EDITORIALS
Emerging Resistance to Fluoroquinolones in Staphylococci: An Alert
1 he fluoroquinolones are orally administered antimicrobial agents introduced in the mid-1980s. Although they are particularly effective for treating gram-negative bacillary infections, some agents, including ciprofloxacin, ofloxacin, and pefloxacin, are also active against gram-positive organisms. These agents have shown promise as alternatives to parenteral vancomycin for treating infections with methicillin-resistant Staphylococcus aureus. With fluoroquinolone use, however, therapeutic failures associated with isolation of fluoroquinolone-resistant strains of staphylococci are being increasingly documented. We discuss the use of fluoroquinolones as therapeutic agents for staphylococcal infections, problems with bacterial resistance, and approaches to suppression of resistance. Staphylococci have long been important causes of both community- and hospital-acquired infections. In the 1950s and 1960s, S. aureus caused widespread outbreaks of severe nosocomial disease. By 1984, S. aureus and coagulase-negative staphylococci were the most frequent causes of nosocomial bacteremia (1). Control of these infections has been complicated by the ability of staphylococci to develop resistance to new antimicrobial agents by various mechanisms, including mutation of chromosomal genes, acquisition of plasmids with resistance genes, and recombination of transposons into the bacterial chromosome. Once present, resistance spreads among organisms by exchange of chromosomal or plasmid DNA and among patients by spread of strains from person to person. Of the two fluoroquinolones available in the United States for several years, ciprofloxacin is more potent than norfloxacin against staphylococci in vitro, with an MIC^ (the lowest concentration that inhibits visible growth of 90% of isolates) of 0.5 mg ciprofloxacin per L, regardless of susceptibility to methicillin (2). Ofloxacin (MIC*), 0.20 mg/L) and pefloxacin (MIC^, 0.20 mg/L) may be more potent than ciprofloxacin against S. aureus in vitro (3), and fluoroquinolones being developed, such as tosufloxacin and WIN 57273, have 10 to 100 times greater activity against gram-positive bacteria than ofloxacin (4, 5). Ciprofloxacin is as effective as vancomycin in killing methicillin-resistant S. aureus (6). Differences in bioavailability of fluoroquinolones may also affect their activity in vivo. In animal models of endocarditis, pefloxacin, ciprofloxacin, ofloxacin, and fleroxacin are equivalent to standard therapies against methicillin-susceptible S. aureus and as effective as vancomycin against methicillinresistant S. aureus (7, 8). In a rabbit model of left-sided endocarditis,fluoroquinoloneresistance emerged in an424
imals treated with ciprofloxacin and fleroxacin but not with ofloxacin (8). Although limited, experience is increasing in the treatment of human staphylococcal infections with fluoroquinolones. Pefloxacin apparently cured S. aureus bone and joint infections in 17 of 20 patients, half of whom had foreign material left in place. The three failures were associated with the emergence of resistance to pefloxacin (9). In contrast, clinical cures with ciprofloxacin were seen in only 15 of 32 patients with mildly to moderately severe methicillin-resistant S. aureus infections of skin, soft tissue, or lung. In 6 patients, ciprofloxacin-resistant strains emerged during treatment (10). For severe staphylococcal infections treated with parenteral ciprofloxacin, the outcome was also fair, with clinical failures in 5 and bacteriologic failures in 12 of 17 patients. The persisting pathogens remained quinolone susceptible (11), suggesting that failure may have been related to poor delivery of drug to the infected site. Development of resistance after use of ciprofloxacin for staphylococcal infections was first reported in 1985 when a resistant S. aureus strain (MIC, 4 mg/L) was isolated from a trauma patient on day 7 of treatment. The isolate was susceptible before treatment (MIC, 0.5 mg/L) (12). In a 1988 survey of 266 S. aureus isolates in Hong Kong, only one was resistant to fluoroquinolones (13). Subsequently, an increasing