Once–daily versus twice–daily intravenous administration of vancomycin for infections in hospitalized patients

Eytan Cohena, Alexander Dadasheva, Moshe Druckerb, Zmira Samrac, Ethan Rubinsteind and Moshe Gartya,*

a Recanati Centre for Medicine and Research and Clinical Pharmacology Unit, b Infectious Diseases Unit and c Microbiology Laboratory, Beilinson Campus, Petach-Tikva and Sackler Medical School, Tel-Aviv; d Infectious Diseases Unit, Chaim Sheba Medical Centre, Tel-Hashomer and Sackler Medical School, Tel-Aviv, Israel


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The efficacy and toxicity of once-daily (od) versus twice-daily (bd) dosing of vancomycin was compared in 121 hospitalized patients. Eighteen patients were then withdrawn from the study. Clinical and bacteriological responses were evaluated in all patients (n = 103). Nephrotoxicity was assessed in patients who did not receive nephrotoxic agents (n = 76). Ototoxicity was assessed in patients who completed two audiograms and were not receiving ototoxic agents (n = 63). No significant difference was found between the two groups for favourable clinical response: 47/51 (92.1%) and 49/52 (94.2%) in the od and bd groups, respectively. In 34 patients vancomycin was the only effective antibiotic. Fifteen of 18 (83.3%) evaluated episodes in the od and 12/16 (75.0%) evaluated episodes in the bd group showed a favourable bacteriological response. There were no significant differences between the od and bd groups for all adverse events. Nephrotoxicity developed in 4/37 (10.8%) and 3/39 (7.7%) patients, respectively. Hearing loss developed in 1/31 (3.2%) and 5/32 (15.6%). Phlebitis occurred in 7/51 (13.7%) and 12/52 (23.0%). Red man syndrome occurred in 7/51 (13.7%) and 5/52 (9.6%) in od and bd groups, respectively. The efficacy and safety profile of od administration of vancomycin is similar to that of the customary, but less convenient, bd administration.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Vancomycin, the agent most commonly used against methicillin-resistant Gram-positive cocci, has been used more frequently in recent years due to the rising occurrence of infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE). Following an initial decrease in vancomycin use due to a high rate of adverse events, a renewed interest in this antibiotic has been stimulated as a result of improved purification techniques.1

The usual daily iv dose of vancomycin in adults with normal renal function is 1 g every 12 h (or 0.5 g every 6 h). It has been shown recently that for vancomycin the pharmacodynamic parameter that correlates best with eradication is area under the concentration–time curve (AUC)24/MIC.2 In the infected fibrin–platelet clot model, vancomycin was administered to simulate regimens of continuous infusion, 2 g every 24 h (q24h), 1 g q12h and 500 mg q6h. In all regimens AUC24/MIC was similar, time (T) > MIC was 100% and bacterial kill was identical.3 The concept of once-daily administration is also supported by the prolonged in vivo post-antibiotic effect (PAE) of vancomycin.4 Additional potential advantages include: simple dosage calculation and fewer assays for monitoring, resulting in lower costs.5 Once-daily administration will thus facilitate home iv therapy.6 Indeed, it has been suggested that the safest and most effective way to administer vancomycin would be to infuse it slowly and at longer intervals, at least every 12 h and possibly every 24 h.7

In the only reported study involving once-daily vancomycin administration, vancomycin was given with tobramycin and was found to be effective in reducing the incidence of infections in severely immunocompromised patients.8 The study, however, was neither comparative nor blinded and used historical controls.

Therefore, despite almost 50 years of use, a consensus regarding an optimal dosing regimen of vancomycin still does not exist. Here we report a prospective, randomized study comparing the efficacy and safety of once- versus twice-daily administration of vancomycin in hospitalized patients.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patient selection

Consecutive patients between 17 and 90 years of age, in a tertiary medical centre, with suspected or confirmed infection for which vancomycin was indicated were eligible. Exclusion criteria were as follows: a known history of allergy to vancomycin; pregnancy; granulocytopenia (<1.0 x 109/L), septic shock; renal impairment (serum creatinine >177 µmol/L or creatinine clearance <50 mL/min); known history of vestibular disease or hearing loss; and all forms of endocarditis. Patients who had been treated with vancomycin within the previous month were also excluded. All patients were classified according to APACHE-II.9 Previous and concomitant diseases and drugs used were also recorded. The study, which was not sponsored, was approved by the hospital ethics committee. All patients signed an informed consent form.

