Efficacy of Intravenous Clindamycin and Methicillin in Gram-positive Soft Tissue Infections KENNETH C. CHESSICK, M.D., LINDA A. BEGLEY, R.N., B.S., LON E. CURTIS, M.D., ERWIN F. HIRSCH, M.D., C. WILLIAM KAISER, M.D., CHARLES A. BUREK, M.D., HARRY S. SOROFF, M.D.
In a comparative study on a general surgical service, intravenous From the Department of Surgery, Tufts University School of Medicine, Tufts Surgical Service, clindamycin phosphate or methicillin was used to treat a varietv Boston City Hospital, Boston, Massachusetts, and of soft tissue infections due to gram-positive organisms, chiefly Citrus Memorial Hospital, Inverness, Florida staphylococci. The infections were rated according to severity, responsible organisms, and site of the infection. Excellent or good clinical and bacteriologic responses were obtained with both clindamvcin and methicillin as adjuncts to basic surgical Methicillin, which was the first of the penicillinasetherapy in these soft tissue infections. The adverse effects of resistant penicillins, has become well established as an aneach drug were detailed, and were comparable. Clindamycin tistaphylococcal druig in the past decade. From their pharphosphate is a satisfactory substitute for methicillin in soft tissue macologic properties and in vitro activity against the usuial infections secondary to gram-positive organisms.
SOFIT T issE INFE('IONS of the extremities are common and significant causes of morbidity. The infecting organisms are commonly staphylococci and streptococci which gain access to the suibcuitaneous tissues following tratima. Most staphylococci, including coagulase-negative strains, are resistant to penicillin G, and alternate therapy with a penicillinase-resistant penicillin or another druig is indicated. Clindamycin,0 an analog of lincomycin, displays greater activity than lincomycin against Staphylococcus aureus and other gram-positive pathogens in vitro.","'1 It acts by interfering with protein synthesis intracellularly and can be bacteriostatic or bactericidal in vitro, depending upon the concentration of the antibiotic and the sensitivity of the organism.22 The druig is widely distributed in fluids and tissuies, incluiding bone, after administration of an oral dosage form.'7 Higher seruim levels of clindamycin can be achieved with parenteral dosing with clindamycin phosphate; this preparation is rapidly hydrolyzed to clindamycin in vivo.7 Suibmitted for publication Jtune 18, 1974. All correspondence: Kenneth C. Chessick, M.D., 316 South Line Ave.,
gram-positive pathogens, it could be predicted that methicillin and clindamycin would show similar efficacy in soft tissuie infections dtue to suich organisms. The pturpose of this sttudy was to compare resuilts of treatment with intravenouisly administered clindamycin phosphate and sodium methicillint in soft tissue infections in patients on a general surgical service.
Materials and Methods One-huindred and ten hospitalized patients gave their informed consent in writing to enter the comparative study. Reasons for excluision from the study were allergy to penicillin or penicillin derivatives or allergy to clindamycin or lincomycin. Patients were assigned to treatment with clindamycin or methicillin by use of a table of random nuimbers. The dosage of clindamycin phosphate ranged 600-1000 mgt every 6 hours; methicillin dosage ranged 500-1000 mg every 6 hours. Both drugs were administered
intravenouisly. Sixty-nine patients completed their course of therapy, but only 53 met all of the criteria for efficacy evaluiations, inclhiding the following: admission cultuires demonstrated a gram-positive organism; soft tissue sites, usuially ex-
Inverness, Florida 32650. ° Cleocin® is The Upjohn Company's U.S. registered trademark for clinf Staphcilling (Bristol). damycin, which is 7(s)-chloro-7-deoxylincomycin; otutside of the U. S. A. t Dosages and sertum concentrations in this paper are stated in terms of clindamycin is also marketed as DALACIN C® (Canada) or SOBELIN®. clindamycin base eqtuivalents.
