1023
CORRESPONDENCE Minocycline as an Alternative Antistaphylococcal Agent
Correspondence: Dr. Temple W. Williams Jr., The Methodist Hospital, 6565 Fannin MS 910, Houston, Texas 77030. Reviews of Infectious Diseases 1991;13:1023-4 © 1991 by The University of Chicago. All rights reserved. 0162-0886/9111305-0052$02.00
Jae H. Yuk, M. Cecilia Dignani, Richard L. Harris, Major W. Bradshaw, and Temple W. Williams, Jr. Departments of Pharmacy and Internal Medicine, The Methodist Hospital, Baylor College of Medicine, Houston, Texas: and the Foundation for Leukemia Research and the Center of Medical Education and Clinical Investigation, Buenos Aires, Argentina
Downloaded from http://cid.oxfordjournals.org/ at University of Toronto Library on July 14, 2015
SIR- Staphylococci continue to playa major role in community- and hospital-acquired infections [1]. Staphylococcus aureus can affect virtually all organ systems and continues to cause life-threatening disease. Staphylococcus epidermidis, which in the past often was dismissed as a culture contaminant, has emerged as a true pathogen, predominantly in prosthetic device-related infections [2]. In addition, both S. aureus and S. epidermidis are versatile organisms that can develop strains resistant to methicillin. Only a few antibiotics are active against methicillin-resistant isolates. Vancomycin continues to be the only antibiotic proven to have consistent clinical efficacy against methicillin-resistant strains. Although vancomycin is generally effective and well tolerated, it requires iv administration and patients may develop adverse reactions while on therapy [3]. Varying success has been achieved with sulfonamides and clindamycin; there also is an increasing awareness of the development of resistance to quinolones during therapy. Minocycline, a derivative of tetracycline, has been tested against staphylococci in a large number of in vitro studies. Its consistent activity against staphylococci, including methicillin-resistant strains, has been documented from early studies conducted in Italy, Japan, and the United States [4-10]. Most of the clinical reports regarding therapy with minocycline have been limited to cases of mild staphylococcal infections, such as skin or soft tissue infections; its efficacy against more serious infections has been reported only sporadically, mainly from investigators in Japan [11-13]. In the last 6 months of 1990, the microbiology laboratory in our hospital identified 723 isolates of S. aureus; 71 % were found to be methicillin-sensitive, 88 % were tetracycline-sensitive, and 96 % were minocycline-sensitive. During that same period, 1,402 isolates of S. epidermidis were identified; 41 % were methicillin-sensitive, 62 % were tetracycline-sensitive, and 98 % were minocycline-sensitive. From September 1987 to December 1989, 124 patients with staphylococcal infections who received minocycline during their hospitalization were identified by microbiologic and pharmacologic records. We reviewed the medical record of each patient and selected a few cases to report. Only cases of osteomyelitis and soft tissue infections that were identified as being caused by a Staphylococcus species on the basis of cultures of surgical-bone and/or surgical-tissue biopsy specimens were included in our analysis. Infections associated with a medical sternotomy wound, extensive cellulitis, or a pacemaker pocket were included without performing surgical cultures (if the culture of the purulence from the infected site yielded only staphylococcal species and if clinical symptoms were strongly suggestive of infection). Periprosthetic joint infections were included if surgical cultures or percutaneous aspirates yielded staphylococcal species.