Study design

Patients were allocated randomly by strata to vancomycin 30 mg/kg iv either once daily (od) or in two divided doses (bd). The patient's stratum was based on three age groups (17–39, 40–64, 65–91 years) and three APACHE-II score levels (2–9, 10–19, 20+). Accordingly, nine strata were used. Total daily dose was determined by one of the authors (A. Dadashev) using Cockcroft & Gault's formula10 for calculating creatinine clearance and Moellering's nomogram11 for dosage adjustment. Vancomycin was administered intravenously over 2 h in the od group and over 1 h in the bd group. Forty-eight hours later, trough and peak levels were obtained just before the next dose and within 1 h after the end of infusion, respectively. Serum assays of vancomycin were performed by fluorescence polarization immunoassay (TDx, Abbott Laboratories, Germany). In the od group, daily doses were reduced when the trough level exceeded 10 mg/L; in the bd group the dose was adjusted to keep peak levels between 30 and 40 mg/L, and trough levels between 5 and 10 mg/L. After adjustment of the dose, peak and trough levels were repeated 48 h later. Thereafter, vancomycin levels were measured once a week. The duration of vancomycin therapy was determined independently by the attending physician.

Evaluation variables

Clinical efficacy.
Clinical efficacy was determined on the last day of therapy by one of the authors (M. Drucker), who was blinded to the dose regimen. It was defined as ‘favourable’ if there was clinical improvement with resolution of symptoms of infection, return to normal body temperature (recorded orally tds; <37.9°C) for at least 48 h, and normalization or a decrease (>=15%) in the white blood cell count. All other responses were considered ‘unfavourable’.12

Bacteriological efficacy.
Before antibiotic treatment with vancomycin, two blood cultures and cultures from any suspected site of infection were obtained. Cultures were repeated every 3 days, if clinically indicated, and on the last day of therapy as well as 4 days after discontinuation of the antibiotic treatment. Bacteria for which the MIC of vancomycin was <1.5 mg/L were considered susceptible. Bacteriological efficacy was determined 4 days after the end of the antibiotic treatment. It was defined as ‘favourable’ if the post-therapy culture was negative, if no more material was obtainable for culture or if a new microorganism was cultured without clinical signs of infection. Response was classified as ‘unfavourable’ when post-therapy cultures were still positive for the same microorganism, when a new microorganism was cultured with clinical signs of infection or when vancomycin resistance developed. Response was considered ‘indeterminate’ when the patient had been treated with another antibiotic to which the microorganism was susceptible or when no microorganism had been cultured at the start of therapy.

Evaluation of toxicity.
Patients who had been treated with aminoglycosides in the 2 weeks before the study or who also received amphotericin B, cisplatin or high dose frusemide (>160 mg/day) were not evaluated for toxicity.

Nephrotoxicity.
Nephrotoxicity was defined as a rise in serum creatinine of >=45 µmol/L.13 It was assessed thrice weekly during therapy and 1 week after discontinuation of vancomycin.

Ototoxicity.
Ototoxicity was assessed in alert patients by air conduction pure tone audiometry. When the patient's condition allowed them to leave the ward, the audiometry tests were performed in a sound-proof chamber at the Audiometry Unit. When the patient was too ill to be transferred, the tests were performed at the bedside using a portable audiometer. Each test was carried out within 72 h after commencement of treatment and following treatment. Hearing loss was defined as perception loss of >=10 dB, in at least two frequencies.14 Other otological symptoms such as tinnitus and vertigo were also recorded.

Red man syndrome.
Pruritus, muscle pain or chest tightness were graded by the patient as mild, moderate or severe; each was awarded one, two or three points, respectively. Flushing was graded by the physician: facial flush, one point; facial and upper body, two points; whole body involvement, three points. Systolic blood pressure drop from the pre-treatment levels was graded as follows: 10–14 mmHg drop, two points; 15–20 mmHg drop, three points; >20 mmHg drop, four points. A total score of >=5 was defined as severe red man syndrome.15

Statistical analysis

A sample size of 100 patients was estimated to have a power of 80% to detect a 20% difference in the primary efficacy variable clinical outcome. Fisher's exact test was conducted to determine significant frequency differences between the two groups. Wilcoxon's signed rank test was used to determine significant differences in continuous variables where normality assumptions were not met or were considered doubtful. Normally distributed variables were analysed using t-tests (two-tailed).


