- Email: [email protected]
Overview of the role of mupirocin
Journal of Hospital Infection (1991) 19 (Supplement
Overview
B), 27730
of the role of mupirocin Y. J. Lamb
SmithKline
Beecham Pharmaceuticals,
Welwyn
Garden City AL 7 1E Y, UK
Summary: Mupirocin is a novel antibiotic, for topical use only, which is unrelated in chemical structure and mode of action to any known class of antibacterial agent. It is active against a wide range of Gram-positive bacteria, including staphylococci and most streptococci, and is moderately active against Gram-negative bacteria. Mupirocin 2% ointment applied 2 or 3 times daily has demonstrable efficacy for the treatment of both primary and secondary skin infections and compares favourably with other topical and systemic treatments. In clinical studies, both elimination of the bacterial pathogen and clinical cure or improvement has been usual in over 90% of patients. Up to 40% of the normal population carry Staphylococcus aureus in the anterior nares and this carriage rate is often increased in hospitalized patients and their attendants. The increasing incidence of multiplyand has been associated with hospital methicillin-resistant S. aureus (MRSA) outbreaks leading to considerable morbidity and disruption of hospital services. Intranasal 2% calcium mupirocin has been shown to be effective in the eradication of nasal carriage; in bacteriologically controlled studies elimination of S. aureus, including MRSA, was achieved in over 95% of subjects. The role of mupirocin in preventing staphylococcal infection is currently undergoing evaluation. Keywords:
Mupirocin;
MRSA,
nasal carriage;
skin infection.
Introduction
Mupirocin, an antibiotic produced by submerged fermentation of Pseudomonasfluorescens, has a novel mode of action, namely the inhibition of bacterial isoleucyl-transfer RNA synthetase. This is thought to be a major factor accounting for the lack of cross-resistance with other antibiotics. Mupirocin is unsuitable for systemic administration as it is rapidly broken down in the plasma into an inactive metabolite; hence it has been developed as a topical agent only. At low concentrations mupirocin has a bacteriostatic action but at higher concentrations, such as those achieved by topical application to skin and mucous membranes, the antibiotic becomes progressively bactericidal.‘y2 Mupirocin has excellent in-vitro activity against the primary Gram-positive bacteria involved in skin infections, with 90% of staphyloccal species, including S. aureus and S. epidermidis, being inhibited at concentrations of 0.12 to 0.5 mg 1-’ .3,4 Strains of S. aureus resistant to multiple antibiotics still remain sensitive to mupirocin (minimum inhibitory concentration, MIC ~0.2 mg l-l), with no evidence of 0195&5701;91/09B027+04
0
$03.00/O
27
1991 The Hospital
Infecnon
Society
Y. J. Lamb
28
cross-resistance.’ variable. Many
Activity against are resistant to
Gram-negative organisms is more mupirocin, with the exception of
Haemophilus influenzae, Neisseria meningitidis, N. gonorrhoeae, Branhamella catarrhalis and Pasteurella multocida (MIC < 0.25 mg 1-‘).3p4
Treatment
of skin
infections
Impetigo and furunculosis caused by S. aweus are the commonest primary bacterial skin infections. Secondary infections of non-infected lesions such as eczema are also common. Mupirocin 2% ointment has been compared with other topical and systemic treatments in a variety of superficial skin infections. In a study of 36 children treated with mupirocin or chlortetracycline cream, clinical success was demonstrated in 95 and 100% of patients respectively.6 Four studies have compared mupirocin with fusidic acid. In all, mupirocin and fusidic acid were similar in both clinical and bacteriological efficacy.7-‘0 The largest of these studies compared mupirocin 2% ointment twice daily with sodium fusidate three-times daily in 413 patients with superficial skin infections. Mupirocin resulted in a clinical success rate of 97% and bacteriological success rate of 93%, compared to 93% and 89%, respectively, for sodium fusidate.” In another study mupirocin and oral erythromycin were compared in 60 patients with primary or secondary skin infections. The clinical success rate was 97% for mupirocin and 77% for erythromycin. Elimination of the causative pathogen was achieved in all of the evaluable mupirocin-treated patients and 81% of those treated with erythromycin.” In another trial, mupirocin cured primary skin infections in 100% of 29 children, compared to 93% of 32 children treated with oral dicloxacillin for S-10 days.12 Further studies have concluded that mupirocin is more effective than oral ampicillin or cloxacillin for the treatment of various skin infections.‘3,‘4
