Efficacy and pharmacodynamics of teicoplanin given daily during the first 3 days and then on alternate days for methicillin-resistant Staphylococcus aureus infections

Carlos Bantara,*, Ricardo Durlachb, Federico Nicolaa, Cristina Freulerb, Pablo Bonvehía, Raul Vazquezb and Jorgelina Smayevskya

a Departments of Microbiology and Infectious Diseases of the Centro de Educación Médica e Investigaciones Clínicas; b Hospital Alemán, Buenos Aires, Argentina


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Fifteen evaluable patients (mean age, 67 years) were enrolled to assess the efficacy of teicoplanin, 6 mg/kg given daily during the first 3 days and then on alternate days, for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. Eight patients had soft tissue infections, four catheter-associated bacteraemia, two osteomyelitis and one pneumonia. Clinical cure was observed in 13 of 15 patients. Both clinical and bacteriological failures were shown in the two patients with osteomyelitis. The mean serum levels of teicoplanin (mg/L) were 22, 8 and 6.7 for peak, 24 h and 48 h troughs, respectively. The dosage employed in this study proved effective in non-deep-seated MRSA infections.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A number of studies have examined the clinical efficacy of teicoplanin given daily for treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections by using different dosages. 1,2 Although a clinical trial evaluating the efficacy of teicoplanin given every other day has been published, it focused only on chronic osteomyelitis and pharmacodynamic parameters were not assessed. 3 The present study evaluates the efficacy and pharmacodynamics of teicoplanin, 6 mg/kg given daily during the first 3 days and then on alternate days, for the treatment of MRSA infections.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patients

The study was conducted following the guidelines of the Declaration of Helsinki and received the approval of the Ethics Committee of the Hospital Alemán, Buenos Aires, Argentina. Informed consent was obtained from the patients or their guardians before enrolment. Patients aged >=18 years with established infection caused by MRSA, other than endocarditis, were eligible for entry into the study. Patients were excluded if they had a history of hypersensitivity to vancomycin, or if they were pregnant or had a creatinine clearance <30 mL/min. Patients were not permitted to receive any other antimicrobial agent and they were excluded from the study if organisms other than S. aureus were isolated from any clinically significant specimen during the study.

Clinical criteria for infections and outcome definitions

Bacteraemia was defined by fever, chills or hypotension and the isolation of MRSA from at least two pretreatment blood cultures. Catheter-associated infection was defined as fever and documented bacteraemia in the presence of an intravascular access catheter and the absence of any other apparent source of bacteraemia. The diagnosis of soft tissue or bone infection required an appropriate examination or compatible radiographic studies plus the isolation of MRSA from a sample obtained by direct closed-space needle aspiration of the infected tissue. Pneumonia was established by the presence of new infiltrates on a chest X-ray plus significant (>10 4 cfu/mL) isolation of MRSA from bronchoalveolar lavage fluid. Patients were considered to be cured clinically if signs and symptoms of infections were eradicated at the end of treatment. Any patient displaying an inadequate clinical response (i.e. persistence of any sign or symptom) was judged to have failed therapy. Follow-up cultures were taken during treatment only if any presumptive lack of response was suspected. When follow-up cultures were not available after treatment (i.e. soft tissue or bone infections), patients were presumed to have been cured bacteriologically if they had complete resolution of clinical signs and symptoms of infection. Follow-up blood cultures for bacteraemia were drawn after 10 days of treatment in patients without fever, or in any case of fever reappearance. Either persistence of S. aureus during therapy or recurrence was considered a bacteriological failure.

Drug administration and determination of antibiotic concentration

Teicoplanin (6 mg/kg) was administered by iv bolus injection every 24 h for 3 days, and was then given every other day. The duration of treatment varied from 10 days to 6 months depending on the type of infection and the clinical and bacteriological response. Blood samples were obtained just before 24 h and 48 h infusion for determination of trough concentrations. Samples for determination of the peak concentration were collected 30 min after infusion. Teicoplanin serum levels were determined by an agar diffusion bioassay as described elsewhere. 4 The standard curve was prepared with sterile human serum in order to correlate with the samples, as teicoplanin displays high binding to human serum proteins. All assays were run in triplicate.