prevalence of resistance among clinical isolates has been documented in antibiotic resistance surveys. A survey of 2193 S. aureus clinical isolates, from New York City hospitals and nursing homes from May 1987 to mid-January 1988, detected only 20 isolates (0.9%) with low-level resistance to ciprofloxacin (MIC range, 2 to 4 mg/L). In the same hospitals, after the release of ciprofloxacin (winter 1987), 149 of 2833 S. aureus strains isolated between January and July 1988 (5.3%) were highly resistant to ciprofloxacin (MIC range, 12.5 to 100 mg/L) (14). Rapid development of resistance of S. aureus to pefloxacin has also been reported in France. In 1980, none of 126 isolates from an intensive care unit was resistant, compared with 31 of 96 (32%) in 1984 after extensive use of pefloxacin (15). In a disturbing report from a Veterans Affairs Medical Center, only 13 of 39 patients with ciprofloxacin-resistant, methicillin-resistant S. aureus had received ciprofloxacin (16). Thus, although initial cases appeared to represent emergence of resistance during therapy, later cases appeared to reflect transmission of resistant strains from person to person. The importance of nosocomial spread of fluoroquinolone-resistant coagulase-negative staphylococci was il-
1 March 1991 • Annals of Internal Medicine • Volume 114 • Number 5
Downloaded From: http://annals.org/ by a McGill University User on 09/24/2013
lustrated by two reports from oncology units in which ciprofloxacin was used prophylactically or for empiric treatment of fever in neutropenic patients with leukemia. In the two units, there were 28 cases of bacteremia caused by ciprofloxacin-resistant, coagulase-negative staphylococci. As determined by DNA and immunoblot fingerprinting, phage typing, or plasmid profiles, the responsible isolates were identical for all patients at each institution (17, 18). The prevalence of fluoroquinolone resistance among methicillin-resistant and methicillin-susceptible S. aureus differs. In an Israeli hospital, 45 of 50 methicillinresistant but none of 20 methicillin-susceptible S. aureus isolates werefluoroquinolone-resistant(19). Similar differences were also seen in France where 28 of 49 methicillin-resistant S. aureus isolates but only 3 of 47 methicillin-susceptible S. aureus isolates were resistant to pefloxacin (15). Whether these differences reflect patterns of fluoroquinolone use or differences in mechanisms of resistance is unknown. The mechanisms of fluoroquinolone resistance (20) are best understood in gram-negative bacteria, particularly Escherichia coli. Two mechanisms resulting from chromosomal mutations are known: alterations in the A or B subunit of the target enzyme DNA gyrase and alterations in drug accumulation related to changes in porin outer membrane proteins. The mechanisms of fluoroquinolone resistance in S. aureus are being investigated. The frequency of single-step mutation to fluoroquinolone resistance in S. aureus ranges from 1.5 x 10"5 at twice the MIC to less than or equal to 3.6 x 10"12 at eight times the MIC. High-level resistance occurs with serial exposure of bacteria to increasing concentrations of fluoroquinolones. Unlike the single-step mutants, which have equivalent cross-resistance among fluoroquinolones, the amount of cross-resistance in highly resistant mutants varies. For example, serial exposure to norfloxacin produces mutants with MICs of 256 mg of norfloxacin/L (256-fold increase), 64 mg of ciprofloxacin/L (256-fold increase), and 8 mg of ofloxacin/!. (16-fold increase) (Trucksis M. Unpublished observations). A DNA fragment cloned from S. aureus that conferred quinolone resistance appears to encode a hydrophobic protein that may be membrane-associated. Introduction of this locus (norA) on a plasmid into S. aureus resulted in reduced accumulation of some quinolones (21). Mutations in the gene for the gyrase A subunit of 5. aureus have been associated with development of resistance in clinical isolates (22). Among possible strategies to limit resistance (and enhance efficacy), fluoroquinolones have been combined with non-quinolone agents with varying results. Synergistic inhibition and killing of methicillin-resistant but not methicillin-susceptible S. aureus have been reported with a combination of oxacillin and a fluoroquinolone (23), but, in general, the interactions of other antimicrobial agents with fluoroquinolones have been indifferent (20). In a rabbit model of endocarditis, the combination of ciprofloxacin with rifampin reduced the emergence of ciprofloxacin-resistant S. aureus compared to ciprofloxacin alone (24). Current data in humans do not allow conclusions about the effect of combination therapy on the emergence of fluoroquinolone resistance, but com-