Elimination of nasal carriage of Staphylococcus aureus Asymptomatic skin and nasal colonization with S. aweus is common. Between 20 and 40% of the general population carry this organism in their anterior nares” and there is an even higher incidence in nurses, children with atopic eczema and hospitalized patients.i6 Hospital outbreaks of methicillin-resistant S. aweus (MRSA) are difficult to control, costly, and may give rise to serious clinical problems in at risk patients. I7 There has been a marked increase in the number of reported outbreaks of hospital infection with MRSA in recent years.‘8v’9 During 1983, the spread of MRSA in UK hospitals, particularly in the North-West, North-East and South-East Thames regions, posed a serious clinical problem, and efforts to treat nasal carriage had been disappointing. Dacre et a1.20treated 1.5 carriers with intranasal mupirocin 2% ointment in a polyethyleneglycol base. Eradication of nasal carriage was achieved in all
Role of mupirocin
29
subjects but the incidence of minor adverse reactions in six cases was considered unacceptable. A formulation of calcium mupirocin 2% ointment in a white soft paraffin base was thus developed and the efficacy of this presentation was demonstrated in an open, bacteriologically controlled study, conducted during hospital outbreaks of MRSA. Nasal carriage of 5’. uureus was eliminated in 97% of 766 assessable subjects, including 97% of 628 subjects colonized with MRSA.*l Whilst subsequent placebo-controlled studies in MRSA carriers have been precluded because of the high level of efficacy, the superiority of mupirocin over the base alone was clearly demonstrated in 32 volunteers with stable carriage of methicillin-sensitive S. uureus.** Treatment with mupirocin produced clearance of bacteria within 48 hours in all subjects, whereas the base had no effect.**. The guidelines published by the Hospital Infection Society and the British Society for Antimicrobial Chemotherapy on the control of epidemic MRSA include treatment of nasal carriers with calcium mupirocin 2% ointment.23 Infection is a major cause of morbidity and mortality in haemodialysis patients, S. aureus being the most frequently isolated pathogen.24T25 A recent prospective controlled study demonstrated that elimination of nasal carriage with mupirocin produced a significant reduction in S. aureus infection in patients undergoing haemodialysis, compared with placebo.26 In conclusion, mupirocin is a novel agent that is particularly active in vitro against staphylococci and most streptococci. It has a high clinical success rate in the treatment of acute superficial skin infections. Its activity against MRSA, together with its lack of cross-resistance to other antibiotics and unavailability in systemic form, suggest that it is likely to become the treatment of choice for nasal carriage of MRSA. Its role in the prevention of certain infections needs further evaluation.
References 1. Hughes J, Mellows G. Inhibition of isoleucyl-transfer ribonucleic acid synthetase in Escherichia coli by pseudomonic acid. Biochem J 1978; 176: 305-318. acid, an antibiotic produced 2. Sutherland R, Comber KR, Mizen LW et al. Pseudomonic by Pseudomonas fluorescens. Proceedings of the 16th Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago 1976. 3. Sutherland R, Boon RJ, Griffin KE et al. Antibacterial activity of mupirocin (pseudomonic acid), a new antibiotic for topical use. Antimicrob Agents Chemother 1985; 27: 495498. activity of mupirocin, an antibiotic 4. White AR, Beale AS, Boon RJ et al. Antibacterial produced by Pseudomonasfluorescens. In: Wilkinson DS, Price JD, Eds. Mupirocin-a Novel Topical Antibiotic, The Royal Society of Medicine International Congress & Symposium
Series 80, 1984; 43-55. MW, Hill RLR. In-vitro activity of mupirocin (pseudomonic acid) against clinical isolates of Staphylococcus aureus. J Antimicrob Chemother 1985; 15: 523-531. trial of mupirocin and chlortetracycline in 6. Huskisson SC, Wainscott G. A comparative general practice and a children’s casualty department. In: Wilkinson DS, Price JD, Eds. Mupirocin-a Novel Topical Antibiotic. The Royal Society of Medicine International Congress and Symposium Series 80, 1984; 109-l 13.
