Journal of Antimicrobial Chemotherapy (1975) 1, 297-303
A clinical, microbiological and toxicological assessment of clindamycin phosphate
R. G. Finch, I. Phillips
and A. M. Geddes Department of Communicable and Tropical Diseases, East Birmingham Hospital Birmingham, B9 5ST, England Clindamycin phosphate, a parenteral clindamycin preparation, was given to 92 patients aged from five months to 83 years suffering from a variety of infections. Eighty-two patients were cured and in a further two there was a partial response. Eight patients failed to respond to clindamycin. Side-effects included pain at the injection site (3), rash (3), diarrhoea (2), phlebitis (1) and pseudo-membranous colitis in one patient who was receiving long-term oral clindamycin hydrochloride following parenteral clindamycin phosphate. Introduction
There is a requirement for a parenteral preparation of clindamycin for the treatment of serious infections or when oral therapy is contraindicated (Geddes, Bridgwater, Williams, Oon & Grimshaw, 1970). Clindamycin phosphate is the 2-phosphate ester of clindamycin (7 (S)-chloro-7-deoxylincomycin), and, unlike clindamycin hydrochloride or palmitate hydrochloride, is suitable for parenteral administration. It is inactive in vitro but, following intravenous or intramuscular injection, is rapidly hydrolysed to microbiologically active clindamycin. The drug is well absorbed following intramuscular injection. Peak serum concentrations of clindamycin are obtained within 3 h in adults (Dehaan, Metzler, Schellenberg & Vanden Bosch, 1973) and in 1 h in children (Kauffman, Shoeman, Wan & Ararnoff, 1972). An intramuscular dose of 300 mg produces an average peak serum concentration of 5 ug/ml (Fass & Saslaw, 1972). Following intravenous injection the serum half-life of active clindamycin is approximately 3 h in adults and 2\ h in children (Kauffman et al, 1972). Clindamycin is highly active against Staphylococcus aureus and streptococci other than Streptococcus faecalis. It is also very active against most anaerobic bacteria causing infection in man (Bartlett, Sutter & Finegold, 1972; Fass, Scholand, Hodges & Saslaw 1973). Clindamycin phosphate has recently been released in the United Kingdom for limited clinical trials and the present paper reports the results of studies with this antibiotic in the treatment of a wide range of infections in children and adults. 297
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Department of Medical Microbiology, St Thomas's Hospital Medical School London, SE1 7EH, England
298
R. G. Finch, L Phillips and A. M. Geddes
Table L Main site of isolation of bacteria from 55 patients treated with clindamycin phosphate Bacteria
Respiratory tract
Totals
4 — — 2 —
1 — — — 2
12 — 2 — —
9 — — — —
5 1 — 3 —
31 1 2 5 2
— —
— 3
4 1
— —
— 1
4 5
— —
2 —
— 1
— 1
— —
2 2
—
—
1
—
—
1
6
8
21
10
10
55
Patients and methods Ninety-two patients admitted to S t Thomas' Hospital, London or East Birmingham Hospital, were selected for treatment with clindamycin phosphate. Sixty were male and 32 female. Their ages ranged from 5 months to 83 years. They suffered from suspected or proven infections caused by staphylococci, pneumococci, streptococci (other than enterococci) and anaerobic organisms. Bacteriological confirmation of infection was obtained in 55 of the 92 patients (Table I). Twenty-four of the remaining 37 patients (mainly children) suffered from respiratory tract infection, 9 from soft tissue infection and 4 from closed bone or joint infection. Three of the 9 patients with soft tissue infections had either a high or rising antistreptolysinOtitre suggesting recent streptococcal infection. Infections were considered to be life-threatening in 37 patients (40%) and serious in 55 (60%). Table II classifies patients by age and site of infection. Specimens for bacteriological culture were obtained before treatment whenever possible. Sensitivity testing on lysed-blood agar with 2 ug clindamycin discs confirmed that Table IL Site of infections in patients of different age groups Age
Site of infection Respiratory Abdomino- Soft Bone or Total no. tissue joint Septicaemia of patients tract pelvic
0-14 15-54 >55
18 7* 5
7 2
3 12 14}
4 5 5
1 4t 5
26 35 31
Totals
30
9
29
14
10
92
• One patient also bacteraemic. t One patient also had soft tissue infection. t One patient also had bone infection.