To evaluate the effect of minocycline on the overall therapeutic outcome, the study was limited to patients who received only minocycline for treatment of staphylococcal infection once therapy with the antibiotic was initiated. In patients who received vancomycin followed by parenteral and/or oral minocycline, the duration of vancomycin therapy had to be significantly shorter than the standard period of treatment or they were excluded from the investigation. Twenty-one patients met the selection criteria, but follow-up information was obtained from only 17 patients. They included six who were found to have osteomyelitis, two with surgical wound infections in whom sternal osteomyelitis was suspected but not proven, three who had wound infections with extensive cellulitis in the leg, hip, or groin, one patient with a septic joint complicated by synovial fistula, one with a foot abscess, possibly complicated by osteomyelitis, and four patients who required long-term oral suppressive therapy for infections of prosthetic joints. There were 23 staphylococcal isolates; all were susceptible to minocycline in vitro. Two were methicillin-sensitive S. aureus, four were methicillin-resistant S. aureus, five were methicillin-sensitive S. epidermidis, and 12 were methicillin-resistant S. epidermidis. Fifteen of the isolates also were tetracycline-resistant. Fifteen of the 17 patients responded to minocycline therapy: five of six with osteomyelitis, four of five with deep surgical wound infections, ODP with a prosthetic joint infection, one with a foot abscess, and four with infections associated with an unremoved foreign body (these latter infections have not relapsed for 5-14 months as of this writing). Therapy was discontinued for one patient because of adverse gastrointestinal effects. No patient developed vestibular toxicity. Three patients developed mucocutaneous candidiasis that was successfully treated with topical nystatin. The number of patients reported in the literature and in this series is still too small to make definite conclusions on the role of minocycline in staphylococcal infections. Our review was retrospective. Findings from a literature review and our experience suggest that minocycline is active against the majority of methicillin-resistant and methicillin-sensitive strains of staphylococci. In methicillin-resistant staphylococcal infections, minocycline may be one of the few options in vancomycin-intolerant patients or in patients who require oral treatment. The incidence of adverse reactions in our experience with a 100-mg dose taken twice daily was much less than previously reported, and the side effects consisted of gastrointestinal intolerance and candidiasis rather than vestibular toxicity. Further in vitro studies and investigations with animal models are in progress. In addition, prospective, long-term studies need to be conducted to better quantitate the efficacy and safety of minocycline. While vancomycin remains the drug of choice for initial parenteral treatment of methicillin-resistant staphylococcal infections, parenteral and oral minocycline deserve further scrutiny as alternative anti staphylococcal treatments.
1024
Correspondence
References
Natural History of Recurrent Urinary Tract Infections in Women SIR-We read with great interest the paper by Stamm and colleagues [1] that describes their experience in managing recurrent urinary tract infections in women. We agree that long-term, low-dose prophylaxis with an appropriate antibiotic is highly effectivefor the management of this condition. Such treatment is rarely associated with breakthrough infections, and the patients' lives may be transformed by the removal of the distressing symptoms and consequent improvement in their social and personal circumstances [2]. Over the past 16 years, we have carried out six trials (including one that is ongoing) involving >425 patients [3-8]. The patients who present to our purpose-planned urinary infection clinic [9] are remarkably similar to those of Stamm et al.; namely, the mean ages of these patients are 45-49 years, and one-quarter to one-third of them have radiologically evident abnormalities of the urinary tract (usually of a minor nature). However, among our patients the attack rate was 3->20 per year, which is higher than that observed by Stamm and co-workers (0.3-7.6 per year). Unfortunately, our studies are not referred to by Stamm et al.; therefore, it is appropriate to emphasize points of similarity and difference between our cumulative findings and those of Stamm and colleagues. We have found that following a 12-month period of prophylaxis 90% of patients benefit greatly, although the remaining 10% show no improvement. Analysis of the latter 10% does not explain why their recurrent attacks fail to respond to prophylaxis. A major discrepancy between our findings and those of Stamm et al. is that rv75% of our patients cease to have infections following the cessation of
