Flucloxacillin is widely used in community practice for the treatment of both minor and more severe skin and soft tissue infections. It is recommended by the 'Antibiotic Guidelines' for these indications1 and, each year, more than one million prescriptions are subsidised by the Pharmaceutical Benefits Scheme (PBS). In many respects, flucloxacillin is a valuable and appropriate drug for skin and soft tissue infections. It has a narrow spectrum of activity ideally suited to covering the community acquired Grampositive pathogens, principally Staphylococcus aureus and Streptococcus pyogenes. Adverse effects are comparatively few, with upper gastrointestinal intolerance and rash being the most common.2
However, in 1989, an association with a prolonged, often severe and debilitating cholestatic hepatitis was reported.3 This was soon followed by other reports in the Australian medical literature5 and a rapid increase in the awareness of this adverse reaction. By August 1994, there had been 310 cases reported to the Adverse Drug Reactions Advisory Committee (ADRAC), including 17 deaths, with 9 of these appearing to be attributable solely to this reaction.6 The incidence of this cholestatic reaction is estimated to be from 1 in 12 000 to 1 in 100 000. Recent Swedish estimates put the rate at 1 per 10 000-30 000 prescriptions. Patients over 55 years old and those taking the drug for more than 14 days have an increased risk.
Given that the reaction can be life threatening, authorities have felt obliged to act. First, a warning was placed under the listing of flucloxacillin in the PBS Schedule, but prescriptions failed to decline. In August 1994, flucloxacillin became a restricted benefit for severe staphylococcal infections, and a special note was placed at the front of the Schedule. Serious consideration is currently being given to listing flucloxacillin as 'authority only' if these restrictions do not reduce its use. Overall, the story is reminiscent of the association between chloramphenicol and aplastic anaemia, where a relatively uncommon (1 in 20 000-40 000), idiosyncratic, but potentially life threatening reaction has led to the drug disappearing from general use. Chloramphenicol is now largely confined to the treatment of bacterial meningitis (apart from its popular topical use in conjunctivitis).
The question now arises, what can be used in place of flucloxacillin for simple skin and soft tissue infections in community practice? A number of options present themselves, although there are potential problems with them all.
Cephalexin, an oral cephalosporin,7 includes S. aureus and S. pyogenes in its spectrum, but has a broader spectrum than flucloxacillin because of activity against common Gramnegative bacteria. Thus, its use for these Grampositive pathogens is likely to add unnecessary selective pressure on intestinal flora and increase the levels of resistance in these Gramnegative bacteria. There is less certainty in some clinicians' minds about its efficacy as an antistaphylococcal drug, although it is recommended and used widely as a substitute for flucloxacillin in patients with penicillin hypersensitivity (unless the patient has had an accelerated reaction, in which case all cephalosporins are contraindicated). Cephalexin is cheaper than flucloxacillin.
Cefaclor could also be used, but as it has a broader spectrum than cephalexin,7 it is probably best reserved for respiratory tract infections.
Macrolides such as erythromycin, and perhaps roxithromycin, might also be considered. However, erythromycin resistant strains of S. aureus are now common (28%) and are emerging in S. pyogenes(4.9%).8 Increased use for skin and soft tissue infections is likely to exacerbate this problem.
Clindamycin is a well proven drug for staphylococcal and streptococcal infections. However, it has been strongly associated with antibiotic associated diarrhoea and pseudomembranous colitis, with an estimated incidence of 1%.9 The latter complication can be troublesome and occasionally life threatening; therefore, clindamycin has been relegated to the second or third line treatment of more serious infections. In addition, there are ongoing concerns about the possibility of cross resistance with erythromycin which does not necessarily show up on laboratory testing.10 For this reason, many laboratories will report all erythromycin resistant staphylococci and streptococci as clindamycin resistant, regardless of the clindamycin test result.
Amoxycillin/potassium clavulanate is a more recent contender to replace flucloxacillin. Potassium clavulanate is a potent inhibitor of staphylococcal beta lactamase, thereby restoring the activity of amoxycillin against the 90% of community acquired S. aureus that produce this enzyme. Amoxycillin/potassium clavulanate has a very broad spectrum, and extending its routine indications beyond the current 'Antibiotic Guidelines' recommendations for respiratory tract infections is not advisable. Extensive use is likely to add significantly to the antibiotic 'burden' and the selection for resistance now being observed in common pathogens such as E. coli. Moreover, amoxycillin/potassium clavulanate has recently been associated with hepatitis11, although the prognosis may be more benign than for hepatitis due to flucloxacillin.
Fusidic acid has also been proposed as a potential alternative. However, this drug also has a number of problems. First, there has been a longstanding concern about the selection of resistance during treatment. Selection of resistant variants occurs readily in vitro. Nevertheless, fusidic acid has been used extensively in the United Kingdom and Denmark with little evidence of increasing resistance.12 Resistance rates to fusidic acid in Australia are currently very low.8 Perhaps this is because its use is minimal and largely directed at hospital acquired multi resistant S. aureusinfections (MRSA), where it is invariably combined with another drug such as rifampicin. More importantly, fusidic acid has poor activity against S. pyogenes.13 As streptococcal infections are often difficult to distinguish clinically from staphylococcal infections, empirical use of fusidic acid may lead to inadequate coverage. Finally, fusidic acid has a considerable incidence of severe nausea at its currently recommended dosage and a lesser, but still common, incidence of hyperbilirubinaemia.14
Rifampicin is a potent antistaphylococcal drug. It is used for the treatment of MRSA infections and also for tuberculosis, leprosy and meningitis prophylaxis. It should be reserved for these indications because of its effectiveness and the ready selection of resistance which emerges when it is used as a single drug. Rifampicin also has poor activity against streptococci, is expensive and has a number of troublesome drug interactions related to hepatic enzyme induction.