203
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Tl1iu.F: 1. Severity of Infections in all Patients and in Those Who Met All Study Criteria
Severity of Infection
Mild Moderate Severe Not rated Total
Clindamycin All Completed Patients Stuidy 16 12 (37%) 24 19 (59%) 1 0 2 1 43 32
Methicillin Completed Study 11 8 (38%) 15 13 (62%) 0 0 0 0 26 21
All Patients
were the focuis of infection; and intravenous antibiotic therapy was maintained for four days or more. Antibiotic therapy was discontinued when the infection was cuired. At the termination of therapy, repeat cultuires were obtained whenever possible to document bacteriologic response. Data from 16 patients could not be evaluated becauise their initial cuiltuires failed to show gram-positive organisms or they couild not complete four days of intravenouis therapy. Clinical laboratory determinations performed at the beginning of antibiotic therapy and again at the end of parenteral therapy incluided the following: complete blood couint; uirinalysis; and measurement of serum urea nitrogen, seruim creatinine, seruim alkaline phosphatase, and serum gluitamic oxalacetic transaminase (SGOT). The nuimbers of patients assigned to each treatment and their distribuition with respect to severity of infection are shown in Table 1. The average age of the clindamycin grouip was 48 years, and the average age of the methicillin grouip was 41. Of the patients completing the study, 25 in the clindamycin group were male and 7 were female, and 13 in the methicillin grouip were male and 8 were female. Table 2 lists the organisms clutuired from wounds, and Table 3 lists the type of infection. Clinical response was juidged on the basis of decrease in pain and swelling, reduction of fever, and healing of wounds. Bacteriologic response was determined by the persistance of organisms on repeat ctultuire at the end of therapy. Antibiotic susceptibility was determined by disc sensitivity tests using 2-mcg clindamycin, 2-mcg erythromycin, 5-mcg methicillin and 2mcg penicillin discs.3
tremities,
Results As shown in Table 4, the clinical response in cases which cotuld be fully evaluated was judged to be excellent or good in 30 of 32 patients treated with clindamycin and all of 21 patients treated with methicillin. Eleven patients had persistent positive cuiltuires at the end of therapy with intravenous clindamycin, and six at the end of methicillin therapy. The two clindamycin-treated patients whose clinical response was reported as poor did not show persistant organisms on followup culture at the end of therapy. One of these patients was a 34-year-old man who developed
Ann.
Stirg. Febrtiary 1975 -
fever and celluilitis secondary to frostbite after 24 hours of exposuire to cold; coagulase-negative staphylococci were isolated from blister material from the left foot. Fever and elevated white blood couint persisted after 5 days of intravenouis clindamycin phosphate therapy. The infection stubsequiently responded to treatment with Suilfamylon cream. The other patient was an 80-year-old woman with a past history of uinexplained fevers. The bone of the 3rd phalanx of the toe was exposed when she was admitted to the hospital from a nursing home, and the wound yielded coaguilase-negative staphylococci. After 4 days of clindamycin therapy, the lesion was dry, yielding no growth on culltuire, buit fever persisted and the white blood cell couint increased from 6,200 to 7,700 per cui mm. Ninety-six per cent of the infecting organisms isolated were staphylococci and 4% were streptococci. Examination of the disc suisceptibility of the staphylococci cultuired (Table 5) prior to treatment shows that only 4 of the 50 staphylococcal isolates were resistant to clindamycin; 13 were resistant to erythromycin. Of the 13 strains which tested resistant to methicillin, only 3 were also resistant to clindamycin; the other clindamycin-resistant strain was suisceptible to methicillin. Thrombophlebitis developed in 6 (14%) of the 43 patients given clindamycin and 8 (24%) of the 32 given methicillin. This was not severe with either drug. Indwelling catheters (Intracath) may have contributed to local irritation in some cases in both grouips. Dizziness, dyspnea, and urticaria developed after each of two suiccessive doses of clindamycin phosphate in a patient who received a total of nine 750 mg infusions. The second episode was also marked by wheezing. Clindamycin was discontinued. Three other systemic reactions in the clindamycin grouip, considered probably not related to the druig, were as follows: The patient with frostbite and secondary celltulitis developed bone marrow depression several days after antibiotic therapy; a 91-year-old woman developed microscopic hematuria; and an 80-year-old woman showed a drop in hematocrit. SGOT increased during clindamycin therapy from 62 to 130 units in a diabetic patient with gangrene and cellulitis of the left great toe, and from 42 to 190 uinits in a burn patient who underwent skin grafting duiring therapy. Two other clindamycin-treated T,iii.i 2. Organisms Cultured From the Wounds of Patients Before Treatment in Evaluatable Cases
Organism
Staphylococcuis, coaguilase-positive Staphylococcuts, coagtulase unknown Staphylococcuis, coaguilase-negative 1 Streptococcuis (not speciated)
Clindamycin 17 8 0 14
Methicillin
1 12 0 0 a-Hemolytic streptococcuis 1 Total 32 22° ° Coagtilase-positive and coagulase-negative staphylococci isolated in 1 case.