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Staphylococcus aureus Staphylococcus epidermidis Streptococcus pyogenes Streptococcus pneumoniae Streptococcus viridans Staphylococcus aureus+ Streptococcus pyogenes Bacteroides fragilis Bacteroides fragilis •+Anaerobic streptococci Actinomyces spp. Cl. perfringens+ Staphylococcus aureus
Site of isolation Abdomino- Soft Bone or Septicaemia Total pelvic tissue joint
Assessment of clindamycin phosphate
299
Results Eighty-two of the 92 patients were cured by clindamycin therapy as judged by clinical response and results of laboratory investigations. A partial response was recorded in 2 patients (Table IH) while 8 failed to respond to treatment (Table IV). One (no. 3) had an underlying malignant lymphoma and one (no. 4) chronic lymphatic leukaemia. A young woman (no. 5) with severe anorexia nervosa requiring intravenous feeding developed a Staph. aureus septicaemia from an infected drip site. After 5 days of clindamycin phosphate therapy blood cultures were still positive and she developed acute endocarditis which was successfully treated with fusidic acid and cloxacillin. The infecting staphylococcus remained throughout sensitive to clindamycin (MIC 0 0 6 ug). Another patient (no. 6) received 35 days of clindamycin phosphate for staphylococcal septic Table HL Patients showing a partial response to clindamycin phosphate Patient 1 2
,A&\ Infection (sex) 15(M) Appendicitis— pelvic abscess 71(M) Bronchitis— lung abscess
**f™ isolated Bacteroides fragilis None
,Ot,her , treatment Drainage
Outcome
Slow improvement, interval drainage Postural Improved. Developed diarrhoea drainage —treatment stopped
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all organisms were sensitive to the antibiotic, with the exception of the Actinomyces species which was n6t tested. Of the 36 Staph. aureus isolates, 30 were resistant to penicillin but none to methicillin. Clindamycin phosphate was supplied in 2 and 4 ml ampoules. Each ml contained clindamycin phosphate equivalent to 150mg of clindamycin base. For intravenous administration 150 mg of the antibiotic was diluted in 25 ml of 5 % dextrose or normal saline and infused over 5 min. Parenteral clindamycin was given for as long as the patients' condition indicated and treatment was then usually completed with oral clindamycin hydrochloride or clindamycin palmitate hydrochloride. Seventy-five patients received clindamycin phosphate by intramuscular injection while 17 were given the antibiotic by intravenous infusion. Seventy-five of the 92 patients received continuation oral therapy with either clindamycin hydrochloride capsules or clindamycin palmitate suspension. Clindamycin phosphate by injection was given for periods ranging from 1 to 35 days. However, the majority of patients (67 %) received between 2 and 4 days' treatment. The dose for adults was 300 to 600 mg every 6 or 8 h and 150 mg 6 or 8 hourly for children. Twenty-three patients (25%) required surgical exploration and drainage of wounds. Eight of these suffered from bone or joint infection, 10 had soft tissue infections with abscess formation and 5 abdomino-pelvic abscesses. Combined therapy with clindamycin phosphate and another antibiotic was given to 6 patients. Toxicological assessment included haemoglobin estimation, total and differential white cell count, platelet count, and measurement of blood urea, creatinine, bilirubin, alkaline phosphatase, serum aminoasparatate transferase (SGOT) and creatine phosphokinase (CPK). Urine was tested for protein and sugar and examined microscopically for red and white blood cells and casts. These investigations were carried out before, during and after treatment.
300
R. G. Finch, L Phillips and A. M. Geddes
Table IV. Patients failing to respond to clindamycin phosphate Patient 3 4
Age (sex)
Infection
Bacteria isolated
Other treatment
Outcome
7endocarditis
6
61(M) Septic arthritis
7 8
23(M) Cellulitis -*• lymphangitis 68(F) Perineal sinuses
9
55(F) Lobar pneumonia
36(M) Appendicitis-•• pelvic abscess
Wound still infected at death — Chronic Staphylococcus Fulminating lymphatic aureus infection. leukaemia Died Anorexia Staphylococcus Intravenous Cured with aureus feeding nervosa fusidic acid & cloxacillin Staphylococcus Drainage — Cured with aureus fusidic acid & flucloxacillin — Streptococcus Settled on benzyl— pyogenes penicillin CorticoNo improvement. Rheuma- Actinomyces spp. steroids Died toid arthritis — — — No improvement after 48 h. Settled on tetracycline — Bacteroides Drainage No response. fragilis Became septicaemic & died lymphoma aureus
