RESEARCH/PRACTICE REPORTS

INTRAVENOUS OR INTRAMUSCULAR TEICOPLANIN ONCE DAILY FOR SKINAND SOFr·TISSUE INFECTIONS Howard E. Edelstein, Sharon E. Oster, Valerie A. Chirurgi, Richard A. Karp, Karen B. Cassano, and Robert E. McCabe

ABSTRACf: Teicoplanin is a new glycopeptideantibiotic with potent activityagainst gram-positivebacteria and pharmacokineticsthat allow once daily administration. To study the efficacy and safety of teicoplanin for skin and soft-tissue infections,75 patients received teicoplanin intravenously (38) or intramuscularly(37, of which 16 were outpatients).Of 62 clinicallyevaluable patients,97 percent of teicoplanin iv and 93 percent of teicoplanin im patients were cured or improved.All teicoplanin iv patients and 64 percent of teicoplanin im patients were cured microbiologicallyat 24-48 hours posttherapy. Persistenceof organisms frequently was associated with skin ulcers or abscess cavities and usually had no bearing on clinical outcome. Possible adverse clinical and laboratory reactions caused by teicoplanin occurred in 4 of 38 teicoplanin iv patients (II percent) and in 8 of 37 teicoplanin im patients (22 percent). Reactions were mild and resolved with discontinuationof teicoplanin in most cases. In this study, teicoplanin appeared to be safe, efficacious, and convenient for both hospital staff and patients, and potentiallycost-effective for the treatmentof skin and soft-tissue infections. In particular, teicoplanin appears to be appropriate for outpatient parenteral therapy.

tncr Ann Pharmacother 1991;25:914-8. TEICOPLANIN IS A GLYCOPEPTIDE ANTIBIOTIC chemically re-

lated to the vancomycin-ristocetin group of antibiotics. It has potent activity in vitro against gram-positive bacteria including methicillin-resistant staphylococci, enterococci, and corynebacteria, and is bactericidal except for enterococci.!" Few data on the clinical efficacy of teicoplanin for the treatment of skin and soft-tissue infections are available, particularly in the US. Our purpose is to report our experience in a Veterans Affairs Medical Center (VAMC) with respect to the efficacy, safety, tolerance, and practicality of teicoplanin administered either by the intravenous or intramuscular routes for treatment of skin and soft-tissue infections. HOWARD E. EDELSTEIN, M.D.•SHARON E. OSTER, M.D.. and VALERIE A. CHIRURGI, M.D.. are Assistant Clinical Professors of Medicine; RICHARD A. KARP, M.D.. is a physician in private practice: KAREN B. CASSANO, R.N.. is a Research Nurse; and ROBERT E. MCCABE, M.D.• is an Associate Professor of Medicine, Medical Service. Department of Veterans Affairs Medical Center. Martinez, CA, and Department of Medicine. University of California Medical School, Davis, CA. Reprints: Robert E. McCabe. M.D.. Medical Service (111Fl. Martinez VAMC, 150 Muir Rd., Martinez, CA 94553. This research was supported by a grant from Merrell-Dow Research Institute and by the Department of Veterans Affairs.