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patients

One hundred and twenty-one patients were randomized and given at least one dose of vancomycin. Eighteen patients were withdrawn from the study for the following reasons: no appropriate culture (n = 5), patient withheld consent (n = 3), death (n = 2), cessation of treatment with vancomycin within 72 h (n = 5) and a diagnosis of endocarditis (n = 3). One hundred and three patients completed the study (51 od, 52 bd). The two groups were comparable with respect to gender (35% and 40% females in the od and bd groups, respectively), age (62 ± 12 years and 65 ± 13 years, respectively), body weight (75.9 ± 13.7 kg and 76.3 ± 15.6 kg, respectively), temperature (38.1 ± 0.9 and 37.9 ± 0.9°C, respectively), mean arterial pressure (112 ± 17 and 109 ± 16 mmHg, respectively) and APACHE-II score (8.3 ± 4.1 and 8.8 ± 4.5, respectively). Both groups had similar concomitant diseases and underlying conditions.

Infections and microorganisms

Primary sites of infection were similar in both groups, the most common being sternum wound infection (11 and 10 in the od and bd groups, respectively), primary bacteraemia (nine and 11, respectively) and septic arthritis (five and seven, respectively). The causative microorganisms were also similar in both groups, the most common being MRSA (14 and 13, respectively), methicillin-susceptible S. epidermidis (MSSE) (10 and nine, respectively), MRSE (nine and nine, respectively) and enterococci (eight and four, respectively). Most of the microorganisms cultured were Gram-positive cocci. The proportion of patients with positive blood cultures, in primary and secondary bacteraemia, was comparable: 29.4% and 30.8%, respectively, in the od and bd groups. The proportion of patients in which no microorganism was cultured was also similar: 41% versus 35%. The proportion of patients with polymicrobial infections was also similar (22 cultures in each group).

Therapy protocol

No statistically significant differences were found between the two groups in the mean initial percentage of standard dose, duration of treatment or cumulative dose (Table 1Go). The slightly higher mean cumulative dose in the od group was the result of a longer average treatment time. As expected, mean vancomycin serum first peak, mean maximal peak as well as the mean peak for all the treatment period were higher in the od group. All differences were significant. The first trough concentration was <10 mg/L in 63.8% of the od group and 48.9% of the bd group. The first peak concentration was between 30 and 40 mg/L in 26.3% and 29.2% of the od and bd groups, respectively (Table 1Go).


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Table 1. Treatment characteristicsa
 
Efficacy

Clinical efficacy.
A favourable clinical response was found in 47 of 51 (92.1%) patients in the od group and in 49 of 52 (94.2%) patients in the bd group (P = 0.72). In both groups one patient died as a result of the underlying disease (acute leukaemia in both cases) (Table 2Go).


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Table 2. Clinical and bacteriological efficacy
 
Bacteriological efficacy.
In 34 patients vancomycin was the only effective antibiotic. Fifteen of 18 (83.3%) evaluated episodes in the od and 12 of 16 (75.0%) evaluated episodes in the bd group showed a favourable bacteriological response (P = 0.68) (Table 2Go). The microorganisms isolated in those patients are shown in Table 3Go.


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Table 3. Microorganisms isolated from patients in whom vancomycin was the only effective antibiotic and outcome
 
Toxicity.
Results are summarized in Table 4Go.


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Table 4. Rate of vancomycin toxicitya
 
Nephrotoxicity.
Nephrotoxicity was assessed only in patients who did not receive any other potentially nephrotoxic agents (n = 76). Four of 37 (10.8%) patients in the od group and three of 39 (7.7%) in the bd group showed a rise in serum creatinine of >45 µmol/L (P = 0.71).

Ototoxicity.
Ototoxicity was assessed only in patients who completed two audiograms and who did not receive ototoxic agents (n = 63). One of 31 (3.2%) patients in the od group and five of 32 (15.6%) patients in the bd developed a significant hearing loss (P = 0.20). In three patients in the bd group the hearing loss was in both ears.

Red man syndrome and thrombophlebitis.
Red man syndrome was observed in seven of 51 (13.7%) patients in the od group and in five of 52 (9.6%) patients in the bd group (P = 0.52). In all patients the syndrome was mild.

Thrombophlebitis.
Thrombophlebitis was observed in seven of 51 (13.7%) patients in the od group and in 12 of 52 (23%) patients in the bd group (P = 0.22).


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This randomized prospective study, in hospitalized patients, compared the clinical and bacteriological efficacy, as well as the safety and side effects, of vancomycin when given either once or twice daily. Both groups, albeit small in number, were comparable with regard to illness severity assessed by APACHE-II score, concomitant disease, site of infection and microorganisms isolated. Since vancomycin is potentially nephrotoxic, patients with creatinine clearance of <50 mL/min were excluded. Serum concentrations were measured in order not to distort the possible clinical effect of either one of the groups.