5. Casewell
Y. J. Lamb
30
7. Gilbert M. Topical 2% mupirocin versus 2% fusidic acid ointment in the treatment of J Am Acad Dermatol 1989; 20: 1083-1087. primary and secondary skin infections. 8. Langdon CG, Mahapatra KS. Efficacy and acceptability of fusidic acid cream and mupirocin ointment in acute skin sepsis. Curr Ther Res 1990; 48: 174-180. 9. Morley PAR, Munot LD. A comparison of sodium fusidate ointment and mupirocin ointment in superficial skin sepsis. Cuvr Med Res and Opinion 1988; 11: 142-148. 10. White DG, Collins PO, Rowsell RB. Topical antibiotics in the treatment of superficial skin infections in general practice-a comparison of mupirocin with sodium fusidate. J Infect 1989; 18: 221-229. 11. Gratton D. Topical mupirocin versus oral erythromycin in the treatment of primary and secondary skin infections. Int J Dermatol 1987; 26: 472473. 12. Arredondo JL. Efficacy and tolerance of topical mupirocin compared with oral dicloxacillin in the treatment of primary skin infections. Curr Ther Res 1987; 41: 121-127. 13. Welsh 0, Saenz C. Topical mupirocin compared with oral ampicillin in the treatment of primary and secondary skin infections. Curr Ther Res 1987; 41: 114120. 14. Guertin-Larochelle S. Efficacy and tolerance of topical Bactroban (2% mupirocin) vs. systemic cloxacillin in the treatment of primary and secondary skin infections. Todays They Trends 1986; 4: 1-14. 15. Williams REO, Health carriage of Staphylococcus aureus: its prevalence and importance.
Bacterial Rev 1963; 27: 56. 16. Wheat LJ, Kohler RB, White A. Treatment of nasal carriers of coagulase-positive staphylococci. In: Maibach H, Aly R, Eds. Skin Microbiology: Relevance to Clinical Infection. New York: Springer Verlag, 1981; 50-58. 17. Duckworth GJ, Lothian JLE, Williams JD. Methicillin-resistant Staphylococcus aureus: report of an outbreak in a London teaching hospital. J Hasp Infect 1988; 11: I-15. 18. Keane CT, Cafferkey MT. Re-emergence of methicillin-resistant Staph. aureus causing severe infection. J Infect 1984; 9: 616. J. Control of a hospital outbreak of 19. Shanson DC, Johnstone D, Midgley methicillin-resistant Staphylococcus aureus infections: value of an isolation unit. J Hosp Infect 1985; 6: 285-292. 20. Dacre JE, Emmerson AM, Jenner EA. Nasal carriage of gentamicin and methicillin resistant Staphylococcus aureus treated with topical pseudomonic acid. Lancet 1983; 2: 1036. 21. Rowsell RB. Early experience with intranasal mupirocin. In: van der Meer JWM, Ed. discussion. Excerpta Medica Nasal carriage of Staphylococcus aureus-a round-table 1990; 33-37. 22. Casewell MW, Hill RLR. Elimination of nasal carriage of Staphylococcus aureus with mupirocin (‘pseudomonic acid’)-a controlled trial. J Antimicrob Chemother 1986; 17: 365-372. 23. Ayliffe GAJ, Duckworth GJ, Brumfitt W et al. Guidelines for the control of epidemic methicillin-resistant Staphylococcus aureus. J Hosp Infect 1986; 7: 193-201. 24. Bradley JR, Evans DB, Calne RY. Long-term survival in haemodialysis patients. Lancet 1987; 1: 295-296. 25. Kaplowitz LG, Comstock JA, Landwehr DM et al. Prospective study of microbial colonization of the nose and skin and infection of the vascular access site in haemodialysis patients. J Clin Microbial 1988; 26: 1257-I 262. 26. Boelaert JR, De Smedt RA, De Baere YA et al. The influence of calcium mupirocin nasal ointment on the incidence of Staphylococcus aureus infections in haemodialysis patients. Nephron Dial Transpl 1989; 4: 278-281.
