit; VAP, ventilator-associated pneumonia. Empirical treatment for febrile neutropenia given as first-line treatment (initial
empirical treatment) or second-line treatment (for persistent fever unresponsive to the first-line regimen).
b
Ages are given in years unless otherwise stated. T, teicoplanin; V, vancomycin.
c
A, adequate allocation concealment methods ensuring that intervention allocations could not have been foreseen in advance of, or during, enrollment; B, unreported or unclear methods; C, inadequate allocation
concealment methods whereby intervention allocations could be foreseen in advance of, or during, enrollment.
d
DB, double blind; TB, triple blind.
VANCOMYCIN VERSUS TEICOPLANIN
4073
bacteria. Seven trials reported qualitatively that no resistant of the differences were statistically significant among children
isolates were detected, except in 3/68 patients in one trial (18) alone (RR for any adverse event, 0.53 [95% CI, 0.24 and 1.18;
who acquired teicoplanin-resistant isolates following treatment four trials and 216 children]; RR for adverse events requiring
with teicoplanin. discontinuation, 0.66 [95% CI, 0.11 and 3.9; two trials and 147
Adverse events. The overall number of adverse events was children]; RR for nephrotoxicity, 0.31 [95% CI, 0.09 to 1.07;
reported in all trials except the unpublished trial (1). There three trials and 197 children]). Severe nephrotoxicity, defined
were significantly fewer total adverse events for teicoplanin as the need for hemodialysis, was reported only with vancomy-
than for vancomycin, when they were reported as the number cin and among adults (RR, 0.16; 95% CI, 0.03 to 0.86; eight
of adverse event episodes per patient episode (RR, 0.61; 95% trials and 341 patients [events were reported in three trials]).
CI, 0.50 to 0.74; 23 trials and 2,046 patient episodes) and when There were no cases of red man syndrome in the teicoplanin
they were reported as the number of patients experiencing at group, whereas there was a 5% incidence of red man syndrome
least one adverse event per patient (RR, 0.57; 95% CI, 0.45 to in the vancomycin group (RR of 0.21 and 95% CI of 0.08 to
0.72; 19 trials and 1,641 patients). There were significantly 0.54 for 10 trials and 756 episodes and RR of 0.24 and 95% CI
fewer adverse events requiring the discontinuation of treat- of 0.08 to 0.76 for 7 trials and 500 patients); this outcome was
ment with teicoplanin (RR of 0.54 and 95% CI of 0.33 to 0.87 assessed only among adults. The occurrence of other rash was
for 13 trials and 904 patient episodes; RR of 0.59 and 95% CI not significantly different between the groups (RR of 0.74 and
of 0.36 to 0.97 for 12 trials and 829 patients). There was 95% CI of 0.49 to 1.12 for 16 trials and 1,707 episodes; RR of
significantly less nephrotoxicity reported for teicoplanin (Fig. 0.65 and 95% CI of 0.41 to 1.03 for 12 trials and 1,398 pa-
4) (RR of 0.44 and 95% CI of 0.32 to 0.61 for 21 trials and tients).
1,992 patient episodes; RR of 0.33 and 95% CI of 0.22 to 0.50 Nephrotoxicity was less frequent with teicoplanin in trials
for 17 trials and 1,587 patients). Nephrotoxicity was defined with both purified and unpurified vancomycin (Fig. 4) and both
heterogeneously as creatinine levels above the normal range in studies that reported routine monitoring of vancomycin lev-
(1.1 to 1.5 mg/dl), by an absolute increase of 0.5 mg/dl or as a els (RR, 0.31; 95% CI, 0.18 to 0.51; 9 studies and 663 episodes)
50% to 100% increase from the baseline level. Similar RRs and in those that did not (RR, 0.60; 95% CI, 0.38 to 0.95; 12
were observed in studies that recruited children, although none studies and 1,329 episodes). In a further sensitivity analysis that
VOL. 53, 2009 VANCOMYCIN VERSUS TEICOPLANIN 4075
TABLE 2. Subgroup analyses for vancomycin versus teicoplanin 0.50), which translates into a number needed to harm (NNH)
RR (95% CI), no. of studies
of 14 (95% CI, 11 to 25) patients. This effect was not associated
Characteristic included in analysis with the year of the study or drug level monitoring. The effect
All-cause mortality Clinical failure
was similar when the analysis was limited to trials that used the
currently available purified preparation of vancomycin (RR,
Study population 0.44 [95% CI, 0.30 to 0.65]; NNH, 20 [95% CI, 14 to 33]).
