The efficacy of continuous infusion flucloxacillin in home therapy for serious staphylococcal infections and cellulitis

Benjamin P. Howden,* and Michael J. Richards,{dagger}

Department of Infectious Diseases, Austin and Repatriation Medical Centre, Studley Road, Heidelberg, Victoria 3084, Australia


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The efficacy and safety of continuous infusion flucloxacillin as home-based treatment was assessed in 62 consecutive patients with proven serious methicillin-susceptible Staphylococcus aureus (MSSA) infections (n = 36) and cellulitis (n = 26). The treatment was well tolerated and resulted in cure or adequate suppression of infection in 27 of 28 (96%) patients in the serious MSSA infection group, and in 24 of 26 (92%) patients in the cellulitis group.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The principal determinant of ß-lactam efficacy is the time for which the drug levels at the site of infection exceed the MIC for the pathogen.1 Continuous infusion may be the optimal method of ß-lactam administration.2 With the advent of small, portable iv infusion devices, home iv antibiotic therapy with continuous infusion of ß-lactam antibiotics is a practical option. A previous study3 with a small number of patients that assessed the efficacy of continuous infusion flucloxacillin in the treatment of serious methicillin-susceptible Staphylococcus aureus (MSSA) infections found it to be safe and effective.

To assess the clinical efficacy, safety and feasibility of continuous infusion therapy, we reviewed the outcomes for a larger group of patients with cellulitis or serious MSSA infections who were treated with continuous infusion flucloxacillin at home after a period of intermittent flucloxacillin in hospital.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
All patients with cellulitis or proven serious MSSA infections suitable for home iv therapy were considered for continuous infusion flucloxacillin. Patients were clinically stable, had adequate social support and consented to home continuous infusion therapy. All patients received intermittent flucloxacillin in hospital and were changed to continuous infusion on discharge at the same total daily dosage. The flucloxacillin was delivered by a portable battery-operated Abbott Provider 5500 Pump (Abbott Laboratories, Chicago, IL, USA). Peripheral iv cannulas were used for short duration therapy, while most patients in the MSSA infection group had a peripherally inserted central catheter (PICC). Initially, the total daily dose of flucloxacillin was added to a 500 mL bag of normal saline for continuous infusion over 24 h. The method of preparation changed at the end of 1997 after an in-house analysis showed degradation of flucloxacillin after 24 h in normal saline at 37°C.4 Subsequently, the daily dosage of flucloxacillin was delivered by two 12 hourly infusions of 100 mL. Patients were reviewed weekly and a nurse and physician were on call at all times. Serum flucloxacillin concentrations were measured at least 48 h after commencement of the continuous infusion. Samples were stored at –20°38;C and levels were measured using high-pressure liquid chromatography (HPLC), with detection by UV absorption at 230 nm.

Patients with suspected, but unproven MSSA infection were excluded. Serious MSSA infection was defined as bacteraemia, deep tissue or prosthetic device infection, with isolation of MSSA from a sterile site. The end points for serious MSSA infections were cure, or for patients with prosthetic joint infection, adequate suppression of the infection. The end point for cellulitis patients was resolution of rash. Patients with bacteraemia, endocarditis and deep abscesses were considered cured if they had no clinical or microbiological evidence of relapse 6 weeks after the completion of antibiotic therapy. For patients with osteomyelitis, septic arthritis, or prosthetic joint or graft infection a minimum follow-up period of 3 months after the completion of antibiotic therapy was required. Patients with prosthetic joint infection were continued on long-term oral antibiotics if the prosthesis was not removed. Adequate suppression of infection in these patients was defined as no clinical or laboratory evidence of active infection 3 months after stopping iv therapy.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Sixty-two patients were included in the study, 26 patients treated for cellulitis and 36 with proven serious MSSA infection. The details of the serious MSSA infection group are shown in Table IGo. In this group the mean age was 57.3 years (range 21–80), with a male predominance (27 versus 9). Thirty-one of 36 (86%) patients had a serious underlying illness or predisposing factor for MSSA infection. The details of the cellulitis group are shown in Table IIGo. Other antibiotics were often given before or after the iv flucloxacillin. Additional therapies in the MSSA infection group included oral rifampicin in five patients, surgical drainage procedures in 11 patients and removal of an iv access device in seven patients with bacteraemia. Flucloxacillin serum concentrations were measured in seven patients receiving continuous infusion flucloxacillin. Six patients receiving flucloxacillin 8 g/day had a mean serum level of 50.3 mg/L (range 33.4–62.7), while one patient receiving flucloxacillin 4 g/day had a serum level of 12.4 mg/L.