Xol. 181 * No. 2
INTRAVENOUS CLINDAMYCIN AND METHICILLIN
Twi.i: :3. Type of Infection in Evaluatable Cases Disease Clindamycin Methicillin Celluilitis Infected wounds Neck Hand or arm Foot or leg Frostbite (foot) Abscess Amptitation site Infected uilcer Infected gangrene Animal bite Huiman bite Buirns
17 12
9 10 0 0 4 1 2 1 1 1 1
1 4 1 0 3 0 1 0 0 0
1
3
2
patients had increases in SGOT within the normal (45 units less) range. A 73-year-old woman developed a skin rash
or
duiring methicillin therapy and the drug was discontinued after 8 doses. A 34-year-old man with stab wounds of the neck showed an increase in SGOT from 54 to 95 units during methicillin therapy. Discussion
Clindamycin appears to be a potent antibiotic against organisms commonly encountered on a general surgical service. Its spectruim of activity in vitro includes most staphylococci, pneuimococci and streptococci (except Streptococcuts faecalis) and gram-positive and gram-negative anaerobes.2""10"1118 It has little or no activity against gramnegative aerobes."6 Methicillin is active against most pneuimococci, streptococci and staphylococci, except for some strains of staphylococci which are resistant not only to methicillin btut to other penicillinase-resistant penicillins and numerouis other antibiotics. Most of the methicillinresistant strains that are mtultiply resistant are sensitive to lincomycin and clindamycin in vitro.1 4"12"19 In ouir study 96% of the infecting organisms isolated were staphylococci. Of the 13 strains resistant to methicillin on disc testing, only 3 also tested resistant to clindamycin. Other laboratory stuidies wouild be requiired to characterize these strains which tested resistant to methicillin and to determine their precise antibiotic suisceptibility pattern. Stuidies by Carlisle and Saslaw'6 showed comparable resuilts with parenteral clindamycin and methicillin in experimental staphyloccal and streptococcal infections in monkeys. In clinical trials, intramisctular or intravenous clindamycin phosphate was uised in 131 patients in a study reported by Schtumer and coworkers.20 The initial pathogens were eradicated in 22 of 28 cases of postoperative wound infections and 11 of 14 cases of celluilitis, although not in 4 cases of infected gangrene. Compromised circulation was a factor in several of the soft tissuie infections that failed to respond. Fass and Saslaw9 also reported generally good resuilts with parenteral clindamycin phosphate in soft tissue
infections. Kerstein14 described good results in soft tissue infections in 8 patients given intravenous clindamycin phosphate at Boston City Hospital; these were among the first patients to be treated intravenously with this drug. A wide variety of soft tissue infections were treated in the comparative stuidy on ouir general surgical service (Table 3). Despite the tuse of random numbers to assign patients to treatment, clindamycin was used more often in conditions less likely to benefit from antibiotic therapy, such as infected gangrene, amputations and frostbite. Nevertheless, the clinical and bacteriologic responses in the clindamycin and methicillin grouips did not differ significantly, and clinical resuilts were good in almost all cases. Although positive cuiltuires couild still be obtained at the end of parenteral therapy in some cases (Table 4), the lesions were healing and signs of infection were abating in these cases. The dosages of clindamycin phosphate and methicillin uised in this stuidy were probably higher than necessary to achieve satisfactory tissue levels, judging from the serum levels attainable with lower doses.7'9"2 In testing 5 staphylococcal strains in vitro, Wagnerova and Vacek22 fouind that 6-8 hours of exposure to clindamycin at the minimuim bactericidal concentration (MBC) was needed to sterilize the cuiltuire completely. The MBC was 0.78 mcg/ml or less in 120 of 125 strains of staphylococci, the highest valuie being 3.12 mcg/ml in one strain. Serum clindamycin concentrations exceeding these levels can be maintained readily with parenteral dosages of 300 mg clindamycin phosphate 3 or 4 times daily.7'9 However, as emphasized by Carlisle and Saslaw,5'6 in antibiotic therapy correlations are not perfect between in vivo results and in vitro susceptibilities and seruim antibacterial activities. According to the manuifactuirers, the usuial adtilt dose of Staphcillin is 1,000 mg every 6 houirs, while recommended dosages of clindamycin phosphate range from 300 mg every 12 hours to 1,200 mg every 6 hours, depending uipon the severity of infection and sensitivity of the infecting organism. The patients receiving clindamycin phosphate experienced fewer local reactions (thrombophlebitis) than those receiving methicillin in ouir study. One methicillin-treated T.ABLE 4. Clinical Response, Bacteriologic Response, of Fever in Clindamycin and Methicillin Treated Clindamycin (32 Patients) Clinical Response 18 Excellent (94%) 12 Good Poor
21 11
Mean
1.09 0-5
Range
Methicillin (21 Patients)
6)
(100%) 15 0
2
Bacteriologic Response Oganism eradicated Organism not eradicated Dturation of Fever (Days)
and Duration Patients
(65%)
15 (71%) 6 1.5 0-4
Ann. Strg. *
CHESSICK AND OTHERS
206
Febrtary 1975
TA,BLE 5. Antibiotic Sensitivities of Organisms Cultured Organism
Clindamycin
No. Sensitive/No. Tested Methicillin Erythromycin
Penicillin
22/24 22/24
20/25 16/23
20/26 14/22
8/23 2/24
Staphylococcus epidermidis
2/2
1/2
a-Hemolytic strepotococcuts Streptococcis (variant sp)
1/1 0/1
1/1 0/1
0/2 1/1
0/2 1/1
0/1
0/1
Staphylococcus, coaguilase-positive Staphylococcuis, coagtulase-negative
patient developed a rash. In one clindamycin-treated patient the druig had to be discontinuied because of systemic reactions marked by dizziness, dyspnea and urticaria. The bone marrow depression, hematuiria and drop in hematocrit noted in one patient each in the clindamycin group were probably not related to clindamycin therapy. Elevations in SGOT may have been druig-related; suich elevations have been reported previouisly during oral or parenteral clindamycin therapy in patients with infection.9'13'21 However, DeHaan et al.8 compared the incidence of SGOT elevations in 210 normal voluinteers, half of whom received oral clindamycin and half, placebo. There was no statistically significant difference between druig- and placebo-treated subjects in the frequiency of SGOT elevation.
