Staphylococcus aureus and Vancomycin: The Sequel C u r r e n t l y , among the many bacterial infections, Staphylococcus aureus infection is often considered to be troublesome but manageable with available antimicrobials. However, when viewed from a broader perspective, such complacency might be challenged. Staphylococcus aureus has demonstrated remarkable persistence and genetic versatility, which have allowed it to keep pace with modern medicine and antimicrobial development. During the early antimicrobial era, 5. aureus bacteremia, with or without concurrent endocarditis, was a dreaded infection and was associated with a mortality rate of 80%. Initially, the introduction of penicillin reduced the death rate to 30% (1). However, the emergence of penicillinase-producing S. aureus as a common cause of severe infections in the early 1950s revealed a major deficiency in the available antimicrobial agents. Despite the use of novobiocin, bacitracin, penicillin, erythromycin, tetracycline, and chloramphenicol, the lethality of bacteremia due to penicillin-resistant staphylococci approached that seen in the pre-antibiotic era. In 1956, vancomycin was recovered from Streptomyces orientalis (subsequently designated Nocardia orientalis and now called Amycolatopsis orientalis) and was recognized to be bactericidal against staphylococci, independent of their susceptibility to penicillin. Vancomycin was rapidly shown to be effective therapy for infections caused by penicillin-resistant staphylococci and was approved for use in 1958. Debilitated patients with life-threatening bacteremic staphylococcal infections were dramatically cured by vancomycin (2). However, 2 years later, methicillin became available and was shown in vitro to be as effective against penicillin-resistant staphylococci as was vancomycin. Methicillin was perceived to cause fewer adverse effects than vancomycin, and, although direct comparative trials were not done, methicillin became the agent of choice for staphylococcal infections. Thereafter, vancomycin use declined and the semi-synthetic penicillinase-resistant penicillins, joined subsequently by the first-generation cephalosporins, became the mainstay of antistaphylococcal therapy. In the 1980s, methicillin-resistant S. aureus (MRSA) and coagulase-negative staphylococci, many of which are resistant to penicillins and cephalosporins, emerged as prominent pathogens in the United States. There was rejuvenated interest in and increased use of vancomycin because of its activity against these staphylococci. Reduced acquisition costs, recognition that toxicity was not a proscription (perhaps because of a more purified product), favorable pharmacokinetics, widely available accurate assays of serum concentration, and nearly universal in-vitro activity against grampositive bacteria, especially staphylococci, have re-
sulted in the widespread use of vancomycin, often for convenience, since the mid-1980s. In this issue of Annals, Levine and coworkers (3) show that S. aureus remains a formidable and obstinate pathogen, and they suggest that vancomycin, although a potent antistaphylococcal antibiotic and the agent of choice for MRS A infection, may be less efficacious than it had been perceived to be in earlier studies. In only 24 months, Levine and colleagues enrolled 42 patients with MRSA endocarditis (38 patients with right-sided infection) in a randomized trial that compared treatment with vancomycin to that with vancomycin plus rifampin. Among evaluable patients, therapy failed (defined as death or need for valve surgery) in 3 of 8 and 3 of 29 patients with left- and right-sided endocarditis, respectively. Half of those who failed therapy died. Life-table analysis of their patients, 17 of whom acquiesced to daily blood cultures, indicated that bacteremia persisted in 52% for 8 days and that fever persisted in 50% for 6 days. Failure rates and duration of bacteremia or fever were not significantly different between the study regimens. Although mortality due to S. aureus endocarditis in intravenous drug abusers is only about 2% as compiled from multiple series (4), the observation by Levine and colleagues (3) of the continued virulence of this pathogen is corroborated easily. For example, Bayer and colleagues (5) noted that in 22 of 53 (42%) patients with right-sided S. aureus endocarditis, fever persisted during appropriate antibiotic therapy for 10 days or more. Similarly, in an earlier study, Levine and coworkers (6) commonly observed prolonged fever in intravenous drug abusers who were receiving therapy for endocarditis caused by either MRSA or methicillin-susceptible S. aureus (MSSA). Some investigators have attributed persistent fever in patients with S. aureus tricuspidvalve endocarditis to pulmonary emboli. In their study, Bayer and colleagues (5) found that persistent fever was associated with the echocardiographic detection, but not with the size, of tricuspid-valve vegetations. Nevertheless, for patients with S. aureus endocarditis that is exclusively right-sided, cardiac surgery is rarely required despite persistent fever and recurrent pulmonary emboli. In fact, right-sided S. aureus endocarditis was cured by antibiotic therapy in 90% of patients described by Levine and coworkers (3) and in 94% of patients described in the earlier series (5, 6). Studies of endocarditis or bacteremia attest further to the continued virulence of 5. aureus. Korzeniowski and coworkers (7) reported death due to S. aureus endocarditis in 7 of 30 (23%) patients who were not addicted to parenteral drugs, and they noted that the mean