914 • DIep, The Annals ofPharmacotherapy •

Methods Hospitalizedand outpatient adults at the Martinez,California,VAMC with moderate to severe skin and soft-tissue infections caused by grampositive bacteria were eligible for enrollment in the study. Patients were entered into either an open study or a randomized study comparing teicoplanin iv or im, and cefazolin, as part of multicenter protocols.Patients who could not receive medication by the iv route (e.g., had no venous access and thus needed im injections)or the im route (e.g., had a coagulopathy and could not receive im injections), or who were suspected to be infected with cefazolin-resistant organisms were entered into the nonrandomized protocol. The studies were approved by the Human Subjects Committee at the Martinez VAMC and written informed consent was obtained from all patients. Exclusioncriteria includedhypersensitivity to vancomycin,pregnancy or nursing, liver function tests four times the upper limit of normal, elevated serum creatinine (> 141 urnol/L), hearing loss or abnormal vestibular function, pathogens resistant to teicoplanin, osteomyelitis,endocarditis, and treatment with effective antibiotics within 48 hours before entry into the study resulting in cultures at the site of infection that did not yield a pathogen susceptible to teicoplanin. Clinical and microbiologic follow up was performed within 48 hours of the end of therapy. All patients who received one or more doses of teicoplan in were assessed for adverse reactions. In addition to standard clinical and laboratory examinations, skin and soft-tissue cultures were done every 3 days during the study and within 48 hours after end of treatment if evidence of infectionpersisted. An initial intravenous dose of teicoplanin 6 mg/kg was administered to all patients (except those in the cefazolin arm of the study). Subsequently, teicoplanin was administered every 24 hours at 3 mg/kg (im or iv depending upon the route to which the patient had been randomized) if the patient was enrolled in the randomized study; if enrolled in the nonrandomized study, the patient received either 3 or 6 mg/kg im or iv at the discretion of the investigator, based on the severity of the infection. Midway through the study, the initial and daily dosages of teicoplanin were increased to 12 mg/kg and 6 mg/kg, respectively, because it was found that investigators were usually choosing the higher dose. Study drug was reconstituted by adding 3.1 mL of sterile water to a 200-mg vial of teicoplanin.The intravenous preparation required further dilution with either 100 mL of NaCI 0.9% or D5W and administration over 30 minutes, or dilution with 20 mL of NaCI 0.9% solution and administration as a direct injection over 5 minutes. Intramuscular preparation required no further dilution, but the use of lidocaine I% was permitted. Cefazolin Ig iv q8h was administered to 17 other patients in a separate arm of the study. Patients in whom mixed infections with gram-negative bacilli or anaerobes were suspected were allowed to receive metronidazole, aztreonam, or both agents. These antibiotics were chosen because their antimi-

/991 September. Volume 25

Downloaded from aop.sagepub.com at UNIV NEBRASKA LIBRARIES on June 8, 2016

crobial spectra do not overlap with that of teicoplanin. An aminoglycoside was allowed only for the first 24 hours of therapy. No other antimicrobial agents were permitted. Susceptibility to teicoplanin was determined by the Kirby-Bauer disk diffusion method with 30-Jlg disks. Zone diameters> 14 mm indicated susceptibility to teicoplanin. Anaerobic cultures were not done routinely. Cultures were obtained of pus, if present (e.g., abscess), purulent drainage (e.g., from ulcers), swabs of ruptured bullae or damaged skin, or aspirates of relatively undamaged skin. At least 3 days of therapy was required before patients were evaluated clinically and microbiologically. Clinical cure was defmed as eradication of signs and symptoms of infection without recurrence. Improvement was defined as clinical findings subsiding during treatment but with incomplete resolution. Recurrence was defined as initial improvement followed by clinical deterioration secondary to either reinfection or relapse. Follow up was done routinely within 48 hours of the last dose of teicoplanin. Failure was defmed as no apparent response to treatment. Microbiologic cure was defined as elimination of initial pathogens. Elimination with relapse was defmed as disappearance of the pathogens by the end of treatment with reappearance of the same organism at the same site at follow up, with or without clinical signs or symptoms of infection. Elimination with reinfection was defined as eradication of the pathogens by the end of treatment, with culture of a new potential pathogen at the same site at time of follow up, with or without clinical signs or symptoms of infection. Persistence was defined as presence of original pathogens in follow-up cultures after end of treatment.