Acknowledgment We wish to thank The Upjohn Company, Kalamazoo, MI, for their
suipply of the druigs and for their suipport of the stuidy.
References 1. Barrett, F. F., McGehee, R. F., Jr. and Finland, M.: Methicillinresistant Staphylococcuis Auireuis at the Boston City Hospital. N. Engl. J. Med., 279:441, 1968. 2. Bartlett, J. G., Stitter, V. L. and Finegold, S. G.: Treatment of Anaerobic Infections with Lincomycin and Clindamycin. N. Engl. J. Med., 287:1006, 1972. 3. Bauier, A. W., Kirby, W. M. M., Sherris, J. C. and Tuirck, M.: Antibiotic Susceptibility Testing by a Standardized Single Disc Method. Am. J. Clin Pathol., 45:493, 1966. 4. Benner, E. J. and Adams, A. P.: Unusuial Resistance of Staphylococctis Auireuts to Lincomycin and 7-chlorolincomycin. Antimicrob. Agents an(l Chemotherapy-1969. Ann Arbor, Am. Society for Microbiology, 100, 1970. 5. Carlisle, H. N. and Saslaw, S.: Comparison of Clindamycin, Ervthromrcnin and Methicillin in Streptococcal Infections in Monkeys. Antimicrob. Agents Chemother., 1:460, 1972. 6.. Carlisle, H. N. anid Saslaw, S.: Therapy of Staphylococcal Infections in Monkeys. VI. Comparison Clindamycin, Erythromycin, and Methicillin. Appl. Microbiol., 21:440, 1971.
7. DeHaan, R. M., et al.: Pharmacokinetic stuidies of Clindamycin Phosphate, J. Clin. Pharmacol., 13:190, 1973. 8. DeHaan, R. M., Schellenberg, D., Vandenbosch, W. D., and Maile, M. H.: Clindamycin Palmitate in Healthy Men: General Tolerance and Effect on Stools. Cuirr. Ther. Res., 14:81, 1972. 9. Fass, R. J. and Saslaw, S.: Clindamycin: Clinical and Laboratory Evaluiation of Parenteral Therapy. Am. J. Med. Sci., 263:369, 1972. 10. Garrison, D. W., DeHaan, R. M. and Lawson, J. B.: Comparison of In Vitro Antibacterial Activities of 7-chloro-deoxylincomycin, Lincomycin and Erythromycin. Antimicro. Agents and Chemother. 1967, Ann Arbor, American Society for Microbioloby, 397, 1971. 11. Geddes, A. M., Bridgewater, F. A., Williams, D. W., et al.: Clinical and Bacteriological Sttudies with Clindamycin (Dalacin C). Br. Med. J., 2:703, 1970. 12. Gilbert, D. N. and Sanford, J. P.: Methicillin: Critical Appraisal After a Decade of Experience. Med. Clin. North Am., 54:1113, 1970. 13. Kauiffman, R. E., Shoeman, D. W., Wan, S. H. and Azarnoff, D. L.: Absorption and Excretion of Clindamycin-2-Phosphate in Children After Intramtuscutlar Injection. Clin. Pharmacol. Ther., 13:704, 1972. 14. Kerstein, M. D.: Intravenotus Clindamycin Phosphate in Staphylococcal Infections. Cturr. Ther. Res., 14:107, 1972. 15. Martin, W. J. Gardner, M. and Washington, J. A. II.: In Vitro Antimicrobial Stusceptibility of Anaerobic Bacteria Isolated from Clinical Specimens. Antimicrob. Agents Chemother., 1:148, 1972. 16. McGehee, R. F., Smith, C. B., Wilcox, C. and Finland, M.: Comparative Sttudies of Abtibacterial Activity in Vitro and Absorption and Excretion of Lincomycin and Clindamycin. Am. J. Med. Sci., 256:279, 1968. 17. Panzer, J. D., Brown, D. C., Epstein, W. L., et al.: Clindamycin Levels in Various Body Tisstues and Fluiids. J. Clin. Pharmacol., 12:259, 1972. 18. Phillips, I., Pernandes, R. and Warren, C.: In Vitro Comparison of Erythromycin, Lincomycin and Clindamycin. Br. Med. J. 2:89, 1970. 19. Rotntree, P. M. and Beard, M. A.: Hospital Strains of Staphylococctus Auiretus, with Particular References to Methicillin-Resistant Strains. Med. J. Auist., 2:1163, 1968. 20. Schutmer, W., Nichols, R. L., Miller, B. et al.: Clindamycin in the Treatment of Soft Tisstue Infections. Arch. Stirg., 106:578, 1973. 21. Stiver, H. G. and Ronald, A. R.: Clinical and Laboratory Experience with Clindamycin. Antimicrobial Agents and Chemotherapy, 1970. Ann Arbor, American Society for Microbiology, 481, 1971. 22. Wagnerova, M. and Vacek, V.: Antistaphylococcal Activity of Clindamycin. Chemother., 16:247, 1971.