Overview
B), 27730
of the role of mupirocin Y. J. Lamb
SmithKline
Beecham Pharmaceuticals,
Welwyn
Garden City AL 7 1E Y, UK
Summary: Mupirocin is a novel antibiotic, for topical use only, which is unrelated in chemical structure and mode of action to any known class of antibacterial agent. It is active against a wide range of Gram-positive bacteria, including staphylococci and most streptococci, and is moderately active against Gram-negative bacteria. Mupirocin 2% ointment applied 2 or 3 times daily has demonstrable efficacy for the treatment of both primary and secondary skin infections and compares favourably with other topical and systemic treatments. In clinical studies, both elimination of the bacterial pathogen and clinical cure or improvement has been usual in over 90% of patients. Up to 40% of the normal population carry Staphylococcus aureus in the anterior nares and this carriage rate is often increased in hospitalized patients and their attendants. The increasing incidence of multiplyand has been associated with hospital methicillin-resistant S. aureus (MRSA) outbreaks leading to considerable morbidity and disruption of hospital services. Intranasal 2% calcium mupirocin has been shown to be effective in the eradication of nasal carriage; in bacteriologically controlled studies elimination of S. aureus, including MRSA, was achieved in over 95% of subjects. The role of mupirocin in preventing staphylococcal infection is currently undergoing evaluation. Keywords:
Mupirocin;
MRSA,
nasal carriage;
skin infection.
Introduction
Mupirocin, an antibiotic produced by submerged fermentation of Pseudomonasfluorescens, has a novel mode of action, namely the inhibition of bacterial isoleucyl-transfer RNA synthetase. This is thought to be a major factor accounting for the lack of cross-resistance with other antibiotics. Mupirocin is unsuitable for systemic administration as it is rapidly broken down in the plasma into an inactive metabolite; hence it has been developed as a topical agent only. At low concentrations mupirocin has a bacteriostatic action but at higher concentrations, such as those achieved by topical application to skin and mucous membranes, the antibiotic becomes progressively bactericidal.‘y2 Mupirocin has excellent in-vitro activity against the primary Gram-positive bacteria involved in skin infections, with 90% of staphyloccal species, including S. aureus and S. epidermidis, being inhibited at concentrations of 0.12 to 0.5 mg 1-’ .3,4 Strains of S. aureus resistant to multiple antibiotics still remain sensitive to mupirocin (minimum inhibitory concentration, MIC ~0.2 mg l-l), with no evidence of 0195&5701;91/09B027+04
0
$03.00/O
27
1991 The Hospital
Infecnon
Society
Y. J. Lamb
28
cross-resistance.’ variable. Many
Activity against are resistant to
Gram-negative organisms is more mupirocin, with the exception of
Haemophilus influenzae, Neisseria meningitidis, N. gonorrhoeae, Branhamella catarrhalis and Pasteurella multocida (MIC < 0.25 mg 1-‘).3p4
Treatment
of skin
infections
Impetigo and furunculosis caused by S. aweus are the commonest primary bacterial skin infections. Secondary infections of non-infected lesions such as eczema are also common. Mupirocin 2% ointment has been compared with other topical and systemic treatments in a variety of superficial skin infections. In a study of 36 children treated with mupirocin or chlortetracycline cream, clinical success was demonstrated in 95 and 100% of patients respectively.6 Four studies have compared mupirocin with fusidic acid. In all, mupirocin and fusidic acid were similar in both clinical and bacteriological efficacy.7-‘0 The largest of these studies compared mupirocin 2% ointment twice daily with sodium fusidate three-times daily in 413 patients with superficial skin infections. Mupirocin resulted in a clinical success rate of 97% and bacteriological success rate of 93%, compared to 93% and 89%, respectively, for sodium fusidate.” In another study mupirocin and oral erythromycin were compared in 60 patients with primary or secondary skin infections. The clinical success rate was 97% for mupirocin and 77% for erythromycin. Elimination of the causative pathogen was achieved in all of the evaluable mupirocin-treated patients and 81% of those treated with erythromycin.” In another trial, mupirocin cured primary skin infections in 100% of 29 children, compared to 93% of 32 children treated with oral dicloxacillin for S-10 days.12 Further studies have concluded that mupirocin is more effective than oral ampicillin or cloxacillin for the treatment of various skin infections.‘3,‘4