arthritis of the hip but cultures remained positive. He eventually recovered when treatment was changed toflucloxacillinand fusidic acid. Patient no. 7 had progressive cellulitis from which Streptococcus pyogenes was isolated. Although his temperature had settled and repeat cultures were sterile, treatment was changed to benzylpenicillin when the identity of the infecting organism was known, although it was sensitive to clindamycin. Patient 8 suffered from rheumatoid arthritis and was receiving long-term corticosteroids. She developed multiple perineal sinuses from which Actinomyces israelii was cultured. Clindamycin was started but she had a pulmonary embolus and died. Patient 9 had clinical and radiological pneumonia. She failed to respond to clindamycin, but did to tetracycline. Finally, patient 10 had severe abdominal sepsis following acute appendicitis. He improved initially but developed a Klebsiella aerogenes septicaemia from an infected drip site and died. Autopsy revealed multiple abdominal abscesses. Possible side-effects of therapy were noted in 10 patients. Minor adverse reactions included pain at the site of injection (3), maculo-papular rash (3), mild diarrhoea (2) and mild thrombophlebitis (1). One patient developed pseudomembranous colitis while receiving oral clindamycin following parenteral therapy. He was initially given 10 days of clindamycin phosphate therapy (23-4 g) followed by 142 days'treatment with oral clindamycin hydrochloride (146 g). Details of this case have been published elsewhere (Bateman, Eykyn & Phillips, 1975). No abnormalities were detected in urine or in haematological tests. Serum aminoaspartate transferase (SGOT), however, was significantly elevated during therapy in 10 patients. Similarly, 37 patients had significant rises in serum creatine phosphokinase (CPK) levels. These changes usually occurred within 72 h
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5
10
Associated disease
Assessment of clindamycin phosphate
301
of commencing parenteral treatment and rapidly returned to normal or near normal levels when the drug was stopped. There were no other biochemical abnormalities that were obviously drug related. Discussion
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Qindamycin has been available for several years as the hydrochloride or palmitate preparations for oral therapy. It is of proven efficacy in a wide variety of infections in which staphylococci or streptococci are the causative agents (Geddes et al., 1970; Kosmidis, Corbett, Cole, Finch, Barker & Geddes, 1973) and is particularly valuable in bone and joint infections and as an alternative to penicillin in hypersensitive patients. More recently it has been shown to be effective in anaerobic infections associated with gastro-intestinal and pelvic sepsis, suppurative lung disease and dental infections (Bartlett, Sutter & Finegold, 1972). In the present study 82 (89 %) of the 92 patients responded satisfactorily to clindamycin. The response to treatment was prompt in the majority of cases. Of the 2 patients who responded partially to treatment 1 had widespread abdominal sepsis with abscess formation following acute appendicitis, and the other a lung abscess. The first patient improved clinically but the pelvic abscess recurred. The second patient was improving clinically but developed mild diarrhoea and treatment was stopped although there was no evidence of colitis. He may well have been cured had therapy been continued. Eight patients (9 %) failed treatment. Of these 3 (patients 3, 4 and 8) had severe underlying diseases, 2 (patients 5 and 7) may have responded had treatment been continued for a longer period, 1 (patient 10) died from an intercurrent opportunistic infection, 1 (patient 9) had no bacteriological diagnosis made and only 1 (patient 6) was a true and unaccountable failure. Adverse reactions to clindamycin phosphate include rashes (Levison, Bran & Ries, 1974), drug fever (Fass & Saslaw, 1972), eosinophilia (Fass et al., 1973), diarrhoea (Fass & Saslaw, 1972), a metallic taste following intravenous infusion (Fass & Saslaw, 1972; Fass et al., 1973), pain at the injection site (Fass et al., 1973; Levison et al, 1974), transient elevation of SGOT, SGPT, alkaline phosphatase and CPK (Fass & Saslaw, 1972; Fass et al., 1973; Levison et al., 1974) and, rarely icteric hepatitis (Levison et al., 197'4; Elmore et al., 1974). The most recently described adverse reaction is pseudomembranous colitis (Tedesco, Barton & Alpers, 1974). Three patients (3 %) in the present study developed rashes, the first having just been changed to oral clindamycin following 13 days of clindamycin phosphate therapy, the second 48 h after starting clindamycin phosphate and following a course of ampicillin, and the third while receiving oral clindamycin following a 4-day course of clindamycin phosphate. The last 2 patients continued on oral clindamycin in spite of the rash without ill effects, but in thefirstcase clindamycin was stopped. The rash was maculo-papular and itchy and identical to that described in patients receiving oral clindamycin in whom it has been reported in up to 10% of patients (Geddes et al., 1970). Diarrhoea developed in 2 patients after 2 and 9 days of clindamycin phosphate respectively. Both patients recovered within 24 h of discontinuing the drug. Proctoscopic and sigmoidoscopic examination of the bowel showed no abnormality. The patient who developed pseudomembranous colitis had been on oral clindamycin for 142 days following an initial 10 days of clindamycin phosphate and had undergone surgery 1 week prior to the onset of diarrhoea. Sigmoidoscopy showed the characteristic mucosal appearance of pseudomembranous colitis. He failed to improve with high doses of corticosteroids and total
302
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Acknowledgements We thank Upjohn Limited for financial support.