Results PATIENT CHARACTERISTICS

Seventy-five patients were treated with teicoplanin (see the clinical response section below for the patients excluded from clinical evaluation). Thirty-eight patients were treated with teicoplanin iv (18 randomized) and 37 with teicoplanin im (19 randomized). Only 17 patients were entered into the cefazolin arm of the study (clinical results were comparable to those observed with teicoplanin iv). As judged by the investigator at time of enrollment, 9 teicoplanin iv patients and 14 teicoplanin im patients had severe infection; only 1 patient was judged to have a mild infection and was treated by the iv route. Eleven and 12 of the iv and im patients, respectively, underwent a surgical procedure for treatment of the infection, usually incision and drainage of an abscess. Sixty of 62 clinically evaluable patients were male. Mean ages of patients receiving teicoplanin iv and im were 59 and 58 years, respectively. Mean durations of therapy for tei-

Table 1. Clinical Infections in 62 Patients Treated with Teicoplanin

Table 2. Microbiologic Outcome in 51 Patients" Treated with Teicoplanin PATIENTS RECEIVING TEICOPLANIN (%) PATHOGEN/OUTCOME

iv

Staphylococcus aureus eradicated persisted Coagulase-negative staphylococci eradicated persisted Streptococci" eradicated persisted Enterococci eradicated persisted

18 18(100) 0 9 8 (89) 1(11) 10 10 (100) 0 2 2 (100) 0

im

16

TOTAL(%)

7 (44) 6

34 27 (79) 7 (21) IS

S (83) I (17) 3 3 (100) 0 I 1(100) 0

13 (87) 2 (13) 13 13 (100) 0 3 3 (100) 0

9 (S6)

"Includes 37 patients infected with single organisms and 14 patients with two organisms. bIncludes group A (S patients). group B (4), group C (I), and group G (3) streptococci.

coplanin iv and im patients were 10 and 8 days, respectively. Aztreonam, metronidazole, or both were given to 10 patients (16 percent) for a mean of7 and 6 days, respectively. Thirty-seven patients (60 percent) received teicoplanin at 3 mg/kg/d (15 by the im route), and the remainder received 6 mg/kg/d (13 by the im route). The types and locations of infections treated with teicoplanin are given in Table 1. Cellulitis predominated, not infrequently associated with ulcers (i.e., diabetic foot, neuropathic, or venous stasis ulcers, not simple ruptured bullae or abrasions) or abscesses. Forty infections (64 percent) involved the leg or foot, 9 (14 percent) the arm or hand, 8 (13 percent) the head or neck, and 5 (8 percent) the trunk. Only 5 patients (8 percent) had no underlying disease. Thirty-six patients (58 percent) had cardiovascular disease, including peripheral vascular disease and congestive heart failure, 22 (35 percent) had substance-abuse problems, 11 (18 percent) had neurologic disease, and 15 (24 percent) had diabetes mellitus. History of recent trauma related to the site of infection occurred in only 3 patients (5 percent). Underlying diseases were distributed evenly between the teicoplanin iv and im groups except for neurologic disease; 10 of the 11 patients with neurologic disease received teicoplanin iv. BACTERIOLOGY

PATIENTS RECEIVING TEICOPLANIN INFECTION

iv

im

TOTAL

Cellulitis without abscess/ulcer with abscess/ulcer Wounds/abscesses leg buttock back chest

30 2S" S' 4 2 0

24 16b 8d 4 2 2 0 0

S4 41 13 8 4 2 I I

I I

"Leg/foot (18 patients); arm/hand (2); head/neck (S). bLeg/foot (12 patients); arm/hand (S). 'Leg/foot (2 patients); arm/hand (I); head/neck (2). dLeg/foot (S patients); arm/hand (I); head/neck (I); chest (I).

Staphylococcus aureus (34 isolates) and coagulase-negative staphylococci (15 isolates) were the most commonly encountered organisms cultured, followed by Streptococcus spp. (13) and Enterococcus spp. (3) (Table 2). Only 2 S. aureus isolates were resistant to methicillin. Single organisms were identified in 37 patients and 2 organisms were identified in 14 patients. CLINICAL RESPONSE

Of the 38 patients who received teicoplanin iv, 4 were not evaluated for clinical response for the following reasons: no gram-positive pathogen (2 patients), adverse effect (1), and death caused by aspiration pneumonitis (1).