binations of rifampin with ciprofloxacin (25) or pefloxacin (26) were effective without development of resistance in small numbers of patients with right-sided 5. aureus endocarditis (25) and chronic staphylococcal osteomyelitis (26), respectively. Other possible strategies for limiting resistance include prudent use, use of optimal doses, development of fluoroquinolones with a higher therapeutic index, and development of fluoroquinolones less prone to select resistant organisms. Fluoroquinolones show promise for treatment of selected staphylococcal infections but should be used judiciously to reduce the possibility of widespread fluoroquinolone resistance. With the increased prevalence of fluoroquinolone-resistant staphylococci, we do not recommend empiric treatment of serious staphylococcal infections with current fluoroquinolones as monotherapy. Combination therapy and therapy with newer, more potentfluoroquinolonesmerit further study. With continued investigation of the mechanisms of fluoroquinolone action and resistance in staphylococci, our basic understanding of this organism will improve, as will the possibility of development of better antistaphylococcal fluoroquinolones. Michele Trucksis, PhD, MD David C. Hooper, MD John S. Wolfson, MD, PhD Massachusetts General Hospital Harvard Medical School Boston, MA 02114-2696 Grant Support: By grants from the Public Health Service and National Institutes of Health ROl AI23988 and Training Grant AI07061. Requests for Reprints: John S. Wolfson, MD, PhD: Infectious Disease Unit, Massachusetts General Hospital, 32 Fruit Street, Boston, MA 02114-26%. Annals
of Internal
Medicine.
1991;114:424-426.
References 1. Horan T, Culver D, Jarvis W, et al. Pathogens causing nosocomial infections: preliminary data from the national nosocomial infections surveillance system. Antimicrobic Newsletter. 1988;5:65-7. 2. Barry AL, Jones RN. In vitro activity of ciprofloxacin against grampositive cocci. Am J Med. 1987;82(Suppl 4A):27-32. 3. Mitsuhashi S. Comparative antibacterial activity of new quinolonecarboxylic acid derivatives. Rev Infect Dis. 1988;10(Suppl. 1):S2731. 4. Espinoza AM, Chin NX, Novelli A, Neu HC. Comparative in vitro activity of a new fluorinated 4-quinolone, T-3262 (A-60969). Antimicrob Agents Chemother. 1988;32:663-70. 5. Jones RN, Barry AL. In vitro evaluation of WIN 57273, a new broad-spectrum fluoroquinolone. Antimicrob Agents Chemother. 1990;34:306-13. 6. Smith SM, Eng RH. Activity of ciprofloxacin against methicillinresistant Staphylococcus aureus. Antimicrob Agents Chemother. 1985;27:688-91. 7. Sande MA, Brooks-Fournier RA, Gerberding JL. Use of animal models in evaluation of the quinolones. Rev Infect Dis. 1988; KKSuppl. 1):S113-6. 8. Kaatz GW, Seo SM, Barriere SL, Albrecht LM, Rybak MJ. Efficacy of ofloxacin in experimental Staphylococcus aureus endocarditis. Antimicrob Agents Chemother. 1990;34:257-60. 9. Desplaces N, Acar JF. New quinolones in the treatment of bone and joint infections. Rev Infect Dis. 1988;10(Suppl. 1):S 179-83. 10. Piercy EA, Barbaro D, Luby JP, Mackowiak PA. Ciprofloxacin for methicillin-resistant Staphylococcus aureus infections. Antimicrob Agents Chemother. 1989;33:128-30. 11. Righter J. Ciprofloxacin treatment of Staphylococcus aureus infections. J Antimicrob Chemother. 1987;20:595-7. 12. Humphreys H, Mulvhill E. Ciprofloxacin-resistant Staphylococcus aureus [Letter]. Lancet. 1985;2:383. 13. French GL, Ling J, Ling T, Hui YW. Susceptibility of Hong Kong
1 March 1991 • Annals of Internal Medicine • Volume 114 • Number 5 Downloaded From: http://annals.org/ by a McGill University User on 09/24/2013
425
14. 15.