References Bartlett, J. G., Sutter, V. L. &Finegold, S. M. Treatment of anaerobic infections with lincomycin and clindamycin. Wen- England Journal of Medicine 287: 1006-10 (1972). Bateman, N . J., Eykyn, S. & Phillips, L Pyogenic liver abscess caused by Streptococcus milleri. Lancet i: 657-9 (1975). Batsakis, J. G., Preston, J. A., Briere, R. O. & Giesen, P. C. Iatrogenic aberrations of serum enzyme activity. Clinical Biochemistry 2: 125-33 (1968). Cohen, L. E., McNeill, C. J. & Wells, R. F. Clindamycin-associated colitis. Journal of the American Medical Association 223:1379-80 (1973). Dehaan, R. M., Metzler, C. M., Schellenberg, D. & Vanden Bosch, W. D. Pharmacokinetic studies of clindamycin phosphate. Journal of Clinical Pharmacology 13: 190-209 (1973). Elmore, M. F., Rissing, J. P., Rink, L. & Brooks, G. F. Clindamycin associated hepatotoxicity. American Journal of Medicine 57: 627-30 (1974). Fass, R. J. & Saslaw, S. Clindamycin: clinical and laboratory evaluation of parenteral therapy. American Journal of the Medical Sciences 263: 369-82 (1972). Fass, R. J., Scholand, J. F., Hodges, G. R. & Saslaw, S. Clindamycin in the treatment of serious anaerobic infections. Annals of Internal Medicine 78: 853-9 (1973). Geddes, A. M., Bridgwater, F. A- J., Williams, D. N. Oon, J. & Grimshaw, G. J. Clinical and bacteriological studies with clindamycin. British Medical Journal ii: 703-4 (1970).
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colectomy was eventually carried out Pseudo-membranous colitis associated with clindamycin therapy has been reported with increasing frequency and has been associated with both the oral and parenteral preparations of the antibiotic (Cohen, McNeill & Wells, 1973; Viteri, Howard &Dyck, 1974;Tedesco etal, 1974). It has also been associated with other antibiotics (Keating, Frank, Barton & Tedesco, 1974), chronic debilitating disease, and surgery (Pettet, Baggenstoss, Dearing & Edward, 1954) and not uncommonly in situations where a combination of all three factors is present. It appears to be unrelated to dose or duration of treatment The severity varies from mild diarrhoea to severe fulminating colitis but in the majority it settles on withdrawal of the drug (Tedesco et al, 1974). The patients in this study with elevated CPK and SGOT levels all received clindamycin by intramuscular injection. No patient receiving intravenous therapy developed raised enzyme levels, although this has been described (Fass & Saslaw, 1972). There was no clinical or biochemical evidence to suggest liver damage. Changes in serum enzyme levels, notably CPK and SGOT, have previously been reported with parenteral clindamycin (Fass & Saslaw, 1972; Fass et al, 1973; Levison et al., 1974). CPK is a very sensitive indicator of tissue damage and is present in striated muscle, lung and brain. Raised levels have been reported following the intramuscular injection of a variety of drugs and are related to local muscle irritation (Batsakis, Preston, Briere & Giesen, 1968). Determination of CPK isoenzyme fracxions can differentiate between lung, brain and striated muscle CPK (Konttinen & Somer, 1973) but this facility is not widely available. The present study suggests that clindamycin phosphate is as safe and effective as the parent compound clindamycin. Its parenteral route of administration makes it suitable for the treatment of serious infections or when oral therapy is not possible.
Assessment of dindamycin phosphate
303
{Manuscript accepted 12 June 1975)
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Kauffman, R. E., Shoeman, D. W., Wan, S. H. & Ararnoff, D. L. Absorption and excretion of clindamycin-2-phosphate in children after intramuscular injection. Clinical Pharmacology and Therapeutics 13: 704-9 (1972). Keating, J. P., Frank, A. L., Barton, L. L. & Tedesco, F. J. Pseudo-membranous colitis associated with ampicillin therapy. American Journal of Diseases of Childhood 128: 369-70 (1974). Konttinen, A. & Somer, H. Specificity of serum creatine kinase isoenzymes in diagnosis of acute myocardial infarction. British Medical Journal i: 386-9 (1973). Kosmidis, J. C, Corbett, V., Cole, A. J. L., Finch, R. G., Barker, J. E. & Geddes, A. M. The treatment of paediatric infections with the lincomycins. British Journal of Clinical Practice 27: 315-8 (1973). Levison, M. E., Bran, J. L. & Ries, K. Treatment of anaerobic bacterial infections with clindamycin-2-phosphate. Antimicrobial Agents and Chemotherapy 5: 276-80 (1974). Pettet, J. D., Baggenstoss, A. H., Dearing, W. H. & Edward, S. J. Post-operative pseudomembranous enterocolitis. Surgery, Gynaecology and Obstetrics 98: 546-52 (1954). Tedesco, F. J., Barton, R. W. & Alpers, D. H. Clindamycin-associated eolith. Annals of Internal Medicine 81: 429-33 (1974). Viteri, A. L., Howard, P. H. & Dyck, W. P. The spectrum of lincomycin-clindamycin colitis. Gastroenterology 66: 1137-44 (1974).