DICP. The Annals ofPharmacotherapy

•

Downloaded from aop.sagepub.com at UNIV NEBRASKA LIBRARIES on June 8, 2016

1991 September, Volume 25 •

915

Of the 37 patients who received teicoplanin im, 9 were not evaluated for clinical response for these reasons: adverse effects (2 patients), diagnosis of osteomyelitis (4), no gram-positive pathogen isolated (1), patient's refusal to receive more therapy because of dislike of being in a study (1), and discontinuation by primary physician because of personal dislike of studies (1). By clinical criteria, teicoplanin iv cured 29 of 34 patients (85 percent) and resulted in improvement in 4 others (12 percent) (Table 3). The single clinical failure was attributed to recurrent infection in a 44-year-old man with peripheral vascular disease who had left leg cellulitis caused by S. aureus and group B streptococcus. Initially he responded well to 14 days of teicoplanin (3 mg/kg), but cellulitis recurred at follow up 6 days after the end of therapy, with skin culture yielding S. hemolyticus. Teicoplanin im cured 23 of 28 patients clinically (82 percent), improved 3 (11 percent), and failed in 2 (7 percent) (Table 3). Persistent infection occurred in a 37-yearold man without underlying disease who had a left great toe abscess and cellulitis caused by S. aureus. Despite seven days of teicop1anin (6 mg/kg im), signs and symptoms of infection persisted. Teicoplanin iv was given for an additional two days, but the infection did not improve, and he eventually recovered with surgical debridement of the toe and nafcillin therapy. Inadequate initial debridement probably contributed to the patient's poor response. A second patient, a 64-year-old man with peripheral vascular disease, type II diabetes mellitus, and a history of alcohol abuse, received seven days of teicoplanin (6 mg/kg) for right leg cellulitis caused by S. aureus, but signs of infection persisted despite eradication of this pathogen. He had a complete and rapid response to cefazolin. No obvious reason for teicoplanin failure was identified. MICROBIOLOGIC RESULTS

All 30 microbiologically evaluable patients (100 percent) who received teicoplanin iv and 14 of 22 patients (64 percent) who received teicoplanin im were cured by microbiologic criteria (Tables 2 and 3). Persistent organisms included S. aureus (7 patients) and coagulase-negative staphylococcus (1). In 5 of 8 patients, persistence of pathogens was associated with an open ulcer or skin defect and had little bearing on clinical outcome. Development of acquired resistance to teicoplanin in the 8 patients with persistently positive cultures was not observed. ADVERSE CLINICAL REACTIONS

Of 38 evaluable teicoplanin iv patients, 2 (5 percent) had adverse reactions, I of which was considered to be definitely related to teicoplanin (Table 3). This patient experienced transient urticarial rash, dizziness, and dyspnea shortly after his first dose of the drug. Another patient died from respiratory arrest during the study, attributed to documented aspiration of large pieces of meat; the arrest was not considered to be related to teicoplanin therapy. Of the 37 teicoplanin im patients evaluable for toxicity, 8 (22 percent) had adverse reactions; 4 were considered to be definitely drug related (Table 3). One patient developed chills and fever lasting two hours after his first dose of teicoplanin iv; he then was dropped from the study. Three other patients developed pain at the site of injection, 2 of 916 •

Table 3. Clinical and Microbiologic Responses and Adverse Reactions in Patients Treated with Teicoplanin PATIENTS RECEIVING TEICOPLANIN (%) OUTCOME

iv

Clincial response cure improvement failure recurrence Microbiologic response cure persistence superinfection Adverse clinical and laboratory results"

34 29 (85) 4 (12) 0 1(3) 30 30 (100) 0 0 4/38 (l1)b

im

28 23 (82) 3 (10) 2 (7) 0 22 14(64) 8 (36)" 0 8/37 (22)