16.
17. 18.
19.
isolates of methicillin-resistant Staphylococcus aureus to antimicrobial agents. J Antimicrob Chemother. 1988;21:581-8. Schaefler S. Methicillin-resistant strains of Staphylococcus aureus resistant to quinolones. J Clin Microbiol. 1989;27:335-6. Wolff M, Bure A, Pathe JP, et al. Evolution des resistances bact£riennes a la pgfloxacine dans le service de ^animation de l'hopital Claude Bernard. In: Pocidalo JJ, Vachon F, Regnier B, eds. Les Nouvelles Quinolones. Paris: Editions Arnette; 1985:213-25. Strausbaugh LJ, Jacobson CM, Sewell DL, Ward IT. Emergence of ciprofloxacin (Cip) resistance during an outbreak caused by methicillin-resistant Staphylococcus aureus (MRSA) in a nursing home care unit (NHCU) [Abstract no. 1257]. Program Abstracts 29th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1989. Oppenheim BA, Hartley JW, Lee W, Burnie JP. Outbreak of coagulase negative staphylococcus highly resistant to ciprofloxacin in a leukaemia unit. BMJ. 1989;299:294-7. Kotilainen P, Nikoskelainen J, Huovinen P. Emergence of ciprofloxacin-resistant coagulase-negative staphylococcal skin flora in immunocompromised patients receiving ciprofloxacin. J Infect Dis. 1990; 161:41-4. Shalit I, Berger SA, Gorea A, Frimerman H. Widespread quinolone resistance among methicillin-resistant Staphylococcus aureus isolates in a general hospital. Antimicrob Agents Chemother. 1989;33: 593-4.
426
20. Wolfson JS, Hooper DC. Fluoroquinolone antimicrobial agents. Clin Microbiol Rev. 1989;2:378-424. 21. Yoshida H, Bogaki M, Nakamura S, Ubukata K, Konno M. Nucleotide sequence and characterization of the Staphylococcus aureus nor A gene, which confers resistance to quinolones. J Bacteriol. 1990;172:6942-9. 22. Sreedharan S, Oram M, Jensen B, Peterson LR, Fisher LM. DNA gyrase gyrA mutations in ciprofloxacin-resistant strains of Staphylococcus aureus: close similarity with quinolone resistance mutations in Escherichia coli. J Bacteriol. 1990;172:7260-2. 23. Rohner P, Herter C, Auckenthaler R, Pechere JC, Waldvogel FA, Lew DP. Synergistic effect of quinolones and oxacillin on methicillin-resistant Staphylococcus species. Antimicrob Agents Chemother. 1989;33:2037-41. 24. Kaatz GW, Seo SM, Barriere SL, Albrecht LM, Rybak MJ. Ciprofloxacin and rifampin, alone and in combination, for therapy of experimental Staphylococcus aureus endocarditis. Antimicrob Agents Chemother. 1989;33:1184-7. 25. Dworkin RJ, Sande MA, Lee BI, Chambers HF. Treatment of rightsided Staphylococcus aureus endocarditis in intravenous drug users with ciprofloxacin and rifampicin. Lancet. 1989;2:1071-3. 26. Desplaces N, Gutmann L, Carlet J, Guibert J, Acar JF. The new quinolones and their combinations with other agents for therapy of severe infections. J Antimicrob Chemother. 1986;17:25-39. © 1991 American College of Physicians
1 March 1991 • Annals of Internal Medicine • Volume 114 • Number 5
Downloaded From: http://annals.org/ by a McGill University User on 09/24/2013
Emerging Resistance to Fluoroquinolones in Staphylococci: An Alert
1 he fluoroquinolones are orally administered antimicrobial agents introduced in the mid-1980s. Although they are particularly effective for treating gram-negative bacillary infections, some agents, including ciprofloxacin, ofloxacin, and pefloxacin, are also active against gram-positive organisms. These agents have shown promise as alternatives to parenteral vancomycin for treating infections with methicillin-resistant Staphylococcus aureus. With fluoroquinolone use, however, therapeutic failures associated with isolation of fluoroquinolone-resistant strains of staphylococci are being increasingly documented. We discuss the use of fluoroquinolones as therapeutic agents for staphylococcal infections, problems with bacterial resistance, and approaches to suppression of resistance. Staphylococci have long been important causes of both community- and