Elimination of nasal carriage of Staphylococcus aureus Asymptomatic skin and nasal colonization with S. aweus is common. Between 20 and 40% of the general population carry this organism in their anterior nares” and there is an even higher incidence in nurses, children with atopic eczema and hospitalized patients.i6 Hospital outbreaks of methicillin-resistant S. aweus (MRSA) are difficult to control, costly, and may give rise to serious clinical problems in at risk patients. I7 There has been a marked increase in the number of reported outbreaks of hospital infection with MRSA in recent years.‘8v’9 During 1983, the spread of MRSA in UK hospitals, particularly in the North-West, North-East and South-East Thames regions, posed a serious clinical problem, and efforts to treat nasal carriage had been disappointing. Dacre et a1.20treated 1.5 carriers with intranasal mupirocin 2% ointment in a polyethyleneglycol base. Eradication of nasal carriage was achieved in all
Role of mupirocin
29
subjects but the incidence of minor adverse reactions in six cases was considered unacceptable. A formulation of calcium mupirocin 2% ointment in a white soft paraffin base was thus developed and the efficacy of this presentation was demonstrated in an open, bacteriologically controlled study, conducted during hospital outbreaks of MRSA. Nasal carriage of 5’. uureus was eliminated in 97% of 766 assessable subjects, including 97% of 628 subjects colonized with MRSA.*l Whilst subsequent placebo-controlled studies in MRSA carriers have been precluded because of the high level of efficacy, the superiority of mupirocin over the base alone was clearly demonstrated in 32 volunteers with stable carriage of methicillin-sensitive S. uureus.** Treatment with mupirocin produced clearance of bacteria within 48 hours in all subjects, whereas the base had no effect.**. The guidelines published by the Hospital Infection Society and the British Society for Antimicrobial Chemotherapy on the control of epidemic MRSA include treatment of nasal carriers with calcium mupirocin 2% ointment.23 Infection is a major cause of morbidity and mortality in haemodialysis patients, S. aureus being the most frequently isolated pathogen.24T25 A recent prospective controlled study demonstrated that elimination of nasal carriage with mupirocin produced a significant reduction in S. aureus infection in patients undergoing haemodialysis, compared with placebo.26 In conclusion, mupirocin is a novel agent that is particularly active in vitro against staphylococci and most streptococci. It has a high clinical success rate in the treatment of acute superficial skin infections. Its activity against MRSA, together with its lack of cross-resistance to other antibiotics and unavailability in systemic form, suggest that it is likely to become the treatment of choice for nasal carriage of MRSA. Its role in the prevention of certain infections needs further evaluation.
References 1. Hughes J, Mellows G. Inhibition of isoleucyl-transfer ribonucleic acid synthetase in Escherichia coli by pseudomonic acid. Biochem J 1978; 176: 305-318. acid, an antibiotic produced 2. Sutherland R, Comber KR, Mizen LW et al. Pseudomonic by Pseudomonas fluorescens. Proceedings of the 16th Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago 1976. 3. Sutherland R, Boon RJ, Griffin KE et al. Antibacterial activity of mupirocin (pseudomonic acid), a new antibiotic for topical use. Antimicrob Agents Chemother 1985; 27: 495498. activity of mupirocin, an antibiotic 4. White AR, Beale AS, Boon RJ et al. Antibacterial produced by Pseudomonasfluorescens. In: Wilkinson DS, Price JD, Eds. Mupirocin-a Novel Topical Antibiotic, The Royal Society of Medicine International Congress & Symposium
Series 80, 1984; 43-55. MW, Hill RLR. In-vitro activity of mupirocin (pseudomonic acid) against clinical isolates of Staphylococcus aureus. J Antimicrob Chemother 1985; 15: 523-531. trial of mupirocin and chlortetracycline in 6. Huskisson SC, Wainscott G. A comparative general practice and a children’s casualty department. In: Wilkinson DS, Price JD, Eds. Mupirocin-a Novel Topical Antibiotic. The Royal Society of Medicine International Congress and Symposium Series 80, 1984; 109-l 13.