In the past, the concept of a single daily dose as a means of reducing antibiotic toxicity, while ensuring adequate serum concentrations, has focused mainly on aminoglycosides. A meta-analysis of randomized trials comparing once-daily aminoglycosides with patients treated with divided doses concluded that clinical and bacteriological responses were similar but that a lower rate of ototoxicity and nephrotoxicity, although without statistical significance, was observed with the once-daily aminoglycoside regimen.16

Vancomycin exerts its bactericidal activity as long as its concentration remains at low multiples of the MIC.17 The concept of comparing the dosing frequency and its effects on the bacterial kill (MRSA) was tested in the infected fibrin model simulating staphylococcal endocarditis. It was found that bacterial kill was unaffected by changing vancomycin dose from continuous infusion to once- or twice-daily dosing (with the same total daily dosage); however, the once-daily dose with the addition of gentamicin was the most effective treatment option.3 The importance of AUC/ MIC (along with Cmax/MIC) was also shown in the survival of mice with Streptococcus pneumoniae peritonitis.18 The irrelevance of the dosing frequency was demonstrated in vitro with human CSF as well as in a child with staphylococcal meningitis.19 In addition, in a recent clinical study with intensive care unit patients, it was also shown that a single daily vancomycin administration, albeit in a continuous infusion, was similar in clinical effectiveness and safety to intermittent administration.20

Taken together, all these studies show that the AUC/ MIC ratio is the most predictive pharmacokinetic/pharmacodynamic parameter correlating with therapeutic efficacy. This is also supported by the probably prolonged in vivo PAE of vancomycin, as was shown in the mouse thigh model.4,21

Another argument for the use of od rather than bd is the height of the trough serum level. There is clinical evidence suggesting that a serum bactericidal titre of >1:8 is associated with favourable outcome.22 A concentration producing such a bacterial titre was probably achieved with both the od and bd regimens when the corresponding peak serum concentration is taken into account (46.9 ± 19.80 and 26.4 ± 8.9 mg/L, respectively). In contrast, others have suggested that trough vancomycin concentrations > 12 mg/L may be associated with a favourable outcome.23 In our patients only the od group had mean trough vancomycin concentrations exceeding 12 mg/L. As regards T > MIC, 96% of the patients in the od group had trough concentrations >2 mg/L and 84% >5 mg/L. These levels are far above the accepted MIC of vancomycin for S. aureus.

It has been suggested that only the protein-unbound fraction of an antibiotic exerts the antibacterial activity, a point that may be of relevance to highly protein-bound antibacterial agents (like teicoplanin and cefazolin); however, this is not the case for vancomycin which is 10–62% bound to human albumin.24

Once-daily administration of vancomycin has not been assessed before. The only study in adults involving once-daily vancomycin administration, together with an aminoglycoside (tobramycin), was reported to be effective in reducing the incidence of infection in severely immunocompromised patients. As stated previously however, this study had severe methodological flaws.8 An additional small uncontrolled study also reported the effectiveness of a single daily administration of vancomycin in paediatric oncology patients.25 The higher doses of vancomycin used in this study and other series have been challenged as unnecessary, and contribute to toxicity and unnecessary concentration measurements for monitoring.26

A recent review has summarized the rate of vancomycin toxicity.27 Our study revealed similar rates of side effects, but without any significant differences between the two groups.

The number of patients evaluated in this study was 103. However, we are aware that in only 34 patients (18 and 16 in each group) was vancomycin the only effective antibiotic. We decided not to exclude patients who were treated with other antibiotics so that an unbiased sample of hospital patients who receive vancomycin could be assessed. This is common practice where patients are given multiple antibiotic regimes before culture results are reported. Moreover, the toxicity of vancomycin could still be assessed in patients who received concomitant antibiotic treatment. Further studies are needed to evaluate larger groups of patients in whom vancomycin is the only effective antibiotic.

In summary, the efficacy and toxicity of once-daily vancomycin seems to be similar to that of the customary but less convenient twice-daily dosing.


    Notes
 
* Correspondence adddress. Recanati Centre for Internal Medicine and Research, Rabin Medical Centre, Beilinson Campus, Petach-Tikva, Israel 49100. Tel: +972-3-9377362; Fax: +972-3-9244663; E-mail: mgarty{at}post.tau.ac.il Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Received 27 April 2001; returned 11 August 2001; revised 17 September 2001; accepted 25 September 2001