Correspondence: Dr. William Brumfitt, Department of Medical Microbiology, Royal Free Hospital School of Medicine, Pond Street, London NW3 2QG, United Kingdom. Reviews of Infectious Diseases 1991;13:1024-5 © 1991 by The University of Chicago. All rights reserved. 0162-0886/9111305-0053$02 .00
8. Van Der Auwera P, Klastersky 1. In vitro activity of coumermycin alone or in combination against Staphylococcus aureus and Staphylococcus epidermidis. Drug Exptl Clin Res 1986;12(4):307-11 9. Segreti J, Gvazdinskas LC, Trenholme GM. In vitro activity of minocycline and rifampin against staphylococci. Diagn Microbiol Infect Dis 1989;12:253-5 10. Maple PAC, Hamilton-Hiller JMT, Brumfitt W. World-wide antibiotic resistance in methicillin-resistant Staphylococcus aureus. Lancet 1989;1:537-9 11. Doutsu Y, Tao Y, Sasayama K. A case of Staphylococcus aureus septisemia after acupuncture therapy. Kansenshogaku Zasshi 1986;60(8): 911-6 12. Iwata S, Yamashita Y, Iwai H. A child case of infective endocarditis due to methicillin-resistant Staphylococcus aureus- analysis of therapeutic course and drug sensitivity of detected organisms. Kansenshogaku Zasshi 1987;61(2):178-88 13. Watanabe K, Takase T, Kinoshita A. A case report of sepsis and multiple lung abscess. Kansenshogaku Zasshi 1988;62(3):266-72
prophylaxis lasting 12 months. Analysis of our data compiled so far has failed to explain this gratifying result, which occurs irrespective of the antibiotic we used. Stamm et al. mention nitrofurantoin, trimethoprim, and trimethoprim-sulfamethoxazole as usefullong-tenn prophylactic agents. We would add norfloxacin [7] and the oral cephalosporins cephradine and cefaclor [6, 8] to this list of agents. The cephalosporins are given in small doses (250 mg at night), which do not alter the fecal flora. The macrocrystalline formulation of nitrofurantoin is preferred to the standard preparation because it causes fewer adverse effects,which were the major reasons for patients' discontinuation of treatment. However, 12 (14%) of 86 of our patients who received the macrocrystalline formulation of nitrofurantoin (100 mg at night) discontinued treatment [3, 5]. In contrast, in three studies [10-12] carried out in the United States and Finland, adverse effects related to the use of the macrocrystalline preparation of nitrofurantoin (75 or 100 mg/d) were, to our surprise, very unusual; only one of 101 patients discontinued treatment. We observed the emergence of bacterial resistance to trimethoprim during our second (1980-1983), but not our first (1978-1980), trial of this compound at a dose of 100 mg each night [4, 5]. Trimethoprim for prophylaxis of urinary tract infections is now useless in our district of London because the incidence of resistance is rv30%. However, with other drugs (nitrofurantoin, cephradine, cefaclor, and norfloxacin), we have not found selective bacterial resistance, either acquired or intrinsic, to be a problem, either in the bowel or among the few strains that cause breakthrough infections. We have found that monitoring of bowel flora for resistance is a useful adjunct to long-term studies of prophylactic antibiotic use [4-7]. In summary, we agree with Stamm et al. that long-term, low-dose antibiotic prophylaxis is an important part of the management of recurrent urinary tract infections in women with and without radiologically evident abnormalities of the urinary tract. In our experience the optimal duration of treatment is 12 months because for the majority of patients a sustained clinical improvement occurs following this period of prophylaxis.
Downloaded from http://cid.oxfordjournals.org/ at University of Toronto Library on July 14, 2015