Organism identification and susceptibility testing

Isolates were identified by conventional methods. Staphylococci were tested for resistance to methicillin by the 6 µg oxacillin agar screening method. Teicoplanin and vancomycin MICs and MBCs were determined by the macrodilution method in cation-supplemented Mueller- Hinton broth (Difco Laboratories, Detroit, MI, USA). Serum bactericidal titre (SBT) was determined by a macromethod following the NCCLS guidelines. 5


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Study patients and outcome

A total of 15 eligible patients, 11 female and four male, were finally enrolled in the study. Mean age was 67 years, ranging from 23 to 90 years. The Table gives the source of infection, clinical situation and the outcome for each patient. Eight patients had soft tissue infections (seven infected surgical wounds and one infected burn) and four were considered to have catheter-associated bacteraemia. Of the remaining three patients, two had osteomyelitis (one diabetic foot and one post-operative vertebral infection) and one had ventilator-associated pneumonia (5 day intubation). Clinical cure was observed in 13 of the 15 patients (Table). Negative follow-up cultures (i.e. bacteriological cure) were obtained in all cases of bacteraemia. Clinical and bacteriological failure occurred in the two patients with osteomyelitis: the patient with the vertebral infection required several surgical debridement procedures while the other patient had his foot amputated. Glycopeptide-susceptible S. aureus strains were obtained from the specimens after treatment for 3 months and 1 month, respectively. No adverse events were observed in any patient.


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Table. Clinical and bacteriological outcome for 15 patients treated with teicoplanin (6 mg/kg on alternate days) for methicillin-resistant S. aureus infections
 
Susceptibility testing

Teicoplanin and vancomycin MICs ranged from <=0.25 to 2 mg/L. Teicoplanin MBCs ranged from 0.5 to 16 mg/L and tolerance was shown by five strains, with MBCs >=8 mg/L.

Antibiotic levels in serum

The mean ± S.D. peak teicoplanin concentration was 22 ± 7 mg/L, with a range of 14- 40 mg/L. No significant difference (P > 0.05, Student’s t-test) was found between the mean concentration from the 24 h and the 48 h troughs (8 ± 3 mg/L and 6.7 ± 3 mg/L, respectively).

Serum bactericidal test

Peak SBT for all patients ranged from <1/2 to 1/256. Nine of fifteen patients displayed SBTs >=1/8 for the peak serum, while the remaining six patients showed titres of <1/2 and 1/4 (three patients each). Titres for the 24 h and 48 h troughs were <1/2 in 10 and 11 patients, respectively. Indeed, only two patients showed an SBT of >=1/8 at the 24 h trough and one patient displayed such a titre at the 48 h trough.


    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Several clinical trials have assessed the efficacy of teicoplanin given once a day at doses of approximately 6 mg/kg after an initial loading dose. 1,6 However, increasing the doses reduces the cost-effectiveness when compared with vancomycin. Thus, we were interested in evaluating the efficacy of teicoplanin given every other day after only 3 days of a once-daily therapy. All of our patients with soft tissue infections and catheter-associated bacteraemia were successfully treated with the dosage evaluated here. Although six of these patients displayed low SBTs (i.e. <=1/4), all of them showed a serum inhibitory activity >1/8 (data not shown), suggesting that bactericidal activity may not be always required for effective therapy in these kinds of infection. These results are comparable to those published by other authors, who used similar doses given once a day for treatment of patients with catheter-associated bacteraemia. 1,6