Ciprofloxacin, although active against almost all strains of community acquired S. aureus, has borderline activity against S. pyogenes. Emergence of resistance in MRSA has already become a problem in some parts of Australia, and widespread use may lead to a rapid increase in resistance in community acquired methicillin susceptible S. aureus. It is also quite expensive.
Tetracyclines have never had a major role in the treatment of skin and soft tissue infections. They could be used, but, unfortunately, resistance is prevalent in both S. aureus and S. pyogenes.8
The possibility of using other antistaphylococcal penicillins should also be considered. Currently, only cloxacillin is available in Australia. There is some interest in drugs used in other countries such as oxacillin and nafcillin for parenteral use, and dicloxacillin for oral use. However, there are some caveats here as well. Hepatic reactions have been recorded with oxacillin16 and cloxacillin.17 Until there is evidence to suggest that the frequency of the reactions is lower than that of flucloxacillin, it would be unwise to suggest a change to any of these drugs.
Where does this leave the average prescriber? There is no doubt that the key drug for serious staphylococcal infections should continue to be flucloxacillin. In these infections, the morbidity and potential mortality are high and the benefits of flucloxacillin clearly outweigh the risks. For less serious skin and soft tissue infections, alternatives to flucloxacillin are required. Collections of pus require drainage which may obviate the need for antibiotics. If antibiotics are required, the two best candidates are cephalexin and erythromycin (or perhaps roxithromycin). Cephalexin holds the edge over erythromycin in terms of tolerance and relative lack of resistance.
The following statements are either true or false.
1. Patients over 55 years of age taking prolonged courses of flucloxacillin are at risk of cholestatic hepatitis.
2. As a substitute for flucloxacillin, cephalexin is preferred to erythromycin as it is cheaper.
Answers to self-test questions
- Antibiotic Guidelines Sub Committee, Victorian Drug Usage Advisory Committee. Antibiotic guidelines. 8th ed. Melbourne: Victorian Medical Postgraduate Foundation, 1994.
- Kucers A, Bennett NMcK. The use of antibiotics. 4th ed. London: William Heinemann, 1987:109-24.
- Turner IB, Eckstein RP, Riley JW, Lunzer MR. Prolonged hepatic cholestasis after flucloxacillin therapy. Med J Aust 1989;151:701-5.
- Miros M, Kerlin P, Walker N, Harris O. Flucloxacillin induced delayed cholestatic hepatitis. Aust NZ J Med 1990;20:251-3.
- Eckstein RP, Dowsett JF, Lunzer MR. Flucloxacillin induced liver disease: histopathological findings at biopsy and autopsy. Pathology 1993;25:223-8.
- Adverse Drug Reactions Advisory Committee. Fatal hepatic reactions to flucloxacillin. Aust Adv Drug React Bull 1994;13:10-1.
- Turnidge J. The choice of cephalosporins [editorial]. Aust Prescr 1992;15:26-8.
- Turnidge J, Bell J, editors. National Antimicrobial Resistance Surveillance Program, 1992 Report. Canberra: National Health and Medical Research Council, 1994.
- Kucers A, Bennett NMcK. The use of antibiotics. 4th ed. London: William Heinemann, 1987:819-50.
- Leclercq R, Courvalin P. Bacterial resistance to macrolide, lincosamide and streptogram in antibiotics by target modification [published erratum appears in Antimicrob Agents Chemother 1991;35:2165]. Antimicrob Agents Chemother 1991;35:1267-72.
- Hebbard GS, Smith KG, Gibson PR, Bhathal PS. Augmentin-induced jaundice with a fatal outcome. Med J Aust 1992;156:285-6.
- Faber M, Rosdahl VT. Susceptibility to fusidic acid among Danish Staphylococcus aureus strains and fusidic acid consumption. J Antimicrob Chemother 1990;25(B Suppl):7S-14S.
- Kucers A, Bennett NMcK. The use of antibiotics. 4th ed. London: William Heinemann, 1987:808-18.
- Eykyn SJ. Staphylococcal bacteraemia and endocarditis and fusidic acid. J Antimicrob Chemother 1990;25(B Suppl):33S-38S.
- Onorato IM, Axelrod JL. Hepatitis from intravenous high-dose oxacillin therapy: findings in an adult inpatient population. Ann Intern Med 1978;89:497-500.q
- Tauris P, Jorgensen NF, Petersen CM, Albertsen K. Prolonged severe cholestasis induced by oxacillin derivatives. A report on two cases. Acta Med Scand 1985;217:567-9.
- Enat R, Pollack S, BenArieh Y, Livni E, Barzilai D. Cholestatic jaundice caused by cloxacillin: macrophage inhibition factor test in preventing rechallenge with hepatotoxic drugs. Br Med J 1980;280:982-3.
Department of Microbiology and Infectious Diseases, Monash Medical Centre, Melbourne