1. Sheagren IN. Staphylococcus aureus: the persistent pathogen. N Engl J Med 1984;310:1368-73, 1437-42 2. Wade JC, Schimptf SC, Newman KA, Wiemik PH. Staphylococcus epidermidis: an increasing cause of infection in patients with granulocytopenia. Ann Intern Med 1982;97:503-8 3. Mellor JA, Kingdom J, Catferkey M, Keane CT. Vancomycin toxicity: a prospective study. J Antimicrob Chemother 1985;15:773 4. Steigbigel NH, Reed CW, Finland M. Susceptibility of common pathogenic bacteria to seven tetracycline antibiotics in vitro. Am J Med Sci 1968;255:179-95 5. Carleton J, Phair JP. The slow bactericidal effect of tetracycline and minocycline on wall-defective staphylococcus. J Infect Dis 1972;126: 457-9 6. Minuth IN, Holmes TM, Musher DM. Activity of tetracycline, doxycycline, andminocycline against methicillin-susceptible and -resistant staphylococci. Antimicrob Agents Chemother 1974;6(4):411-414 7. Arai T. Antibiotic susceptibility of the clinically isolated staphylococcal strains resistant to cephalosporin derivatives. Jpn J Antibiot 1985;38(2):199-202
RID 1991;13 (September-October)
CORRESPONDENCE Minocycline as an Alternative Antistaphylococcal Agent
Correspondence: Dr. Temple W. Williams Jr., The Methodist Hospital, 6565 Fannin MS 910, Houston, Texas 77030. Reviews of Infectious Diseases 1991;13:1023-4 © 1991 by The University of Chicago. All rights reserved. 0162-0886/9111305-0052$02.00
Jae H. Yuk, M. Cecilia Dignani, Richard L. Harris, Major W. Bradshaw, and Temple W. Williams, Jr. Departments of Pharmacy and Internal Medicine, The Methodist Hospital, Baylor College of Medicine, Houston, Texas: and the Foundation for Leukemia Research and the Center of Medical Education and Clinical Investigation, Buenos Aires, Argentina
Downloaded from http://cid.oxfordjournals.org/ at University of Toronto Library on July 14, 2015
SIR- Staphylococci continue to playa major role in community- and hospital-acquired infections [1]. Staphylococcus aureus can affect virtually all organ systems and continues to cause life-threatening disease. Staphylococcus epidermidis, which in the past often was dismissed as a culture contaminant, has emerged as a true pathogen, predominantly in prosthetic device-related infections [2]. In addition, both S. aureus and S. epidermidis are versatile organisms that can develop strains resistant to methicillin. Only a few antibiotics are active against methicillin-resistant isolates. Vancomycin continues to be the only antibiotic proven to have consistent clinical efficacy against methicillin-resistant strains. Although vancomycin is generally effective and well tolerated, it requires iv administration and patients may develop adverse reactions while on therapy [3]. Varying success has been achieved with sulfonamides and clindamycin; there also is an increasing awareness of the development of resistance to quinolones during therapy. Minocycline, a derivative of tetracycline, has been tested against staphylococci in a large number of in vitro studies. Its consistent activity against staphylococci, including methicillin-resistant strains, has been documented from early studies conducted in Italy, Japan, and the United States [4-10]. Most of the clinical reports regarding therapy with minocycline have been limited to cases of mild staphylococcal infections, such as skin or soft tissue infections; its efficacy against more serious infections has been reported only sporadically, mainly from investigators in Japan [11-13]. In the last 6 months of 1990, the microbiology laboratory in our hospital identified 723 isolates of S. aureus; 71 % were found to be methicillin-sensitive, 88 % were tetracycline-sensitive, and 96 % were minocycline-sensitive. During that same period, 1,402 isolates of S. epidermidis were identified; 41 % were methicillin-sensitive, 62 % were tetracycline-sensitive, and 98 % were minocycline-sensitive. From September 1987 to December 1989, 124 patients with staphylococcal infections who received minocycline during their hospitalization were identified by microbiologic and pharmacologic records. We reviewed the medical record of each patient and selected a few cases to report. Only cases of osteomyelitis and soft tissue infections that were identified as being caused by a Staphylococcus species on the basis of cultures of surgical-bone and/or surgical-tissue biopsy specimens were included in our analysis. Infections associated with a medical sternotomy wound, extensive cellulitis, or a pacemaker pocket were included without performing surgical cultures (if the culture of the purulence from the infected site yielded only staphylococcal species and if clinical symptoms were strongly suggestive of infection). Periprosthetic joint infections were included if surgical cultures or percutaneous aspirates yielded staphylococcal species.