View this table:
[in this window]
[in a new window]
 
Table I. Details of patients treated with continuous infusion flucloxacillin for severe MSSA infections
 

View this table:
[in this window]
[in a new window]
 
Table II. Summary of patients with cellulitis who received continuous infusion flucloxacillin
 
All patients in the cellulitis group completed iv flucloxacillin therapy. In the MSSA infection group four patients did not complete therapy, three patients developed a drug side-effect (rash, interstitial nephritis and cholestasis), and another patient with MSSA prosthetic mitral valve endocarditis had enlarging vegetations, subsequently found to be caused by Streptococcus sanguis, with a high MIC of penicillin.

Twenty-four of 26 (92%) patients had resolution of cellulitis at the end of antibiotic therapy. One patient had persisting leg erythema and another with diabetes and leg ulcers failed to respond to flucloxacillin alone. Both patients were treated after 1997 when the infusion method had changed. In the serious MSSA infection group follow-up was available for a median of 20 weeks (mean 30.4 weeks, range 2–111 weeks), and was incomplete in four cases. Three patients died from a serious pre-existing illness and one patient travelled overseas. None had evidence of relapsed MSSA infection at the time of last review. Twenty-seven of 28 (96%) patients who completed therapy and follow-up were cured, or had adequate suppression of prosthetic joint infection. One patient had a second episode of MSSA bacteraemia 5 weeks after completing therapy. The second episode was Hickman catheter related. This patient was also treated after 1997.

Four patients complained of nausea and two developed mild, transient neutropenia while receiving flucloxacillin 8 g/day. One patient developed Hickman-related Gram-negative bacteraemia after completing flucloxacillin therapy. Blockage of the PICC line occurred in three patients.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Evidence exists that supports the use of home continuous infusion ß-lactam therapy in some clinical situations, such as treatment of cystic fibrosis.5 Only one study has used such therapy for severe MSSA infections in humans.3 It showed that continuous infusion flucloxacillin was well tolerated, and led to cure of infection in 14 of 17 (82%) patients who completed therapy. There have been no previous reports of home continuous infusion therapy for the treatment of cellulitis. Continuous infusion flucloxacillin provides an alternative form of home-based treatment for serious MSSA infections and cellulitis. Third-generation cephalosporins and glycopeptides are effective for home treatment of these conditions;6,7 however, these agents have a broader spectrum of activity and are associated with the development of resistant organisms such as vancomycin-resistant Enterococcus, although this has only been demonstrated in the hospital setting.8

In this study, continuous infusion flucloxacillin was safe, convenient and effective for the home-based treatment of serious MSSA infections and cellulitis in patients who were clinically stable. The two ‘failures’ in the cellulitis group were explained by reasons other than mode of administration. A diabetic patient who had cellulitis associated with chronic leg ulcers probably had polymicrobial infection. A second patient had persistent leg erythema that did not require further treatment, indicating that infection had been cured. A number of patients in the cellulitis group received a relatively long course of iv treatment. This may reflect the tendency for more severe cases to be referred for continued iv treatment at home. The one treatment failure in the serious MSSA infection group most likely suffered a new infection. None of the patients with incomplete follow-up had evidence of infection at the time of last review. The potential treatment failures were not related to the use of the 24 h infusions before the end of 1997.