Neutropenic patients 0.95 (0.68, 1.34), 9 0.98 (0.83, 1.16), 9
Comparative assessment for the development of resistance
Nonneutropenic 0.94 (0.66, 1.32), 9 0.84 (0.68, 1.03), 12
patients is of interest in an era of glycopeptide resistance, especially
Treatment when a policy of using one or another glycopeptide is being
administration considered. It is an important untoward effect of antibiotic
Empirical 0.92 (0.65, 1.30), 7 0.97 (0.82, 1.15), 8 therapy with implications for the individual treated and future
Semiempirical/ 0.99 (0.70, 1.39), 11 0.86 (0.71, 1.05), 13
definitive patients. Randomized controlled trials provide a well-con-
Age group trolled framework for its assessment. However, resistance de-
Adults mostly 0.92 (0.71, 1.19), 15 0.92 (0.81, 1.05), 18 velopment was poorly reported in all trials, both old and new.
FIG. 3. Funnel plots. (A) All-cause mortality; (B) nephrotoxicity. RRs are plotted against standard errors, as a measure of the study’s precision.
cin level monitoring and dosing. For complicated infections As these doses are associated with increased nephrotoxicity
(bacteremia, endocarditis, osteomyelitis, meningitis, and hos- (36), monitoring of trough serum levels is recommended (56).
pital-acquired pneumonia) and for infections caused by strains Similar data for teicoplanin are largely lacking. A mean daily
with MICs of ⬎1 g/ml, trough levels of 15 to 20 g/ml are dose of 4 mg/kg was associated with treatment failure when
recommended (56). The usual dosing strategies are insufficient compared to a mean daily dose of 6 mg/kg, but even the higher
to achieve these concentrations in patients with normal renal dose resulted in low mean trough levels of 7.8 ⫾ 4.8 g/ml (24).
function, and doses of vancomycin up to 4 g/day are necessary. Doses of 6 mg/kg twice daily achieved serum concentrations of
VOL. 53, 2009 VANCOMYCIN VERSUS TEICOPLANIN 4077
⬎10 g/ml by the second day of treatment. Thus, the admin- Given the similar efficacies teicoplanin and vancomycin and
istration of teicoplanin loading doses of 6 mg/kg twice daily for the lower rate of adverse events with teicoplanin, including
48 h has been recommended for all infections, and for com- serious adverse events, the use of teicoplanin for the treatment
plicated infections, continuation of the high-dose regimen is of infections caused by MRSA and other resistant gram-posi-
recommended (6). Notably, in our review demonstrating the tive organisms should be considered. Uncomplicated infections
similar efficacies of teicoplanin and vancomycin, once-daily permit once-daily dosing of teicoplanin and the possibility of
dosing of teicoplanin was used in all studies. intramuscular injection. Complicated infections probably man-
To resolve the remaining questions on the efficacy and safety date higher dosing strategies for both vancomycin and teico-
of vancomycin versus those of teicoplanin, a contemporary trial planin that should be accompanied by monitoring for renal
that uses adequate randomization methods and that recruits toxicity, especially with vancomycin.
patients with bacteremia (preferably MRSA bacteremia) is
needed. Such a trial is important, given the common use of ACKNOWLEDGMENTS
these agents and the implication of a policy to use one or We thank the authors who responded to our mail and provided
another drug. New lipoglycopeptides targeting improved phar- additional data.
macokinetics, antibacterial activity, and spectrum of coverage We have no conflicts of interest to declare.
This work was performed in partial fulfillment of the M.D. thesis
against vancomycin-resistant enterococci and staphylococci requirements of the Sackler Faculty of Medicine, Tel Aviv University
have been developed. Telvancin, dalbavancin, and oritavancin (S.S.).
are currently undergoing clinical testing (Fig. 1). Trials assess-
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