To evaluate the effect of minocycline on the overall therapeutic outcome, the study was limited to patients who received only minocycline for treatment of staphylococcal infection once therapy with the antibiotic was initiated. In patients who received vancomycin followed by parenteral and/or oral minocycline, the duration of vancomycin therapy had to be significantly shorter than the standard period of treatment or they were excluded from the investigation. Twenty-one patients met the selection criteria, but follow-up information was obtained from only 17 patients. They included six who were found to have osteomyelitis, two with surgical wound infections in whom sternal osteomyelitis was suspected but not proven, three who had wound infections with extensive cellulitis in the leg, hip, or groin, one patient with a septic joint complicated by synovial fistula, one with a foot abscess, possibly complicated by osteomyelitis, and four patients who required long-term oral suppressive therapy for infections of prosthetic joints. There were 23 staphylococcal isolates; all were susceptible to minocycline in vitro. Two were methicillin-sensitive S. aureus, four were methicillin-resistant S. aureus, five were methicillin-sensitive S. epidermidis, and 12 were methicillin-resistant S. epidermidis. Fifteen of the isolates also were tetracycline-resistant. Fifteen of the 17 patients responded to minocycline therapy: five of six with osteomyelitis, four of five with deep surgical wound infections, ODP with a prosthetic joint infection, one with a foot abscess, and four with infections associated with an unremoved foreign body (these latter infections have not relapsed for 5-14 months as of this writing). Therapy was discontinued for one patient because of adverse gastrointestinal effects. No patient developed vestibular toxicity. Three patients developed mucocutaneous candidiasis that was successfully treated with topical nystatin. The number of patients reported in the literature and in this series is still too small to make definite conclusions on the role of minocycline in staphylococcal infections. Our review was retrospective. Findings from a literature review and our experience suggest that minocycline is active against the majority of methicillin-resistant and methicillin-sensitive strains of staphylococci. In methicillin-resistant staphylococcal infections, minocycline may be one of the few options in vancomycin-intolerant patients or in patients who require oral treatment. The incidence of adverse reactions in our experience with a 100-mg dose taken twice daily was much less than previously reported, and the side effects consisted of gastrointestinal intolerance and candidiasis rather than vestibular toxicity. Further in vitro studies and investigations with animal models are in progress. In addition, prospective, long-term studies need to be conducted to better quantitate the efficacy and safety of minocycline. While vancomycin remains the drug of choice for initial parenteral treatment of methicillin-resistant staphylococcal infections, parenteral and oral minocycline deserve further scrutiny as alternative anti staphylococcal treatments.
1024
Correspondence
References
Natural History of Recurrent Urinary Tract Infections in Women SIR-We read with great interest the paper by Stamm and colleagues [1] that describes their experience in managing recurrent urinary tract infections in women. We agree that long-term, low-dose prophylaxis with an appropriate antibiotic is highly effectivefor the management of this condition. Such treatment is rarely associated with breakthrough infections, and the patients' lives may be transformed by the removal of the distressing symptoms and consequent improvement in their social and personal circumstances [2]. Over the past 16 years, we have carried out six trials (including one that is ongoing) involving >425 patients [3-8]. The patients who present to our purpose-planned urinary infection clinic [9] are remarkably similar to those of Stamm et al.; namely, the mean ages of these patients are 45-49 years, and one-quarter to one-third of them have radiologically evident abnormalities of the urinary tract (usually of a minor nature). However, among our patients the attack rate was 3->20 per year, which is higher than that observed by Stamm and co-workers (0.3-7.6 per year). Unfortunately, our studies are not referred to by Stamm et al.; therefore, it is appropriate to emphasize points of similarity and difference between our cumulative findings and those of Stamm and colleagues. We have found that following a 12-month period of prophylaxis 90% of patients benefit greatly, although the remaining 10% show no improvement. Analysis of the latter 10% does not explain why their recurrent attacks fail to respond to prophylaxis. A major discrepancy between our findings and those of Stamm et al. is that rv75% of our patients cease to have infections following the cessation of