In a comparative study on a general surgical service, intravenous From the Department of Surgery, Tufts University School of Medicine, Tufts Surgical Service, clindamycin phosphate or methicillin was used to treat a varietv Boston City Hospital, Boston, Massachusetts, and of soft tissue infections due to gram-positive organisms, chiefly Citrus Memorial Hospital, Inverness, Florida staphylococci. The infections were rated according to severity, responsible organisms, and site of the infection. Excellent or good clinical and bacteriologic responses were obtained with both clindamvcin and methicillin as adjuncts to basic surgical Methicillin, which was the first of the penicillinasetherapy in these soft tissue infections. The adverse effects of resistant penicillins, has become well established as an aneach drug were detailed, and were comparable. Clindamycin tistaphylococcal druig in the past decade. From their pharphosphate is a satisfactory substitute for methicillin in soft tissue macologic properties and in vitro activity against the usuial infections secondary to gram-positive organisms.
SOFIT T issE INFE('IONS of the extremities are common and significant causes of morbidity. The infecting organisms are commonly staphylococci and streptococci which gain access to the suibcuitaneous tissues following tratima. Most staphylococci, including coagulase-negative strains, are resistant to penicillin G, and alternate therapy with a penicillinase-resistant penicillin or another druig is indicated. Clindamycin,0 an analog of lincomycin, displays greater activity than lincomycin against Staphylococcus aureus and other gram-positive pathogens in vitro.","'1 It acts by interfering with protein synthesis intracellularly and can be bacteriostatic or bactericidal in vitro, depending upon the concentration of the antibiotic and the sensitivity of the organism.22 The druig is widely distributed in fluids and tissuies, incluiding bone, after administration of an oral dosage form.'7 Higher seruim levels of clindamycin can be achieved with parenteral dosing with clindamycin phosphate; this preparation is rapidly hydrolyzed to clindamycin in vivo.7 Suibmitted for publication Jtune 18, 1974. All correspondence: Kenneth C. Chessick, M.D., 316 South Line Ave.,
gram-positive pathogens, it could be predicted that methicillin and clindamycin would show similar efficacy in soft tissuie infections dtue to suich organisms. The pturpose of this sttudy was to compare resuilts of treatment with intravenouisly administered clindamycin phosphate and sodium methicillint in soft tissue infections in patients on a general surgical service.
Materials and Methods One-huindred and ten hospitalized patients gave their informed consent in writing to enter the comparative study. Reasons for excluision from the study were allergy to penicillin or penicillin derivatives or allergy to clindamycin or lincomycin. Patients were assigned to treatment with clindamycin or methicillin by use of a table of random nuimbers. The dosage of clindamycin phosphate ranged 600-1000 mgt every 6 hours; methicillin dosage ranged 500-1000 mg every 6 hours. Both drugs were administered
intravenouisly. Sixty-nine patients completed their course of therapy, but only 53 met all of the criteria for efficacy evaluiations, inclhiding the following: admission cultuires demonstrated a gram-positive organism; soft tissue sites, usuially ex-
Inverness, Florida 32650. ° Cleocin® is The Upjohn Company's U.S. registered trademark for clinf Staphcilling (Bristol). damycin, which is 7(s)-chloro-7-deoxylincomycin; otutside of the U. S. A. t Dosages and sertum concentrations in this paper are stated in terms of clindamycin is also marketed as DALACIN C® (Canada) or SOBELIN®. clindamycin base eqtuivalents.
203
204
CHESSICK AND OTHERS
Tl1iu.F: 1. Severity of Infections in all Patients and in Those Who Met All Study Criteria
Severity of Infection
Mild Moderate Severe Not rated Total
Clindamycin All Completed Patients Stuidy 16 12 (37%) 24 19 (59%) 1 0 2 1 43 32
Methicillin Completed Study 11 8 (38%) 15 13 (62%) 0 0 0 0 26 21
All Patients
were the focuis of infection; and intravenous antibiotic therapy was maintained for four days or more. Antibiotic therapy was discontinued when the infection was cuired. At the termination of therapy, repeat cultuires were obtained whenever possible to document bacteriologic response. Data from 16 patients could not be evaluated becauise their initial cuiltuires failed to show gram-positive organisms or they couild not complete four days of intravenouis therapy. Clinical laboratory determinations performed at the beginning of antibiotic therapy and again at the end of parenteral therapy incluided the following: complete blood couint; uirinalysis; and measurement of serum urea nitrogen, seruim creatinine, seruim alkaline phosphatase, and serum gluitamic oxalacetic transaminase (SGOT). The nuimbers of patients assigned to each treatment and their distribuition with respect to severity of infection are shown in Table 1. The average age of the clindamycin grouip was 48 years, and the average age of the methicillin grouip was 41. Of the patients completing the study, 25 in the clindamycin group were male and 7 were female, and 13 in the methicillin grouip were male and 8 were female. Table 2 lists the organisms clutuired from wounds, and Table 3 lists the type of infection. Clinical response was juidged on the basis of decrease in pain and swelling, reduction of fever, and healing of wounds. Bacteriologic response was determined by the persistance of organisms on repeat ctultuire at the end of therapy. Antibiotic susceptibility was determined by disc sensitivity tests using 2-mcg clindamycin, 2-mcg erythromycin, 5-mcg methicillin and 2mcg penicillin discs.3
tremities,
Results As shown in Table 4, the clinical response in cases which cotuld be fully evaluated was judged to be excellent or good in 30 of 32 patients treated with clindamycin and all of 21 patients treated with methicillin. Eleven patients had persistent positive cuiltuires at the end of therapy with intravenous clindamycin, and six at the end of methicillin therapy. The two clindamycin-treated patients whose clinical response was reported as poor did not show persistant organisms on followup culture at the end of therapy. One of these patients was a 34-year-old man who developed
Ann.