hospital-acquired infections. In the 1950s and 1960s, S. aureus caused widespread outbreaks of severe nosocomial disease. By 1984, S. aureus and coagulase-negative staphylococci were the most frequent causes of nosocomial bacteremia (1). Control of these infections has been complicated by the ability of staphylococci to develop resistance to new antimicrobial agents by various mechanisms, including mutation of chromosomal genes, acquisition of plasmids with resistance genes, and recombination of transposons into the bacterial chromosome. Once present, resistance spreads among organisms by exchange of chromosomal or plasmid DNA and among patients by spread of strains from person to person. Of the two fluoroquinolones available in the United States for several years, ciprofloxacin is more potent than norfloxacin against staphylococci in vitro, with an MIC^ (the lowest concentration that inhibits visible growth of 90% of isolates) of 0.5 mg ciprofloxacin per L, regardless of susceptibility to methicillin (2). Ofloxacin (MIC*), 0.20 mg/L) and pefloxacin (MIC^, 0.20 mg/L) may be more potent than ciprofloxacin against S. aureus in vitro (3), and fluoroquinolones being developed, such as tosufloxacin and WIN 57273, have 10 to 100 times greater activity against gram-positive bacteria than ofloxacin (4, 5). Ciprofloxacin is as effective as vancomycin in killing methicillin-resistant S. aureus (6). Differences in bioavailability of fluoroquinolones may also affect their activity in vivo. In animal models of endocarditis, pefloxacin, ciprofloxacin, ofloxacin, and fleroxacin are equivalent to standard therapies against methicillin-susceptible S. aureus and as effective as vancomycin against methicillinresistant S. aureus (7, 8). In a rabbit model of left-sided endocarditis,fluoroquinoloneresistance emerged in an424
imals treated with ciprofloxacin and fleroxacin but not with ofloxacin (8). Although limited, experience is increasing in the treatment of human staphylococcal infections with fluoroquinolones. Pefloxacin apparently cured S. aureus bone and joint infections in 17 of 20 patients, half of whom had foreign material left in place. The three failures were associated with the emergence of resistance to pefloxacin (9). In contrast, clinical cures with ciprofloxacin were seen in only 15 of 32 patients with mildly to moderately severe methicillin-resistant S. aureus infections of skin, soft tissue, or lung. In 6 patients, ciprofloxacin-resistant strains emerged during treatment (10). For severe staphylococcal infections treated with parenteral ciprofloxacin, the outcome was also fair, with clinical failures in 5 and bacteriologic failures in 12 of 17 patients. The persisting pathogens remained quinolone susceptible (11), suggesting that failure may have been related to poor delivery of drug to the infected site. Development of resistance after use of ciprofloxacin for staphylococcal infections was first reported in 1985 when a resistant S. aureus strain (MIC, 4 mg/L) was isolated from a trauma patient on day 7 of treatment. The isolate was susceptible before treatment (MIC, 0.5 mg/L) (12). In a 1988 survey of 266 S. aureus isolates in Hong Kong, only one was resistant to fluoroquinolones (13). Subsequently, an increasing prevalence of resistance among clinical isolates has been documented in antibiotic resistance surveys. A survey of 2193 S. aureus clinical isolates, from New York City hospitals and nursing homes from May 1987 to mid-January 1988, detected only 20 isolates (0.9%) with low-level resistance to ciprofloxacin (MIC range, 2 to 4 mg/L). In the same hospitals, after the release of ciprofloxacin (winter 1987), 149 of 2833 S. aureus strains isolated between January and July 1988 (5.3%) were highly resistant to ciprofloxacin (MIC range, 12.5 to 100 mg/L) (14). Rapid development of resistance of S. aureus to pefloxacin has also