Correspondence: Dr. William Brumfitt, Department of Medical Microbiology, Royal Free Hospital School of Medicine, Pond Street, London NW3 2QG, United Kingdom. Reviews of Infectious Diseases 1991;13:1024-5 © 1991 by The University of Chicago. All rights reserved. 0162-0886/9111305-0053$02 .00
8. Van Der Auwera P, Klastersky 1. In vitro activity of coumermycin alone or in combination against Staphylococcus aureus and Staphylococcus epidermidis. Drug Exptl Clin Res 1986;12(4):307-11 9. Segreti J, Gvazdinskas LC, Trenholme GM. In vitro activity of minocycline and rifampin against staphylococci. Diagn Microbiol Infect Dis 1989;12:253-5 10. Maple PAC, Hamilton-Hiller JMT, Brumfitt W. World-wide antibiotic resistance in methicillin-resistant Staphylococcus aureus. Lancet 1989;1:537-9 11. Doutsu Y, Tao Y, Sasayama K. A case of Staphylococcus aureus septisemia after acupuncture therapy. Kansenshogaku Zasshi 1986;60(8): 911-6 12. Iwata S, Yamashita Y, Iwai H. A child case of infective endocarditis due to methicillin-resistant Staphylococcus aureus- analysis of therapeutic course and drug sensitivity of detected organisms. Kansenshogaku Zasshi 1987;61(2):178-88 13. Watanabe K, Takase T, Kinoshita A. A case report of sepsis and multiple lung abscess. Kansenshogaku Zasshi 1988;62(3):266-72
prophylaxis lasting 12 months. Analysis of our data compiled so far has failed to explain this gratifying result, which occurs irrespective of the antibiotic we used. Stamm et al. mention nitrofurantoin, trimethoprim, and trimethoprim-sulfamethoxazole as usefullong-tenn prophylactic agents. We would add norfloxacin [7] and the oral cephalosporins cephradine and cefaclor [6, 8] to this list of agents. The cephalosporins are given in small doses (250 mg at night), which do not alter the fecal flora. The macrocrystalline formulation of nitrofurantoin is preferred to the standard preparation because it causes fewer adverse effects,which were the major reasons for patients' discontinuation of treatment. However, 12 (14%) of 86 of our patients who received the macrocrystalline formulation of nitrofurantoin (100 mg at night) discontinued treatment [3, 5]. In contrast, in three studies [10-12] carried out in the United States and Finland, adverse effects related to the use of the macrocrystalline preparation of nitrofurantoin (75 or 100 mg/d) were, to our surprise, very unusual; only one of 101 patients discontinued treatment. We observed the emergence of bacterial resistance to trimethoprim during our second (1980-1983), but not our first (1978-1980), trial of this compound at a dose of 100 mg each night [4, 5]. Trimethoprim for prophylaxis of urinary tract infections is now useless in our district of London because the incidence of resistance is rv30%. However, with other drugs (nitrofurantoin, cephradine, cefaclor, and norfloxacin), we have not found selective bacterial resistance, either acquired or intrinsic, to be a problem, either in the bowel or among the few strains that cause breakthrough infections. We have found that monitoring of bowel flora for resistance is a useful adjunct to long-term studies of prophylactic antibiotic use [4-7]. In summary, we agree with Stamm et al. that long-term, low-dose antibiotic prophylaxis is an important part of the management of recurrent urinary tract infections in women with and without radiologically evident abnormalities of the urinary tract. In our experience the optimal duration of treatment is 12 months because for the majority of patients a sustained clinical improvement occurs following this period of prophylaxis.
Downloaded from http://cid.oxfordjournals.org/ at University of Toronto Library on July 14, 2015
1. Sheagren IN. Staphylococcus aureus: the persistent pathogen. N Engl J Med 1984;310:1368-73, 1437-42 2. Wade JC, Schimptf SC, Newman KA, Wiemik PH. Staphylococcus epidermidis: an increasing cause of infection in patients with granulocytopenia. Ann Intern Med 1982;97:503-8 3. Mellor JA, Kingdom J, Catferkey M, Keane CT. Vancomycin toxicity: a prospective study. J Antimicrob Chemother 1985;15:773 4. Steigbigel NH, Reed CW, Finland M. Susceptibility of common pathogenic bacteria to seven tetracycline antibiotics in vitro. Am J Med Sci 1968;255:179-95 5. Carleton J, Phair JP. The slow bactericidal effect of tetracycline and minocycline on wall-defective staphylococcus. J Infect Dis 1972;126: 457-9 6. Minuth IN, Holmes TM, Musher DM. Activity of tetracycline, doxycycline, andminocycline against methicillin-susceptible and -resistant staphylococci. Antimicrob Agents Chemother 1974;6(4):411-414 7. Arai T. Antibiotic susceptibility of the clinically isolated staphylococcal strains resistant to cephalosporin derivatives. Jpn J Antibiot 1985;38(2):199-202
RID 1991;13 (September-October)