Stirg. Febrtiary 1975 -
fever and celluilitis secondary to frostbite after 24 hours of exposuire to cold; coagulase-negative staphylococci were isolated from blister material from the left foot. Fever and elevated white blood couint persisted after 5 days of intravenouis clindamycin phosphate therapy. The infection stubsequiently responded to treatment with Suilfamylon cream. The other patient was an 80-year-old woman with a past history of uinexplained fevers. The bone of the 3rd phalanx of the toe was exposed when she was admitted to the hospital from a nursing home, and the wound yielded coaguilase-negative staphylococci. After 4 days of clindamycin therapy, the lesion was dry, yielding no growth on culltuire, buit fever persisted and the white blood cell couint increased from 6,200 to 7,700 per cui mm. Ninety-six per cent of the infecting organisms isolated were staphylococci and 4% were streptococci. Examination of the disc suisceptibility of the staphylococci cultuired (Table 5) prior to treatment shows that only 4 of the 50 staphylococcal isolates were resistant to clindamycin; 13 were resistant to erythromycin. Of the 13 strains which tested resistant to methicillin, only 3 were also resistant to clindamycin; the other clindamycin-resistant strain was suisceptible to methicillin. Thrombophlebitis developed in 6 (14%) of the 43 patients given clindamycin and 8 (24%) of the 32 given methicillin. This was not severe with either drug. Indwelling catheters (Intracath) may have contributed to local irritation in some cases in both grouips. Dizziness, dyspnea, and urticaria developed after each of two suiccessive doses of clindamycin phosphate in a patient who received a total of nine 750 mg infusions. The second episode was also marked by wheezing. Clindamycin was discontinued. Three other systemic reactions in the clindamycin grouip, considered probably not related to the druig, were as follows: The patient with frostbite and secondary celltulitis developed bone marrow depression several days after antibiotic therapy; a 91-year-old woman developed microscopic hematuria; and an 80-year-old woman showed a drop in hematocrit. SGOT increased during clindamycin therapy from 62 to 130 units in a diabetic patient with gangrene and cellulitis of the left great toe, and from 42 to 190 uinits in a burn patient who underwent skin grafting duiring therapy. Two other clindamycin-treated T,iii.i 2. Organisms Cultured From the Wounds of Patients Before Treatment in Evaluatable Cases
Organism
Staphylococcuis, coaguilase-positive Staphylococcuts, coagtulase unknown Staphylococcuis, coaguilase-negative 1 Streptococcuis (not speciated)
Clindamycin 17 8 0 14
Methicillin
1 12 0 0 a-Hemolytic streptococcuis 1 Total 32 22° ° Coagtilase-positive and coagulase-negative staphylococci isolated in 1 case.