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duration of S. aureus bacteremia during therapy with nafcillin or nafcillin plus gentamicin was, respectively, 3.4 days (range, 2 to 6 days) and 2.9 days (range, 2 to 6 days) in those addicted to parenteral drugs and 4.1 days (range, 2 to 6 days) and 2.8 days (range, 1 to 5 days) in non-addicts (7). Among patients with or without endocarditis who were receiving appropriate therapy for S. aureus bacteremia, Eng and colleagues (8) noted that 83% remained bacteremic after 1 day of therapy; 48%, after 2 days; 32%, after 3 days; and 15%, after 4 days (8). After 5 days of appropriate antimicrobial therapy, two patients had continued bacteremia: One patient with S. aureus tricuspid valve endocarditis who was treated with nafcillin remained bacteremic until the valve was resected on day 16, and a second patient remained bacteremic for 14 days despite vancomycin treatment. Among all patients with catheter-associated S. aureus bacteremia, 20% have complicating endocarditis or metastatic infection; furthermore, even 5% to 10% of lower-risk patients who are selected for short-course (2 weeks) intravenous antibiotic treatment experience these complications (9). Although most of these reports derive from studies of patients with MSSA infection, the morbidity and mortality of bacteremic infection due to MSSA and MRSA are similar (10). The persistence of S. aureus bacteremia during therapy with either vancomycin or vancomycin plus rifampin, despite optimal serum vancomycin concentrations, prompted Levine and coworkers (3) to speculate that vancomycin may be a less efficacious antistaphylococcal agent than the beta-lactam antibiotics. Although vancomycin remains the agent of choice for treatment of MRSA infections, the clinical response appears to be slow (3, 6). Although important, the efficacy of vancomycin in MSSA infections relative to the efficacy of appropriate beta-lactam agents is difficult to assess. Invitro vancomycin is slowly and incompletely bactericidal against MSSA (4, 11) and less so than analogous concentrations of nafcillin (4). Nevertheless, studies using a rat model of endocarditis indicate that cloxacillin and vancomycin have a similar efficacy in MSSA infection (11, 12). The concerns expressed by Levine and colleagues (3) are given additional credence by the findings of Small and Chambers (4). These investigators found that vancomycin therapy for S. aureus endocarditis failed to cure 5 of 13 intravenous drug abusers (3 of 9 with right-sided endocarditis and 2 of 4 with left-sided or bilateral endocarditis). In four of the patients who failed vancomycin therapy, MSSA bacteremia persisted for 7 to 16 days (4). In contrast, among 24 intravenous drug abusers with MSSA endocarditis who were treated with nafcillin, bacteremia during therapy was noted for a mean of 3.4 days (median, 3 days; range, 2 to 6 days) (7). Furthermore, in this study of 48 intravenous drug abusers who were treated with either nafcillin or nafcillin plus gentamicin, only 2 were not cured with antimicrobial therapy. The observations by Levine and coworkers (3), coupled with the reports in the literature, should cause clinicians to pause when confronted with a patient who has severe S. aureus infection. Staphylococcus aureus
740
is not an "also ran" organism; it remains a formidable pathogen and becomes even more so with the continued spread of methicillin-resistant strains. Furthermore, the uncertainty about the efficacy of vancomycin when compared with that of semi-synthetic penicillinase-resistant penicillins (for example, nafcillin, oxacillin) for the treatment of MSSA infections will not be resolved by direct comparative trials soon. Thus, in treating patients with MSSA infections, physicians must weigh carefully the decision to use vancomycin for convenience alone. Additionally, because of the therapeutic implications, physicians must be cautious in interpreting or applying the "allergic to penicillin" label. Despite doubts raised by the persistence of bacteremia during therapy with vancomycin, this drug remains the treatment of choice for MRSA infections. On the other hand, the increasing recognition of infections caused by MRSA in tertiary care hospitals (13), in nursing homes (14), and in some community settings (3, 6, 15) defines an urgent need for effective alternatives to vancomycin, and for additional studies of antibiotic combinations for the treatment of MRSA infections. Adolf W. Karchmer, MD New England Deaconess Hospital and Harvard Medical School Boston, Massachusetts The author receives no financial support from the manufacturer(s) of products described in this editorial. Annals
of Internal
Medicine.