been reported in France. In 1980, none of 126 isolates from an intensive care unit was resistant, compared with 31 of 96 (32%) in 1984 after extensive use of pefloxacin (15). In a disturbing report from a Veterans Affairs Medical Center, only 13 of 39 patients with ciprofloxacin-resistant, methicillin-resistant S. aureus had received ciprofloxacin (16). Thus, although initial cases appeared to represent emergence of resistance during therapy, later cases appeared to reflect transmission of resistant strains from person to person. The importance of nosocomial spread of fluoroquinolone-resistant coagulase-negative staphylococci was il-
1 March 1991 • Annals of Internal Medicine • Volume 114 • Number 5
Downloaded From: http://annals.org/ by a McGill University User on 09/24/2013
lustrated by two reports from oncology units in which ciprofloxacin was used prophylactically or for empiric treatment of fever in neutropenic patients with leukemia. In the two units, there were 28 cases of bacteremia caused by ciprofloxacin-resistant, coagulase-negative staphylococci. As determined by DNA and immunoblot fingerprinting, phage typing, or plasmid profiles, the responsible isolates were identical for all patients at each institution (17, 18). The prevalence of fluoroquinolone resistance among methicillin-resistant and methicillin-susceptible S. aureus differs. In an Israeli hospital, 45 of 50 methicillinresistant but none of 20 methicillin-susceptible S. aureus isolates werefluoroquinolone-resistant(19). Similar differences were also seen in France where 28 of 49 methicillin-resistant S. aureus isolates but only 3 of 47 methicillin-susceptible S. aureus isolates were resistant to pefloxacin (15). Whether these differences reflect patterns of fluoroquinolone use or differences in mechanisms of resistance is unknown. The mechanisms of fluoroquinolone resistance (20) are best understood in gram-negative bacteria, particularly Escherichia coli. Two mechanisms resulting from chromosomal mutations are known: alterations in the A or B subunit of the target enzyme DNA gyrase and alterations in drug accumulation related to changes in porin outer membrane proteins. The mechanisms of fluoroquinolone resistance in S. aureus are being investigated. The frequency of single-step mutation to fluoroquinolone resistance in S. aureus ranges from 1.5 x 10"5 at twice the MIC to less than or equal to 3.6 x 10"12 at eight times the MIC. High-level resistance occurs with serial exposure of bacteria to increasing concentrations of fluoroquinolones. Unlike the single-step mutants, which have equivalent cross-resistance among fluoroquinolones, the amount of cross-resistance in highly resistant mutants varies. For example, serial exposure to norfloxacin produces mutants with MICs of 256 mg of norfloxacin/L (256-fold increase), 64 mg of ciprofloxacin/L (256-fold increase), and 8 mg of ofloxacin/!. (16-fold increase) (Trucksis M. Unpublished observations). A DNA fragment cloned from S. aureus that conferred quinolone resistance appears to encode a hydrophobic protein that may be membrane-associated. Introduction of this locus (norA) on a plasmid into S. aureus resulted in reduced accumulation of some quinolones (21). Mutations in the gene for the gyrase A subunit of 5. aureus have been associated with development of resistance in clinical isolates (22). Among possible strategies to limit resistance (and enhance efficacy), fluoroquinolones have been combined with non-quinolone agents with varying results. Synergistic inhibition and killing of methicillin-resistant but not methicillin-susceptible S. aureus have been reported with a combination of oxacillin and a fluoroquinolone (23), but, in general, the interactions of other antimicrobial agents with fluoroquinolones have been indifferent (20). In a rabbit model of endocarditis, the combination of ciprofloxacin with rifampin reduced the emergence of ciprofloxacin-resistant S. aureus compared to ciprofloxacin alone (24). Current data in humans do not allow conclusions about the effect of combination therapy on the emergence of fluoroquinolone resistance, but com-