A clinical, microbiological and toxicological assessment of clindamycin phosphate
R. G. Finch, I. Phillips
and A. M. Geddes Department of Communicable and Tropical Diseases, East Birmingham Hospital Birmingham, B9 5ST, England Clindamycin phosphate, a parenteral clindamycin preparation, was given to 92 patients aged from five months to 83 years suffering from a variety of infections. Eighty-two patients were cured and in a further two there was a partial response. Eight patients failed to respond to clindamycin. Side-effects included pain at the injection site (3), rash (3), diarrhoea (2), phlebitis (1) and pseudo-membranous colitis in one patient who was receiving long-term oral clindamycin hydrochloride following parenteral clindamycin phosphate. Introduction
There is a requirement for a parenteral preparation of clindamycin for the treatment of serious infections or when oral therapy is contraindicated (Geddes, Bridgwater, Williams, Oon & Grimshaw, 1970). Clindamycin phosphate is the 2-phosphate ester of clindamycin (7 (S)-chloro-7-deoxylincomycin), and, unlike clindamycin hydrochloride or palmitate hydrochloride, is suitable for parenteral administration. It is inactive in vitro but, following intravenous or intramuscular injection, is rapidly hydrolysed to microbiologically active clindamycin. The drug is well absorbed following intramuscular injection. Peak serum concentrations of clindamycin are obtained within 3 h in adults (Dehaan, Metzler, Schellenberg & Vanden Bosch, 1973) and in 1 h in children (Kauffman, Shoeman, Wan & Ararnoff, 1972). An intramuscular dose of 300 mg produces an average peak serum concentration of 5 ug/ml (Fass & Saslaw, 1972). Following intravenous injection the serum half-life of active clindamycin is approximately 3 h in adults and 2\ h in children (Kauffman et al, 1972). Clindamycin is highly active against Staphylococcus aureus and streptococci other than Streptococcus faecalis. It is also very active against most anaerobic bacteria causing infection in man (Bartlett, Sutter & Finegold, 1972; Fass, Scholand, Hodges & Saslaw 1973). Clindamycin phosphate has recently been released in the United Kingdom for limited clinical trials and the present paper reports the results of studies with this antibiotic in the treatment of a wide range of infections in children and adults. 297
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Department of Medical Microbiology, St Thomas's Hospital Medical School London, SE1 7EH, England
298
R. G. Finch, L Phillips and A. M. Geddes
Table L Main site of isolation of bacteria from 55 patients treated with clindamycin phosphate Bacteria
Respiratory tract
Totals
4 — — 2 —
1 — — — 2
12 — 2 — —
9 — — — —
5 1 — 3 —
31 1 2 5 2
— —
— 3
4 1
— —
— 1
4 5
— —
2 —
— 1
— 1
— —
2 2
—
—
1
—
—
1
6
8
21
10
10
55
Patients and methods Ninety-two patients admitted to S t Thomas' Hospital, London or East Birmingham Hospital, were selected for treatment with clindamycin phosphate. Sixty were male and 32 female. Their ages ranged from 5 months to 83 years. They suffered from suspected or proven infections caused by staphylococci, pneumococci, streptococci (other than enterococci) and anaerobic organisms. Bacteriological confirmation of infection was obtained in 55 of the 92 patients (Table I). Twenty-four of the remaining 37 patients (mainly children) suffered from respiratory tract infection, 9 from soft tissue infection and 4 from closed bone or joint infection. Three of the 9 patients with soft tissue infections had either a high or rising antistreptolysinOtitre suggesting recent streptococcal infection. Infections were considered to be life-threatening in 37 patients (40%) and serious in 55 (60%). Table II classifies patients by age and site of infection. Specimens for bacteriological culture were obtained before treatment whenever possible. Sensitivity testing on lysed-blood agar with 2 ug clindamycin discs confirmed that Table IL Site of infections in patients of different age groups Age
Site of infection Respiratory Abdomino- Soft Bone or Total no. tissue joint Septicaemia of patients tract pelvic
0-14 15-54 >55
18 7* 5
7 2
3 12 14}
4 5 5
1 4t 5
26 35 31
Totals
30
9
29
14
10
92
• One patient also bacteraemic. t One patient also had soft tissue infection. t One patient also had bone infection.