1991;115:739-741.
References 1. Spink WW. Staphylococcal infections and problem of antibiotic resistant staphylococci. Arch Intern Med. 1954;94:167-96. 2. Kirby WM, Perry DM, Bauer AW. Treatment of staphylococcal septicemia with vancomycin: report of thirty-three cases. N Engl J Med. 1960;262:49-55. 3. Levine DP, Fromm BS, Reddy BR. Delayed response to vancomycin or vancomycin plus rifampin therapy among patients with methicillin-resistant Staphylococcus aureus endocarditis. Ann Intern Med. 1991;115:674-80. 4. Small PM, Chambers HF. Vancomycin for Staphylococcus aureus endocarditis in intravenous drug users. Antimicrob Agents Chemother. 1990;34:1227-31. 5. Bayer AS, Blomquist IK, Bello E, Chiu CY, Ward JI, Ginzton LE. Tricuspid valve endocarditis due to Staphylococcus aureus: correlation of two-dimensional echocardiography with clinical outcome. Chest 1988;93:247-53. 6. Levine DP, Crane LR, Zervos MJ. Bacteremia in narcotic addicts at the Detroit Medical Center. II. Infectious Endocarditis: a prospective comparative study. Rev Infect Dis. 1986;8:374-96. 7. Korzeniowski O, Sande MA. Combination antimicrobial therapy for Staphylococcus aureus endocarditis in patients addicted to parenteral drugs and in nonaddicts: a prospective study. Ann Intern Med. 1982;97:496-503. 8. Eng RH, Bishburg E, Smith SM, Scadutto P. Staphylococcus aureus bacteremia during therapy. J Infect Dis. 1987;155:1331-5. 9. Ehni WF, Reller B. Short-course therapy for catheter-associated Staphylococcus aureus bacteremia. Arch Intern Med. 1989; 149: 533-6. 10. Sorrell TC, Packham DR, Shanker S, Foldes M, Munro R. Vancomycin therapy for methicillin-resistant Staphylococcus aureus. Ann Intern Med. 1982;97:344-50. 11. Cantoni L, Glauser MP, Bille J. Comparative efficacy of daptomycin, vancomycin, and cloxacillin for the treatment of Staphylococcus aureus endocarditis in rats and role of test conditions in this determination. Antimicrob Agents Chemother. 1990;34:2348-53. 12. Cantoni L, Wenger A, Glauser MP, Bille J. Comparative efficacy of amoxicillin-clavulanate, cloxacillin, and vancomycin against methicillin-sensitive and methicillin-resistant Staphylococcus aureus endocarditis in rats. J Infect Dis. 1989;159:989-93.
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13. Boyce JM. Methicillin-resistant Staphylococcus aureus: detection, epidemiology, and control measures. Infect Dis Clin North Am. 1989;3:901-13. 14. Storch GA, Radcliff JL, Meyer PL, Hinrichs JH. Methicillin-resistant Staphylococcus aureus in a nursing home. Infect Control. 1987;8: 24-9.