binations of rifampin with ciprofloxacin (25) or pefloxacin (26) were effective without development of resistance in small numbers of patients with right-sided 5. aureus endocarditis (25) and chronic staphylococcal osteomyelitis (26), respectively. Other possible strategies for limiting resistance include prudent use, use of optimal doses, development of fluoroquinolones with a higher therapeutic index, and development of fluoroquinolones less prone to select resistant organisms. Fluoroquinolones show promise for treatment of selected staphylococcal infections but should be used judiciously to reduce the possibility of widespread fluoroquinolone resistance. With the increased prevalence of fluoroquinolone-resistant staphylococci, we do not recommend empiric treatment of serious staphylococcal infections with current fluoroquinolones as monotherapy. Combination therapy and therapy with newer, more potentfluoroquinolonesmerit further study. With continued investigation of the mechanisms of fluoroquinolone action and resistance in staphylococci, our basic understanding of this organism will improve, as will the possibility of development of better antistaphylococcal fluoroquinolones. Michele Trucksis, PhD, MD David C. Hooper, MD John S. Wolfson, MD, PhD Massachusetts General Hospital Harvard Medical School Boston, MA 02114-2696 Grant Support: By grants from the Public Health Service and National Institutes of Health ROl AI23988 and Training Grant AI07061. Requests for Reprints: John S. Wolfson, MD, PhD: Infectious Disease Unit, Massachusetts General Hospital, 32 Fruit Street, Boston, MA 02114-26%. Annals
of Internal
Medicine.
1991;114:424-426.
References 1. Horan T, Culver D, Jarvis W, et al. Pathogens causing nosocomial infections: preliminary data from the national nosocomial infections surveillance system. Antimicrobic Newsletter. 1988;5:65-7. 2. Barry AL, Jones RN. In vitro activity of ciprofloxacin against grampositive cocci. Am J Med. 1987;82(Suppl 4A):27-32. 3. Mitsuhashi S. Comparative antibacterial activity of new quinolonecarboxylic acid derivatives. Rev Infect Dis. 1988;10(Suppl. 1):S2731. 4. Espinoza AM, Chin NX, Novelli A, Neu HC. Comparative in vitro activity of a new fluorinated 4-quinolone, T-3262 (A-60969). Antimicrob Agents Chemother. 1988;32:663-70. 5. Jones RN, Barry AL. In vitro evaluation of WIN 57273, a new broad-spectrum fluoroquinolone. Antimicrob Agents Chemother. 1990;34:306-13. 6. Smith SM, Eng RH. Activity of ciprofloxacin against methicillinresistant Staphylococcus aureus. Antimicrob Agents Chemother. 1985;27:688-91. 7. Sande MA, Brooks-Fournier RA, Gerberding JL. Use of animal models in evaluation of the quinolones. Rev Infect Dis. 1988; KKSuppl. 1):S113-6. 8. Kaatz GW, Seo SM, Barriere SL, Albrecht LM, Rybak MJ. Efficacy of ofloxacin in experimental Staphylococcus aureus endocarditis. Antimicrob Agents Chemother. 1990;34:257-60. 9. Desplaces N, Acar JF. New quinolones in the treatment of bone and joint infections. Rev Infect Dis. 1988;10(Suppl. 1):S 179-83. 10. Piercy EA, Barbaro D, Luby JP, Mackowiak PA. Ciprofloxacin for methicillin-resistant Staphylococcus aureus infections. Antimicrob Agents Chemother. 1989;33:128-30. 11. Righter J. Ciprofloxacin treatment of Staphylococcus aureus infections. J Antimicrob Chemother. 1987;20:595-7. 12. Humphreys H, Mulvhill E. Ciprofloxacin-resistant Staphylococcus aureus [Letter]. Lancet. 1985;2:383. 13. French GL, Ling J, Ling T, Hui YW. Susceptibility of Hong Kong
1 March 1991 • Annals of Internal Medicine • Volume 114 • Number 5 Downloaded From: http://annals.org/ by a McGill University User on 09/24/2013
425
14. 15.