The two failures we observed were both osteomyelitis cases. The difficulties of treating two similar cases of staphylococcal infections, even with higher doses given once a day, have already been described. 6 Like these authors, we observed clinical and bacteriological failure even though acceptable serum bactericidal activity was obtained: the patient undergoing amputation had SBTs of 1/256, 1/64 and 1/32 for peak, 24 h and 48 h troughs, respectively, whereas the respective titres for the vertebral osteomyelitis case were 1/16, 1/4 and 1/2. SBTs may not correlate with the concentration of antibiotics obtained in infected bone with poor blood supply. Graninger et al. 3 reported the outcome of 37 patients with chronic osteomyelitis, including 12 cases produced by MRSA, treated with teicoplanin every other day. These authors demonstrated a 38% cure rate, 46% rate of improvement and 16% of failures with doses ranging from 9 to 25 mg/kg. The only failure they observed among the 12 MRSA infections was a case of vertebral osteomyelitis, which was unsuccessfully treated with a median dose of 17 mg/kg for 2 months. Three staphylococcal foot infections were also included in that study, and none of these was cured (two failures and one improvement). Unfortunately, these authors did not perform pharmacodynamic studies. Thus, the role of the ‘ every-other-day’ dosage in the failures is difficult to analyse. Furthermore, all patients received different doses. In any event, the failures displayed by our patients with osteomyelitis, where high bactericidal rate and multiple surgical debridement are often required, 3,6 may be attributable to 6 mg/kg being a low dose to be used every other day in bone infections, or to the fact that a loading dose regimen (i.e. three initial doses given at 12 h intervals) was not employed in our study. Although this practice was not well established in our country when we started our study, its benefits are now clearly stated. 3

In summary, teicoplanin serum levels displayed by our patients suggest that a 6 mg/kg dose is sufficient to achieve similar concentrations at the 24 h and 48 h troughs, with mean concentrations (8 and 6.7 mg/L, respectively) exceeding the MIC 90 for MRSA strains (i.e. 2 mg/L), proving effective for treatment of soft tissue and catheter- associated MRSA infections. On the basis of pharmacodynamics and results described here, further studies including larger number of patients would be useful to definitively establish this cost-effective dosage recommendation for the treatment of non-deep-seated infections.


    Notes
 
* Correspondence address. Laboratorio de Bacteriología, Billinghurst 2447, Buenos Aires 1425, Argentina. Fax: +54-114-805-3233; E-mail: bantar{at}drwebsa.com.ar Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Bibler, M. R., Frame, P. T., Hagler, D. N., Bode, M. R., Staneck, J. L., Thamlikikul, V. et al. (1987). Clinical evaluation of efficacy, pharmacokinetics, and safety of teicoplanin for serious gram- positive infections. Antimicrobial Agents and Chemotherapy 31 , 207 –12.[ISI][Medline]

2 . Wilson, A. P. R. & Gruneberg, R. N. (1994). Use of teicoplanin in community medicine. European Journal of Clinical Microbiology and Infectious Diseases 13 , 701 –10.[ISI][Medline]

3 . Graninger, W., Wenisch, C., Wiesinger, E., Menschik, M., Karimi, J. & Presterl, E. (1995). Experience with outpatient intravenous teicoplanin therapy for chronic osteomyelitis. European Journal of Clinical Microbiology and Infectious Diseases 14 , 643 –7.[ISI][Medline]

4 . Cavenaghi, L., Corti, A. & Cassani, G. (1986). Comparison of the solid phase enzyme receptor assay (SPERA) and the microbiological assay for teicoplanin. Journal of Hospital Infection 7 , Suppl. A, 85 –9.[ISI][Medline]

5 . National Committee for Clinical Laboratory Standards. (1997). Methodology for the Serum Bactericidal Test— Fourth Edition: Proposed Guideline M21-P. NCCLS, Villanova, PA.

6 . Greenberg, R. N. (1990). Treatment of bone, joint, and vascular-access-associated gram-positive bacterial infections with teicoplanin. Antimicrobial Agents and Chemotherapy 34 , 2392 –7.[ISI][Medline]

Received 12 August 1998; returned 12 November 1998; revised 7 December 1998; accepted 17 December 1998