15. Saravolatz LD, Pohlod DJ, Arking LM. Community-acquired methicillin-resistant Staphylococcus aureus infections: A new source for nosocomial outbreaks. Ann Intern Med. 1982;97:325-9. ©1991 American College of Physicians
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sulted in the widespread use of vancomycin, often for convenience, since the mid-1980s. In this issue of Annals, Levine and coworkers (3) show that S. aureus remains a formidable and obstinate pathogen, and they suggest that vancomycin, although a potent antistaphylococcal antibiotic and the agent of choice for MRS A infection, may be less efficacious than it had been perceived to be in earlier studies. In only 24 months, Levine and colleagues enrolled 42 patients with MRSA endocarditis (38 patients with right-sided infection) in a randomized trial that compared treatment with vancomycin to that with vancomycin plus rifampin. Among evaluable patients, therapy failed (defined as death or need for valve surgery) in 3 of 8 and 3 of 29 patients with left- and right-sided endocarditis, respectively. Half of those who failed therapy died. Life-table analysis of their patients, 17 of whom acquiesced to daily blood cultures, indicated that bacteremia persisted in 52% for 8 days and that fever persisted in 50% for 6 days. Failure rates and duration of bacteremia or fever were not significantly different between the study regimens. Although mortality due to S. aureus endocarditis in intravenous drug abusers is only about 2% as compiled from multiple series (4), the observation by Levine and colleagues (3) of the continued virulence of this pathogen is corroborated easily. For example, Bayer and colleagues (5) noted that in 22 of 53 (42%) patients with right-sided S. aureus endocarditis, fever persisted during appropriate antibiotic therapy for 10 days or more. Similarly, in an earlier study, Levine and coworkers (6) commonly observed prolonged fever in intravenous drug abusers who were receiving therapy for endocarditis caused by either MRSA or methicillin-susceptible S. aureus (MSSA). Some investigators have attributed persistent fever in patients with S. aureus tricuspidvalve endocarditis to pulmonary emboli. In their study, Bayer and colleagues (5) found that persistent fever was associated with the echocardiographic detection, but not with the size, of tricuspid-valve vegetations. Nevertheless, for patients with S. aureus endocarditis that is exclusively right-sided, cardiac surgery is rarely required despite persistent fever and recurrent pulmonary emboli. In fact, right-sided S. aureus endocarditis was cured by antibiotic therapy in 90% of patients described by Levine and coworkers (3) and in 94% of patients described in the earlier series (5, 6). Studies of endocarditis or bacteremia attest further to the continued virulence of 5. aureus. Korzeniowski and coworkers (7) reported death due to S. aureus endocarditis in 7 of 30 (23%) patients who were not addicted to parenteral drugs, and they noted that the mean
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duration of S. aureus bacteremia during therapy with nafcillin or nafcillin plus gentamicin was, respectively, 3.4 days (range, 2 to 6 days) and 2.9 days (range, 2 to 6 days) in those addicted to parenteral drugs and 4.1 days (range, 2 to 6 days) and 2.8 days (range, 1 to 5 days) in non-addicts (7). Among patients with or without endocarditis who were receiving appropriate therapy for S. aureus bacteremia, Eng and colleagues (8) noted that 83% remained bacteremic after 1 day of therapy; 48%, after 2 days; 32%, after 3 days; and 15%, after 4 days (8). After 5 days of appropriate antimicrobial therapy, two patients had continued bacteremia: One patient with S. aureus tricuspid valve endocarditis who was treated with nafcillin remained bacteremic until the valve was resected on day 16, and a second patient remained bacteremic for 14 days despite vancomycin treatment. Among all patients with catheter-associated S. aureus bacteremia, 20% have complicating endocarditis or metastatic infection; furthermore, even 5% to 10% of lower-risk patients who are selected for short-course (2 weeks) intravenous antibiotic treatment experience these complications (9). Although most of these reports derive from studies of patients with MSSA infection, the morbidity and mortality of bacteremic infection due to MSSA and MRSA are similar (10). The persistence of S. aureus bacteremia during therapy with either vancomycin or vancomycin plus rifampin, despite optimal serum vancomycin concentrations, prompted Levine and coworkers (3) to speculate that vancomycin may be a less efficacious antistaphylococcal agent than the beta-lactam antibiotics. Although vancomycin remains the agent of choice for treatment of MRSA infections, the clinical response appears to be slow (3, 6). Although important, the efficacy of vancomycin in MSSA infections relative to the efficacy of appropriate beta-lactam agents is difficult to assess. Invitro vancomycin is slowly and incompletely bactericidal against MSSA (4, 11) and less so than analogous concentrations of nafcillin (4). Nevertheless, studies using a rat model of endocarditis indicate that cloxacillin and vancomycin have a similar efficacy in MSSA infection (11, 12). The concerns expressed by Levine and colleagues (3) are given additional credence by the findings of Small and Chambers (4). These investigators found that vancomycin therapy for S. aureus endocarditis failed to cure 5 of 13 intravenous drug abusers (3 of 9 with right-sided endocarditis and 2 of 4 with left-sided or bilateral endocarditis). In four of the patients who failed vancomycin therapy, MSSA bacteremia persisted for 7 to 16 days (4). In contrast, among 24 intravenous drug abusers with MSSA endocarditis who were treated with nafcillin, bacteremia during therapy was noted for a mean of 3.4 days (median, 3 days; range, 2 to 6 days) (7). Furthermore, in this study of 48 intravenous drug abusers who were treated with either nafcillin or nafcillin plus gentamicin, only 2 were not cured with antimicrobial therapy. The observations by Levine and coworkers (3), coupled with the reports in the literature, should cause clinicians to pause when confronted with a patient who has severe S. aureus infection. Staphylococcus aureus
740
is not an "also ran" organism; it remains a formidable pathogen and becomes even more so with the continued spread of methicillin-resistant strains. Furthermore, the uncertainty about the efficacy of vancomycin when compared with that of semi-synthetic penicillinase-resistant penicillins (for example, nafcillin, oxacillin) for the treatment of MSSA infections will not be resolved by direct comparative trials soon. Thus, in treating patients with MSSA infections, physicians must weigh carefully the decision to use vancomycin for convenience alone. Additionally, because of the therapeutic implications, physicians must be cautious in interpreting or applying the "allergic to penicillin" label. Despite doubts raised by the persistence of bacteremia during therapy with vancomycin, this drug remains the treatment of choice for MRSA infections. On the other hand, the increasing recognition of infections caused by MRSA in tertiary care hospitals (13), in nursing homes (14), and in some community settings (3, 6, 15) defines an urgent need for effective alternatives to vancomycin, and for additional studies of antibiotic combinations for the treatment of MRSA infections. Adolf W. Karchmer, MD New England Deaconess Hospital and Harvard Medical School Boston, Massachusetts The author receives no financial support from the manufacturer(s) of products described in this editorial. Annals
of Internal
Medicine.