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Staphylococcus aureus Staphylococcus epidermidis Streptococcus pyogenes Streptococcus pneumoniae Streptococcus viridans Staphylococcus aureus+ Streptococcus pyogenes Bacteroides fragilis Bacteroides fragilis •+Anaerobic streptococci Actinomyces spp. Cl. perfringens+ Staphylococcus aureus
Site of isolation Abdomino- Soft Bone or Septicaemia Total pelvic tissue joint
Assessment of clindamycin phosphate
299
Results Eighty-two of the 92 patients were cured by clindamycin therapy as judged by clinical response and results of laboratory investigations. A partial response was recorded in 2 patients (Table IH) while 8 failed to respond to treatment (Table IV). One (no. 3) had an underlying malignant lymphoma and one (no. 4) chronic lymphatic leukaemia. A young woman (no. 5) with severe anorexia nervosa requiring intravenous feeding developed a Staph. aureus septicaemia from an infected drip site. After 5 days of clindamycin phosphate therapy blood cultures were still positive and she developed acute endocarditis which was successfully treated with fusidic acid and cloxacillin. The infecting staphylococcus remained throughout sensitive to clindamycin (MIC 0 0 6 ug). Another patient (no. 6) received 35 days of clindamycin phosphate for staphylococcal septic Table HL Patients showing a partial response to clindamycin phosphate Patient 1 2
,A&\ Infection (sex) 15(M) Appendicitis— pelvic abscess 71(M) Bronchitis— lung abscess
**f™ isolated Bacteroides fragilis None
,Ot,her , treatment Drainage
Outcome
Slow improvement, interval drainage Postural Improved. Developed diarrhoea drainage —treatment stopped
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all organisms were sensitive to the antibiotic, with the exception of the Actinomyces species which was n6t tested. Of the 36 Staph. aureus isolates, 30 were resistant to penicillin but none to methicillin. Clindamycin phosphate was supplied in 2 and 4 ml ampoules. Each ml contained clindamycin phosphate equivalent to 150mg of clindamycin base. For intravenous administration 150 mg of the antibiotic was diluted in 25 ml of 5 % dextrose or normal saline and infused over 5 min. Parenteral clindamycin was given for as long as the patients' condition indicated and treatment was then usually completed with oral clindamycin hydrochloride or clindamycin palmitate hydrochloride. Seventy-five patients received clindamycin phosphate by intramuscular injection while 17 were given the antibiotic by intravenous infusion. Seventy-five of the 92 patients received continuation oral therapy with either clindamycin hydrochloride capsules or clindamycin palmitate suspension. Clindamycin phosphate by injection was given for periods ranging from 1 to 35 days. However, the majority of patients (67 %) received between 2 and 4 days' treatment. The dose for adults was 300 to 600 mg every 6 or 8 h and 150 mg 6 or 8 hourly for children. Twenty-three patients (25%) required surgical exploration and drainage of wounds. Eight of these suffered from bone or joint infection, 10 had soft tissue infections with abscess formation and 5 abdomino-pelvic abscesses. Combined therapy with clindamycin phosphate and another antibiotic was given to 6 patients. Toxicological assessment included haemoglobin estimation, total and differential white cell count, platelet count, and measurement of blood urea, creatinine, bilirubin, alkaline phosphatase, serum aminoasparatate transferase (SGOT) and creatine phosphokinase (CPK). Urine was tested for protein and sugar and examined microscopically for red and white blood cells and casts. These investigations were carried out before, during and after treatment.
300
R. G. Finch, L Phillips and A. M. Geddes
Table IV. Patients failing to respond to clindamycin phosphate Patient 3 4
Age (sex)
Infection
Bacteria isolated
Other treatment
Outcome
7endocarditis
6
61(M) Septic arthritis
7 8
23(M) Cellulitis -*• lymphangitis 68(F) Perineal sinuses
9
55(F) Lobar pneumonia
36(M) Appendicitis-•• pelvic abscess
Wound still infected at death — Chronic Staphylococcus Fulminating lymphatic aureus infection. leukaemia Died Anorexia Staphylococcus Intravenous Cured with aureus feeding nervosa fusidic acid & cloxacillin Staphylococcus Drainage — Cured with aureus fusidic acid & flucloxacillin — Streptococcus Settled on benzyl— pyogenes penicillin CorticoNo improvement. Rheuma- Actinomyces spp. steroids Died toid arthritis — — — No improvement after 48 h. Settled on tetracycline — Bacteroides Drainage No response. fragilis Became septicaemic & died lymphoma aureus