The optimal dosing of flucloxacillin by continuous infusion is currently unknown. In all patients where serum flucloxacillin concentrations were measured, levels appeared adequate. Patients receiving flucloxacillin 8 g/day had levels many times above the MIC for MSSA, which is <=0.5 mg/L.9 The serum concentration of 12.4 mg/L in the patient receiving flucloxacillin 4 g/day was also well above the expected MIC for S. aureus and Streptococcus pyogenes.9 These concentrations can be considered quite high, and support the possibility that lower total daily doses can be used during continuous infusion therapy. Although the free serum concentration of flucloxacillin was not measured directly, assuming a normal level of protein binding in this patient group (94%),9 the patients receiving continuous infusion flucloxacillin 8 g/day would have had a mean serum free flucloxacillin concentration of 3.0 mg/L (range 2.0–3.8), still well above the expected MIC for MSSA.

This study has a number of limitations. It is not comparative, and the in-patient and oral antibiotic therapy confuses the results. The high success rates with continuous infusion therapy make it unlikely that comparative studies with intermittent dosing or alternative agents will show better outcomes. Benefits are likely to lie with patient convenience, and less quantifiable benefits such as the reduced selective pressure for antimicrobial resistance with the use of narrow-spectrum agents. Flucloxacillin concentrations were measured in a small number of patients, but were consistently high. The period of follow-up for patients with prosthetic joint infection and osteomyelitis was relatively short as late relapses can occur; however, continuous infusion therapy did achieve adequate control of these infections.

Further studies are warranted to address the optimal dosing and duration of continuous infusion flucloxacillin, and the role of continuous infusion flucloxacillin in the initial acute management of serious MSSA infections in particular.


    Acknowledgments
 
We would like to thank the Austin and Repatriation Medical Centre Hospital in the Home staff and pharmacy staff for their assistance.


    Notes
 
Correspondence address. Infectious Diseases and Clinical Epidemiology Department, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. Tel: +61-3-9594-4564; Fax: +61-3-9594-4533; E-mail: Ben.Howden{at}med.monash.edu.au Back

Present address. Victorian Infectious Disease Service, Royal Melbourne Hospital, Grattan Street, Carlton, Victoria 3053, Australia Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1 . Turnidge, J. D. (1998). The pharmacodynamics of ß-lactams. Clinical Infectious Diseases 27, 10–22.[ISI][Medline]

2 . Vondracek, T. G. (1995). ß-lactam antibiotics: is continuous infusion the preferred method of administration? Annals of Pharmacotherapy 29, 415–24.[Abstract]

3 . Leder, K., Turnidge, J. D., Korman, T. M. & Grayson, M. L. (1999). The clinical efficacy of continuous-infusion flucloxacillin in serious staphylococcal sepsis. Journal of Antimicrobial Chemotherapy 43, 113–8.[Abstract/Free Full Text]

4 . To, T. P. & Garrett, M. K. (1998). Stability of flucloxacillin in a Hospital in the Home program. Australian Journal of Hospital Pharmacy 28, 289–90.

5 . Vinks, A. A. T. M. M., Brimicombe, R. W., Heijerman, H. G. M. & Bakker, W. (1997). Continuous infusion of ceftazidime in cystic fibrosis patients during home treatment: clinical outcome, microbiology and pharmacokinetics. Journal of Antimicrobial Chemotherapy 40, 125–33.[Abstract]

6 . Nathwani, D. (2000). Place of parenteral cephalosporins in the ambulatory setting. Drugs 59, Suppl. 3, 37–46.[Medline]

7 . 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 & Infectious Diseases 14, 643–7.[ISI][Medline]

8 . Boyce, J. M. (1997). Vancomycin-resistant enterococcus. Detection, epidemiology, and control measures. Infectious Disease Clinics of North America 11, 367–84.[ISI][Medline]

9 . Kucers, A. (1997). Isoxazolyl penicillins: oxacillin, cloxacillin, dicloxacillin and flucloxacillin. In The Use of Antibiotics, 5th edn, (Kucers, A., Crowe, S. M., Grayson, M. L. & Hoy, J. F., Eds), pp. 90–101. Butterworth-Heinemann, Oxford, UK.

Received 8 January 2001; returned 7 March 2001; revised 17 April 2001; accepted 21 May 2001