1991;115:739-741.
References 1. Spink WW. Staphylococcal infections and problem of antibiotic resistant staphylococci. Arch Intern Med. 1954;94:167-96. 2. Kirby WM, Perry DM, Bauer AW. Treatment of staphylococcal septicemia with vancomycin: report of thirty-three cases. N Engl J Med. 1960;262:49-55. 3. Levine DP, Fromm BS, Reddy BR. Delayed response to vancomycin or vancomycin plus rifampin therapy among patients with methicillin-resistant Staphylococcus aureus endocarditis. Ann Intern Med. 1991;115:674-80. 4. Small PM, Chambers HF. Vancomycin for Staphylococcus aureus endocarditis in intravenous drug users. Antimicrob Agents Chemother. 1990;34:1227-31. 5. Bayer AS, Blomquist IK, Bello E, Chiu CY, Ward JI, Ginzton LE. Tricuspid valve endocarditis due to Staphylococcus aureus: correlation of two-dimensional echocardiography with clinical outcome. Chest 1988;93:247-53. 6. Levine DP, Crane LR, Zervos MJ. Bacteremia in narcotic addicts at the Detroit Medical Center. II. Infectious Endocarditis: a prospective comparative study. Rev Infect Dis. 1986;8:374-96. 7. Korzeniowski O, Sande MA. Combination antimicrobial therapy for Staphylococcus aureus endocarditis in patients addicted to parenteral drugs and in nonaddicts: a prospective study. Ann Intern Med. 1982;97:496-503. 8. Eng RH, Bishburg E, Smith SM, Scadutto P. Staphylococcus aureus bacteremia during therapy. J Infect Dis. 1987;155:1331-5. 9. Ehni WF, Reller B. Short-course therapy for catheter-associated Staphylococcus aureus bacteremia. Arch Intern Med. 1989; 149: 533-6. 10. Sorrell TC, Packham DR, Shanker S, Foldes M, Munro R. Vancomycin therapy for methicillin-resistant Staphylococcus aureus. Ann Intern Med. 1982;97:344-50. 11. Cantoni L, Glauser MP, Bille J. Comparative efficacy of daptomycin, vancomycin, and cloxacillin for the treatment of Staphylococcus aureus endocarditis in rats and role of test conditions in this determination. Antimicrob Agents Chemother. 1990;34:2348-53. 12. Cantoni L, Wenger A, Glauser MP, Bille J. Comparative efficacy of amoxicillin-clavulanate, cloxacillin, and vancomycin against methicillin-sensitive and methicillin-resistant Staphylococcus aureus endocarditis in rats. J Infect Dis. 1989;159:989-93.
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13. Boyce JM. Methicillin-resistant Staphylococcus aureus: detection, epidemiology, and control measures. Infect Dis Clin North Am. 1989;3:901-13. 14. Storch GA, Radcliff JL, Meyer PL, Hinrichs JH. Methicillin-resistant Staphylococcus aureus in a nursing home. Infect Control. 1987;8: 24-9.
15. Saravolatz LD, Pohlod DJ, Arking LM. Community-acquired methicillin-resistant Staphylococcus aureus infections: A new source for nosocomial outbreaks. Ann Intern Med. 1982;97:325-9. ©1991 American College of Physicians
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