Xol. 181 * No. 2
INTRAVENOUS CLINDAMYCIN AND METHICILLIN
Twi.i: :3. Type of Infection in Evaluatable Cases Disease Clindamycin Methicillin Celluilitis Infected wounds Neck Hand or arm Foot or leg Frostbite (foot) Abscess Amptitation site Infected uilcer Infected gangrene Animal bite Huiman bite Buirns
17 12
9 10 0 0 4 1 2 1 1 1 1
1 4 1 0 3 0 1 0 0 0
1
3
2
patients had increases in SGOT within the normal (45 units less) range. A 73-year-old woman developed a skin rash
or
duiring methicillin therapy and the drug was discontinued after 8 doses. A 34-year-old man with stab wounds of the neck showed an increase in SGOT from 54 to 95 units during methicillin therapy. Discussion
Clindamycin appears to be a potent antibiotic against organisms commonly encountered on a general surgical service. Its spectruim of activity in vitro includes most staphylococci, pneuimococci and streptococci (except Streptococcuts faecalis) and gram-positive and gram-negative anaerobes.2""10"1118 It has little or no activity against gramnegative aerobes."6 Methicillin is active against most pneuimococci, streptococci and staphylococci, except for some strains of staphylococci which are resistant not only to methicillin btut to other penicillinase-resistant penicillins and numerouis other antibiotics. Most of the methicillinresistant strains that are mtultiply resistant are sensitive to lincomycin and clindamycin in vitro.1 4"12"19 In ouir study 96% of the infecting organisms isolated were staphylococci. Of the 13 strains resistant to methicillin on disc testing, only 3 also tested resistant to clindamycin. Other laboratory stuidies wouild be requiired to characterize these strains which tested resistant to methicillin and to determine their precise antibiotic suisceptibility pattern. Stuidies by Carlisle and Saslaw'6 showed comparable resuilts with parenteral clindamycin and methicillin in experimental staphyloccal and streptococcal infections in monkeys. In clinical trials, intramisctular or intravenous clindamycin phosphate was uised in 131 patients in a study reported by Schtumer and coworkers.20 The initial pathogens were eradicated in 22 of 28 cases of postoperative wound infections and 11 of 14 cases of celluilitis, although not in 4 cases of infected gangrene. Compromised circulation was a factor in several of the soft tissuie infections that failed to respond. Fass and Saslaw9 also reported generally good resuilts with parenteral clindamycin phosphate in soft tissue
infections. Kerstein14 described good results in soft tissue infections in 8 patients given intravenous clindamycin phosphate at Boston City Hospital; these were among the first patients to be treated intravenously with this drug. A wide variety of soft tissue infections were treated in the comparative stuidy on ouir general surgical service (Table 3). Despite the tuse of random numbers to assign patients to treatment, clindamycin was used more often in conditions less likely to benefit from antibiotic therapy, such as infected gangrene, amputations and frostbite. Nevertheless, the clinical and bacteriologic responses in the clindamycin and methicillin grouips did not differ significantly, and clinical resuilts were good in almost all cases. Although positive cuiltuires couild still be obtained at the end of parenteral therapy in some cases (Table 4), the lesions were healing and signs of infection were abating in these cases. The dosages of clindamycin phosphate and methicillin uised in this stuidy were probably higher than necessary to achieve satisfactory tissue levels, judging from the serum levels attainable with lower doses.7'9"2 In testing 5 staphylococcal strains in vitro, Wagnerova and Vacek22 fouind that 6-8 hours of exposure to clindamycin at the minimuim bactericidal concentration (MBC) was needed to sterilize the cuiltuire completely. The MBC was 0.78 mcg/ml or less in 120 of 125 strains of staphylococci, the highest valuie being 3.12 mcg/ml in one strain. Serum clindamycin concentrations exceeding these levels can be maintained readily with parenteral dosages of 300 mg clindamycin phosphate 3 or 4 times daily.7'9 However, as emphasized by Carlisle and Saslaw,5'6 in antibiotic therapy correlations are not perfect between in vivo results and in vitro susceptibilities and seruim antibacterial activities. According to the manuifactuirers, the usuial adtilt dose of Staphcillin is 1,000 mg every 6 houirs, while recommended dosages of clindamycin phosphate range from 300 mg every 12 hours to 1,200 mg every 6 hours, depending uipon the severity of infection and sensitivity of the infecting organism. The patients receiving clindamycin phosphate experienced fewer local reactions (thrombophlebitis) than those receiving methicillin in ouir study. One methicillin-treated T.ABLE 4. Clinical Response, Bacteriologic Response, of Fever in Clindamycin and Methicillin Treated Clindamycin (32 Patients) Clinical Response 18 Excellent (94%) 12 Good Poor
21 11
Mean
1.09 0-5
Range
Methicillin (21 Patients)
6)
(100%) 15 0
2
Bacteriologic Response Oganism eradicated Organism not eradicated Dturation of Fever (Days)
and Duration Patients
(65%)
15 (71%) 6 1.5 0-4
Ann. Strg. *
CHESSICK AND OTHERS
206
Febrtary 1975
TA,BLE 5. Antibiotic Sensitivities of Organisms Cultured Organism
Clindamycin
No. Sensitive/No. Tested Methicillin Erythromycin
Penicillin
22/24 22/24
20/25 16/23
20/26 14/22
8/23 2/24
Staphylococcus epidermidis
2/2
1/2
a-Hemolytic strepotococcuts Streptococcis (variant sp)
1/1 0/1
1/1 0/1
0/2 1/1
0/2 1/1
0/1
0/1
Staphylococcus, coaguilase-positive Staphylococcuis, coagtulase-negative
patient developed a rash. In one clindamycin-treated patient the druig had to be discontinuied because of systemic reactions marked by dizziness, dyspnea and urticaria. The bone marrow depression, hematuiria and drop in hematocrit noted in one patient each in the clindamycin group were probably not related to clindamycin therapy. Elevations in SGOT may have been druig-related; suich elevations have been reported previouisly during oral or parenteral clindamycin therapy in patients with infection.9'13'21 However, DeHaan et al.8 compared the incidence of SGOT elevations in 210 normal voluinteers, half of whom received oral clindamycin and half, placebo. There was no statistically significant difference between druig- and placebo-treated subjects in the frequiency of SGOT elevation.