16.
17. 18.
19.
isolates of methicillin-resistant Staphylococcus aureus to antimicrobial agents. J Antimicrob Chemother. 1988;21:581-8. Schaefler S. Methicillin-resistant strains of Staphylococcus aureus resistant to quinolones. J Clin Microbiol. 1989;27:335-6. Wolff M, Bure A, Pathe JP, et al. Evolution des resistances bact£riennes a la pgfloxacine dans le service de ^animation de l'hopital Claude Bernard. In: Pocidalo JJ, Vachon F, Regnier B, eds. Les Nouvelles Quinolones. Paris: Editions Arnette; 1985:213-25. Strausbaugh LJ, Jacobson CM, Sewell DL, Ward IT. Emergence of ciprofloxacin (Cip) resistance during an outbreak caused by methicillin-resistant Staphylococcus aureus (MRSA) in a nursing home care unit (NHCU) [Abstract no. 1257]. Program Abstracts 29th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1989. Oppenheim BA, Hartley JW, Lee W, Burnie JP. Outbreak of coagulase negative staphylococcus highly resistant to ciprofloxacin in a leukaemia unit. BMJ. 1989;299:294-7. Kotilainen P, Nikoskelainen J, Huovinen P. Emergence of ciprofloxacin-resistant coagulase-negative staphylococcal skin flora in immunocompromised patients receiving ciprofloxacin. J Infect Dis. 1990; 161:41-4. Shalit I, Berger SA, Gorea A, Frimerman H. Widespread quinolone resistance among methicillin-resistant Staphylococcus aureus isolates in a general hospital. Antimicrob Agents Chemother. 1989;33: 593-4.
426
20. Wolfson JS, Hooper DC. Fluoroquinolone antimicrobial agents. Clin Microbiol Rev. 1989;2:378-424. 21. Yoshida H, Bogaki M, Nakamura S, Ubukata K, Konno M. Nucleotide sequence and characterization of the Staphylococcus aureus nor A gene, which confers resistance to quinolones. J Bacteriol. 1990;172:6942-9. 22. Sreedharan S, Oram M, Jensen B, Peterson LR, Fisher LM. DNA gyrase gyrA mutations in ciprofloxacin-resistant strains of Staphylococcus aureus: close similarity with quinolone resistance mutations in Escherichia coli. J Bacteriol. 1990;172:7260-2. 23. Rohner P, Herter C, Auckenthaler R, Pechere JC, Waldvogel FA, Lew DP. Synergistic effect of quinolones and oxacillin on methicillin-resistant Staphylococcus species. Antimicrob Agents Chemother. 1989;33:2037-41. 24. Kaatz GW, Seo SM, Barriere SL, Albrecht LM, Rybak MJ. Ciprofloxacin and rifampin, alone and in combination, for therapy of experimental Staphylococcus aureus endocarditis. Antimicrob Agents Chemother. 1989;33:1184-7. 25. Dworkin RJ, Sande MA, Lee BI, Chambers HF. Treatment of rightsided Staphylococcus aureus endocarditis in intravenous drug users with ciprofloxacin and rifampicin. Lancet. 1989;2:1071-3. 26. Desplaces N, Gutmann L, Carlet J, Guibert J, Acar JF. The new quinolones and their combinations with other agents for therapy of severe infections. J Antimicrob Chemother. 1986;17:25-39. © 1991 American College of Physicians
1 March 1991 • Annals of Internal Medicine • Volume 114 • Number 5
Downloaded From: http://annals.org/ by a McGill University User on 09/24/2013
