GORRESPON DENCE
Combination antibiotic therapy in prosthetic endocarditis due to Staphylococcus epidermidis To the editor: I agree with the conclusion of Drs. Gregory W. Hammond and H. Grant Stiver (Can Med Assoc J 118: 524, 1978) that combination therapy is often necessary in cases of prosthetic endocarditis due to Staphylococcus epidermidis. However, they fail to show how proper interpretation of laboratory data can predict the need for combination therapy. On the basis of the data on minimum inhibitory concentrations (MICs) of Andriole and Lyons1 they claim that cephalothin is more active than methicillin against S. epidermidis. Isolates found to be cephalothin-sensitive, methicillin-resistant by Kirby-Bauer or broth MIC sensitivity testing may be so reported to the clinician; this is often an inappropriate interpretation and can lead to inadequate therapy (low serum bactericidal titres and failure of therapy), as was initially instituted in the cases reported by Hammond and Stiver. Further analysis of Andriole and Lyons' data shows cumulative percent sensitivity (MIC/minimum bactericidal concentration [MBC]) as: methicillin 56/36, oxacillin 52/40 and cephalothin 88/64. Thus, 24% (88 - 64) of S. epidermidis isolates sensitive to cephalothin will show a wide separation between inhibitory and bactericidal titres. In these instances combination therapy is required, for successful treatment of contributions to the correspondence section are welcomed and if considered suitable will be published as space permits. They should be typewritten double-spaced and, except for case reports, should be no longer than 1½ manuscript pages.
endocarditis seems to correlate with a serum bactericidal (not inhibitory) titre of 1:8 or greater. Hammond and Stiver mention a report of such a separation for methicillin against S. aureus.' Further evidence exists for a parallel situation with cephalothin against S. aureus. Richmond and colleagues3 pointed out that methicillin-resistant strains of S. aureus may appear to be sensitive to cephalothin by disc testing, relatively resistanc by broth MIC testing and totally resistant by MBC testing (subculture of clear MIC tubes and drug-free agar). In fact, the Center for Disease Control in Atlanta, Georgia, has recommended that "S. aureus exhibiting resistance to methicillin discs should be reported as resistant to cephalosporin type antibiotics regardless of zone size."4 According to the experience of Hammond and Stiver a parallel phenomenon seems to exist for at least some strains of S. epidermidis. The use of combination therapy with an aminoglycoside is routine in patients with enterococcal endocarditis and is being considered even in penicillin-sensitive patients with endocarditis caused by Strevtococcus viridans. There is little evidence that cephalothin offers any in vitro or in vivo advantage over a penicillinaseresistant penicillin, when combined with an aminoglycoside, in the treatment of S. epidermidis endocarditis. Combinations with clindamycin or vancomycin are probably more toxic and should not be used routinely. J. ZEVI SHAINHOUSE, MD Fellow, infectious diseases Stanford University Palo Alto, California
To the editor: We appreciate Dr. Shainhouse's comments regarding the
556 CMA JOURNAL/SEPTEMBER 23, 1978/VOL. 119
need for determining MBCs as well as MICs of antibiotics against S. epidermidis to help the clinician choose the most effective antibiotic regimen for S. epidermidis endocarditis. We did not state that as a rule these organisms are more susceptible to cephalothin than methicillin, but in our series and that of Andriole and Lyons1 they were. In the latter study the median MIC and MBC of methicillin for 25 strains were 6.25 and 25 /.Lg/mL respectively, a fourfold spread. Comparative values for cephalothin were 0.39 and 3.13 /.Lg/mL respectively, a 9- to 10-fold spread. However, since the serum concentrations achievable with methicillin and cephalothin are similar (15 to 20 .g/mL after a 1 -g dose administered intravenously), microbial killing in the patient may be greater with cephalothin. We agree that most methicillinresistant strains of S. aureus are likewise resistant to cephalothin. However, this relation does not hold for S. epidermidis; 78% of methicillinresistant strains remain sensitive to cephalothin according to disc sensitivity tests and broth dilution tests. MBCs indicate that 47% of methicillin-resistant strains are both inhibited and killed by 6.25 .tg/mL or less of cephalothin.5 It is probably unwise to adopt any routine antibiotic regimen for S. epidermidis endocarditis. Of course, penicillin-sensitive strains are treated with penicillin whenever possible. We choose a semisynthetic penicillin or cephalosporin, depending on which drug has the lowest MBC, as Dr. Shainhouse suggests, and which achieves the highest serum bactericidal titres. An aminoglycoside