arthritis of the hip but cultures remained positive. He eventually recovered when treatment was changed toflucloxacillinand fusidic acid. Patient no. 7 had progressive cellulitis from which Streptococcus pyogenes was isolated. Although his temperature had settled and repeat cultures were sterile, treatment was changed to benzylpenicillin when the identity of the infecting organism was known, although it was sensitive to clindamycin. Patient 8 suffered from rheumatoid arthritis and was receiving long-term corticosteroids. She developed multiple perineal sinuses from which Actinomyces israelii was cultured. Clindamycin was started but she had a pulmonary embolus and died. Patient 9 had clinical and radiological pneumonia. She failed to respond to clindamycin, but did to tetracycline. Finally, patient 10 had severe abdominal sepsis following acute appendicitis. He improved initially but developed a Klebsiella aerogenes septicaemia from an infected drip site and died. Autopsy revealed multiple abdominal abscesses. Possible side-effects of therapy were noted in 10 patients. Minor adverse reactions included pain at the site of injection (3), maculo-papular rash (3), mild diarrhoea (2) and mild thrombophlebitis (1). One patient developed pseudomembranous colitis while receiving oral clindamycin following parenteral therapy. He was initially given 10 days of clindamycin phosphate therapy (23-4 g) followed by 142 days'treatment with oral clindamycin hydrochloride (146 g). Details of this case have been published elsewhere (Bateman, Eykyn & Phillips, 1975). No abnormalities were detected in urine or in haematological tests. Serum aminoaspartate transferase (SGOT), however, was significantly elevated during therapy in 10 patients. Similarly, 37 patients had significant rises in serum creatine phosphokinase (CPK) levels. These changes usually occurred within 72 h
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5
10
Associated disease
Assessment of clindamycin phosphate
301
of commencing parenteral treatment and rapidly returned to normal or near normal levels when the drug was stopped. There were no other biochemical abnormalities that were obviously drug related. Discussion
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Qindamycin has been available for several years as the hydrochloride or palmitate preparations for oral therapy. It is of proven efficacy in a wide variety of infections in which staphylococci or streptococci are the causative agents (Geddes et al., 1970; Kosmidis, Corbett, Cole, Finch, Barker & Geddes, 1973) and is particularly valuable in bone and joint infections and as an alternative to penicillin in hypersensitive patients. More recently it has been shown to be effective in anaerobic infections associated with gastro-intestinal and pelvic sepsis, suppurative lung disease and dental infections (Bartlett, Sutter & Finegold, 1972). In the present study 82 (89 %) of the 92 patients responded satisfactorily to clindamycin. The response to treatment was prompt in the majority of cases. Of the 2 patients who responded partially to treatment 1 had widespread abdominal sepsis with abscess formation following acute appendicitis, and the other a lung abscess. The first patient improved clinically but the pelvic abscess recurred. The second patient was improving clinically but developed mild diarrhoea and treatment was stopped although there was no evidence of colitis. He may well have been cured had therapy been continued. Eight patients (9 %) failed treatment. Of these 3 (patients 3, 4 and 8) had severe underlying diseases, 2 (patients 5 and 7) may have responded had treatment been continued for a longer period, 1 (patient 10) died from an intercurrent opportunistic infection, 1 (patient 9) had no bacteriological diagnosis made and only 1 (patient 6) was a true and unaccountable failure. Adverse reactions to clindamycin phosphate include rashes (Levison, Bran & Ries, 1974), drug fever (Fass & Saslaw, 1972), eosinophilia (Fass et al., 1973), diarrhoea (Fass & Saslaw, 1972), a metallic taste following intravenous infusion (Fass & Saslaw, 1972; Fass et al., 1973), pain at the injection site (Fass et al., 1973; Levison et al, 1974), transient elevation of SGOT, SGPT, alkaline phosphatase and CPK (Fass & Saslaw, 1972; Fass et al., 1973; Levison et al., 1974) and, rarely icteric hepatitis (Levison et al., 197'4; Elmore et al., 1974). The most recently described adverse reaction is pseudomembranous colitis (Tedesco, Barton & Alpers, 1974). Three patients (3 %) in the present study developed rashes, the first having just been changed to oral clindamycin following 13 days of clindamycin phosphate therapy, the second 48 h after starting clindamycin phosphate and following a course of ampicillin, and the third while receiving oral clindamycin following a 4-day course of clindamycin phosphate. The last 2 patients continued on oral clindamycin in spite of the rash without ill effects, but in thefirstcase clindamycin was stopped. The rash was maculo-papular and itchy and identical to that described in patients receiving oral clindamycin in whom it has been reported in up to 10% of patients (Geddes et al., 1970). Diarrhoea developed in 2 patients after 2 and 9 days of clindamycin phosphate respectively. Both patients recovered within 24 h of discontinuing the drug. Proctoscopic and sigmoidoscopic examination of the bowel showed no abnormality. The patient who developed pseudomembranous colitis had been on oral clindamycin for 142 days following an initial 10 days of clindamycin phosphate and had undergone surgery 1 week prior to the onset of diarrhoea. Sigmoidoscopy showed the characteristic mucosal appearance of pseudomembranous colitis. He failed to improve with high doses of corticosteroids and total
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R. G. Finch, L Phillips and A. M. Geddes
Acknowledgements We thank Upjohn Limited for financial support.