5. Casewell
Y. J. Lamb
30
7. Gilbert M. Topical 2% mupirocin versus 2% fusidic acid ointment in the treatment of J Am Acad Dermatol 1989; 20: 1083-1087. primary and secondary skin infections. 8. Langdon CG, Mahapatra KS. Efficacy and acceptability of fusidic acid cream and mupirocin ointment in acute skin sepsis. Curr Ther Res 1990; 48: 174-180. 9. Morley PAR, Munot LD. A comparison of sodium fusidate ointment and mupirocin ointment in superficial skin sepsis. Cuvr Med Res and Opinion 1988; 11: 142-148. 10. White DG, Collins PO, Rowsell RB. Topical antibiotics in the treatment of superficial skin infections in general practice-a comparison of mupirocin with sodium fusidate. J Infect 1989; 18: 221-229. 11. Gratton D. Topical mupirocin versus oral erythromycin in the treatment of primary and secondary skin infections. Int J Dermatol 1987; 26: 472473. 12. Arredondo JL. Efficacy and tolerance of topical mupirocin compared with oral dicloxacillin in the treatment of primary skin infections. Curr Ther Res 1987; 41: 121-127. 13. Welsh 0, Saenz C. Topical mupirocin compared with oral ampicillin in the treatment of primary and secondary skin infections. Curr Ther Res 1987; 41: 114120. 14. Guertin-Larochelle S. Efficacy and tolerance of topical Bactroban (2% mupirocin) vs. systemic cloxacillin in the treatment of primary and secondary skin infections. Todays They Trends 1986; 4: 1-14. 15. Williams REO, Health carriage of Staphylococcus aureus: its prevalence and importance.
Bacterial Rev 1963; 27: 56. 16. Wheat LJ, Kohler RB, White A. Treatment of nasal carriers of coagulase-positive staphylococci. In: Maibach H, Aly R, Eds. Skin Microbiology: Relevance to Clinical Infection. New York: Springer Verlag, 1981; 50-58. 17. Duckworth GJ, Lothian JLE, Williams JD. Methicillin-resistant Staphylococcus aureus: report of an outbreak in a London teaching hospital. J Hasp Infect 1988; 11: I-15. 18. Keane CT, Cafferkey MT. Re-emergence of methicillin-resistant Staph. aureus causing severe infection. J Infect 1984; 9: 616. J. Control of a hospital outbreak of 19. Shanson DC, Johnstone D, Midgley methicillin-resistant Staphylococcus aureus infections: value of an isolation unit. J Hosp Infect 1985; 6: 285-292. 20. Dacre JE, Emmerson AM, Jenner EA. Nasal carriage of gentamicin and methicillin resistant Staphylococcus aureus treated with topical pseudomonic acid. Lancet 1983; 2: 1036. 21. Rowsell RB. Early experience with intranasal mupirocin. In: van der Meer JWM, Ed. discussion. Excerpta Medica Nasal carriage of Staphylococcus aureus-a round-table 1990; 33-37. 22. Casewell MW, Hill RLR. Elimination of nasal carriage of Staphylococcus aureus with mupirocin (‘pseudomonic acid’)-a controlled trial. J Antimicrob Chemother 1986; 17: 365-372. 23. Ayliffe GAJ, Duckworth GJ, Brumfitt W et al. Guidelines for the control of epidemic methicillin-resistant Staphylococcus aureus. J Hosp Infect 1986; 7: 193-201. 24. Bradley JR, Evans DB, Calne RY. Long-term survival in haemodialysis patients. Lancet 1987; 1: 295-296. 25. Kaplowitz LG, Comstock JA, Landwehr DM et al. Prospective study of microbial colonization of the nose and skin and infection of the vascular access site in haemodialysis patients. J Clin Microbial 1988; 26: 1257-I 262. 26. Boelaert JR, De Smedt RA, De Baere YA et al. The influence of calcium mupirocin nasal ointment on the incidence of Staphylococcus aureus infections in haemodialysis patients. Nephron Dial Transpl 1989; 4: 278-281.