Combination antibiotic therapy in prosthetic endocarditis due to Staphylococcus epidermidis To the editor: I agree with the conclusion of Drs. Gregory W. Hammond and H. Grant Stiver (Can Med Assoc J 118: 524, 1978) that combination therapy is often necessary in cases of prosthetic endocarditis due to Staphylococcus epidermidis. However, they fail to show how proper interpretation of laboratory data can predict the need for combination therapy. On the basis of the data on minimum inhibitory concentrations (MICs) of Andriole and Lyons1 they claim that cephalothin is more active than methicillin against S. epidermidis. Isolates found to be cephalothin-sensitive, methicillin-resistant by Kirby-Bauer or broth MIC sensitivity testing may be so reported to the clinician; this is often an inappropriate interpretation and can lead to inadequate therapy (low serum bactericidal titres and failure of therapy), as was initially instituted in the cases reported by Hammond and Stiver. Further analysis of Andriole and Lyons' data shows cumulative percent sensitivity (MIC/minimum bactericidal concentration [MBC]) as: methicillin 56/36, oxacillin 52/40 and cephalothin 88/64. Thus, 24% (88 - 64) of S. epidermidis isolates sensitive to cephalothin will show a wide separation between inhibitory and bactericidal titres. In these instances combination therapy is required, for successful treatment of contributions to the correspondence section are welcomed and if considered suitable will be published as space permits. They should be typewritten double-spaced and, except for case reports, should be no longer than 1½ manuscript pages.
endocarditis seems to correlate with a serum bactericidal (not inhibitory) titre of 1:8 or greater. Hammond and Stiver mention a report of such a separation for methicillin against S. aureus.' Further evidence exists for a parallel situation with cephalothin against S. aureus. Richmond and colleagues3 pointed out that methicillin-resistant strains of S. aureus may appear to be sensitive to cephalothin by disc testing, relatively resistanc by broth MIC testing and totally resistant by MBC testing (subculture of clear MIC tubes and drug-free agar). In fact, the Center for Disease Control in Atlanta, Georgia, has recommended that "S. aureus exhibiting resistance to methicillin discs should be reported as resistant to cephalosporin type antibiotics regardless of zone size."4 According to the experience of Hammond and Stiver a parallel phenomenon seems to exist for at least some strains of S. epidermidis. The use of combination therapy with an aminoglycoside is routine in patients with enterococcal endocarditis and is being considered even in penicillin-sensitive patients with endocarditis caused by Strevtococcus viridans. There is little evidence that cephalothin offers any in vitro or in vivo advantage over a penicillinaseresistant penicillin, when combined with an aminoglycoside, in the treatment of S. epidermidis endocarditis. Combinations with clindamycin or vancomycin are probably more toxic and should not be used routinely. J. ZEVI SHAINHOUSE, MD Fellow, infectious diseases Stanford University Palo Alto, California
To the editor: We appreciate Dr. Shainhouse's comments regarding the
556 CMA JOURNAL/SEPTEMBER 23, 1978/VOL. 119
need for determining MBCs as well as MICs of antibiotics against S. epidermidis to help the clinician choose the most effective antibiotic regimen for S. epidermidis endocarditis. We did not state that as a rule these organisms are more susceptible to cephalothin than methicillin, but in our series and that of Andriole and Lyons1 they were. In the latter study the median MIC and MBC of methicillin for 25 strains were 6.25 and 25 /.Lg/mL respectively, a fourfold spread. Comparative values for cephalothin were 0.39 and 3.13 /.Lg/mL respectively, a 9- to 10-fold spread. However, since the serum concentrations achievable with methicillin and cephalothin are similar (15 to 20 .g/mL after a 1 -g dose administered intravenously), microbial killing in the patient may be greater with cephalothin. We agree that most methicillinresistant strains of S. aureus are likewise resistant to cephalothin. However, this relation does not hold for S. epidermidis; 78% of methicillinresistant strains remain sensitive to cephalothin according to disc sensitivity tests and broth dilution tests. MBCs indicate that 47% of methicillin-resistant strains are both inhibited and killed by 6.25 .tg/mL or less of cephalothin.5 It is probably unwise to adopt any routine antibiotic regimen for S. epidermidis endocarditis. Of course, penicillin-sensitive strains are treated with penicillin whenever possible. We choose a semisynthetic penicillin or cephalosporin, depending on which drug has the lowest MBC, as Dr. Shainhouse suggests, and which achieves the highest serum bactericidal titres. An aminoglycoside