References Bartlett, J. G., Sutter, V. L. &Finegold, S. M. Treatment of anaerobic infections with lincomycin and clindamycin. Wen- England Journal of Medicine 287: 1006-10 (1972). Bateman, N . J., Eykyn, S. & Phillips, L Pyogenic liver abscess caused by Streptococcus milleri. Lancet i: 657-9 (1975). Batsakis, J. G., Preston, J. A., Briere, R. O. & Giesen, P. C. Iatrogenic aberrations of serum enzyme activity. Clinical Biochemistry 2: 125-33 (1968). Cohen, L. E., McNeill, C. J. & Wells, R. F. Clindamycin-associated colitis. Journal of the American Medical Association 223:1379-80 (1973). Dehaan, R. M., Metzler, C. M., Schellenberg, D. & Vanden Bosch, W. D. Pharmacokinetic studies of clindamycin phosphate. Journal of Clinical Pharmacology 13: 190-209 (1973). Elmore, M. F., Rissing, J. P., Rink, L. & Brooks, G. F. Clindamycin associated hepatotoxicity. American Journal of Medicine 57: 627-30 (1974). Fass, R. J. & Saslaw, S. Clindamycin: clinical and laboratory evaluation of parenteral therapy. American Journal of the Medical Sciences 263: 369-82 (1972). Fass, R. J., Scholand, J. F., Hodges, G. R. & Saslaw, S. Clindamycin in the treatment of serious anaerobic infections. Annals of Internal Medicine 78: 853-9 (1973). Geddes, A. M., Bridgwater, F. A- J., Williams, D. N. Oon, J. & Grimshaw, G. J. Clinical and bacteriological studies with clindamycin. British Medical Journal ii: 703-4 (1970).
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colectomy was eventually carried out Pseudo-membranous colitis associated with clindamycin therapy has been reported with increasing frequency and has been associated with both the oral and parenteral preparations of the antibiotic (Cohen, McNeill & Wells, 1973; Viteri, Howard &Dyck, 1974;Tedesco etal, 1974). It has also been associated with other antibiotics (Keating, Frank, Barton & Tedesco, 1974), chronic debilitating disease, and surgery (Pettet, Baggenstoss, Dearing & Edward, 1954) and not uncommonly in situations where a combination of all three factors is present. It appears to be unrelated to dose or duration of treatment The severity varies from mild diarrhoea to severe fulminating colitis but in the majority it settles on withdrawal of the drug (Tedesco et al, 1974). The patients in this study with elevated CPK and SGOT levels all received clindamycin by intramuscular injection. No patient receiving intravenous therapy developed raised enzyme levels, although this has been described (Fass & Saslaw, 1972). There was no clinical or biochemical evidence to suggest liver damage. Changes in serum enzyme levels, notably CPK and SGOT, have previously been reported with parenteral clindamycin (Fass & Saslaw, 1972; Fass et al, 1973; Levison et al., 1974). CPK is a very sensitive indicator of tissue damage and is present in striated muscle, lung and brain. Raised levels have been reported following the intramuscular injection of a variety of drugs and are related to local muscle irritation (Batsakis, Preston, Briere & Giesen, 1968). Determination of CPK isoenzyme fracxions can differentiate between lung, brain and striated muscle CPK (Konttinen & Somer, 1973) but this facility is not widely available. The present study suggests that clindamycin phosphate is as safe and effective as the parent compound clindamycin. Its parenteral route of administration makes it suitable for the treatment of serious infections or when oral therapy is not possible.
Assessment of dindamycin phosphate
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{Manuscript accepted 12 June 1975)
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Kauffman, R. E., Shoeman, D. W., Wan, S. H. & Ararnoff, D. L. Absorption and excretion of clindamycin-2-phosphate in children after intramuscular injection. Clinical Pharmacology and Therapeutics 13: 704-9 (1972). Keating, J. P., Frank, A. L., Barton, L. L. & Tedesco, F. J. Pseudo-membranous colitis associated with ampicillin therapy. American Journal of Diseases of Childhood 128: 369-70 (1974). Konttinen, A. & Somer, H. Specificity of serum creatine kinase isoenzymes in diagnosis of acute myocardial infarction. British Medical Journal i: 386-9 (1973). Kosmidis, J. C, Corbett, V., Cole, A. J. L., Finch, R. G., Barker, J. E. & Geddes, A. M. The treatment of paediatric infections with the lincomycins. British Journal of Clinical Practice 27: 315-8 (1973). Levison, M. E., Bran, J. L. & Ries, K. Treatment of anaerobic bacterial infections with clindamycin-2-phosphate. Antimicrobial Agents and Chemotherapy 5: 276-80 (1974). Pettet, J. D., Baggenstoss, A. H., Dearing, W. H. & Edward, S. J. Post-operative pseudomembranous enterocolitis. Surgery, Gynaecology and Obstetrics 98: 546-52 (1954). Tedesco, F. J., Barton, R. W. & Alpers, D. H. Clindamycin-associated eolith. Annals of Internal Medicine 81: 429-33 (1974). Viteri, A. L., Howard, P. H. & Dyck, W. P. The spectrum of lincomycin-clindamycin colitis. Gastroenterology 66: 1137-44 (1974).