Acknowledgment We wish to thank The Upjohn Company, Kalamazoo, MI, for their
suipply of the druigs and for their suipport of the stuidy.
References 1. Barrett, F. F., McGehee, R. F., Jr. and Finland, M.: Methicillinresistant Staphylococcuis Auireuis at the Boston City Hospital. N. Engl. J. Med., 279:441, 1968. 2. Bartlett, J. G., Stitter, V. L. and Finegold, S. G.: Treatment of Anaerobic Infections with Lincomycin and Clindamycin. N. Engl. J. Med., 287:1006, 1972. 3. Bauier, A. W., Kirby, W. M. M., Sherris, J. C. and Tuirck, M.: Antibiotic Susceptibility Testing by a Standardized Single Disc Method. Am. J. Clin Pathol., 45:493, 1966. 4. Benner, E. J. and Adams, A. P.: Unusuial Resistance of Staphylococctis Auireuts to Lincomycin and 7-chlorolincomycin. Antimicrob. Agents an(l Chemotherapy-1969. Ann Arbor, Am. Society for Microbiology, 100, 1970. 5. Carlisle, H. N. and Saslaw, S.: Comparison of Clindamycin, Ervthromrcnin and Methicillin in Streptococcal Infections in Monkeys. Antimicrob. Agents Chemother., 1:460, 1972. 6.. Carlisle, H. N. anid Saslaw, S.: Therapy of Staphylococcal Infections in Monkeys. VI. Comparison Clindamycin, Erythromycin, and Methicillin. Appl. Microbiol., 21:440, 1971.
7. DeHaan, R. M., et al.: Pharmacokinetic stuidies of Clindamycin Phosphate, J. Clin. Pharmacol., 13:190, 1973. 8. DeHaan, R. M., Schellenberg, D., Vandenbosch, W. D., and Maile, M. H.: Clindamycin Palmitate in Healthy Men: General Tolerance and Effect on Stools. Cuirr. Ther. Res., 14:81, 1972. 9. Fass, R. J. and Saslaw, S.: Clindamycin: Clinical and Laboratory Evaluiation of Parenteral Therapy. Am. J. Med. Sci., 263:369, 1972. 10. Garrison, D. W., DeHaan, R. M. and Lawson, J. B.: Comparison of In Vitro Antibacterial Activities of 7-chloro-deoxylincomycin, Lincomycin and Erythromycin. Antimicro. Agents and Chemother. 1967, Ann Arbor, American Society for Microbioloby, 397, 1971. 11. Geddes, A. M., Bridgewater, F. A., Williams, D. W., et al.: Clinical and Bacteriological Sttudies with Clindamycin (Dalacin C). Br. Med. J., 2:703, 1970. 12. Gilbert, D. N. and Sanford, J. P.: Methicillin: Critical Appraisal After a Decade of Experience. Med. Clin. North Am., 54:1113, 1970. 13. Kauiffman, R. E., Shoeman, D. W., Wan, S. H. and Azarnoff, D. L.: Absorption and Excretion of Clindamycin-2-Phosphate in Children After Intramtuscutlar Injection. Clin. Pharmacol. Ther., 13:704, 1972. 14. Kerstein, M. D.: Intravenotus Clindamycin Phosphate in Staphylococcal Infections. Cturr. Ther. Res., 14:107, 1972. 15. Martin, W. J. Gardner, M. and Washington, J. A. II.: In Vitro Antimicrobial Stusceptibility of Anaerobic Bacteria Isolated from Clinical Specimens. Antimicrob. Agents Chemother., 1:148, 1972. 16. McGehee, R. F., Smith, C. B., Wilcox, C. and Finland, M.: Comparative Sttudies of Abtibacterial Activity in Vitro and Absorption and Excretion of Lincomycin and Clindamycin. Am. J. Med. Sci., 256:279, 1968. 17. Panzer, J. D., Brown, D. C., Epstein, W. L., et al.: Clindamycin Levels in Various Body Tisstues and Fluiids. J. Clin. Pharmacol., 12:259, 1972. 18. Phillips, I., Pernandes, R. and Warren, C.: In Vitro Comparison of Erythromycin, Lincomycin and Clindamycin. Br. Med. J. 2:89, 1970. 19. Rotntree, P. M. and Beard, M. A.: Hospital Strains of Staphylococctus Auiretus, with Particular References to Methicillin-Resistant Strains. Med. J. Auist., 2:1163, 1968. 20. Schutmer, W., Nichols, R. L., Miller, B. et al.: Clindamycin in the Treatment of Soft Tisstue Infections. Arch. Stirg., 106:578, 1973. 21. Stiver, H. G. and Ronald, A. R.: Clinical and Laboratory Experience with Clindamycin. Antimicrobial Agents and Chemotherapy, 1970. Ann Arbor, American Society for Microbiology, 481, 1971. 22. Wagnerova, M. and Vacek, V.: Antistaphylococcal Activity of Clindamycin. Chemother., 16:247, 1971.
