Cefsulodin Therapy for Osteomyelitis Due to Pseudomonas aeruginosa

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1 REVIEWS OF INFECTIOUS DISEASES VOL. 6, SUPPLEMENT SEPTEMBER-OCTOBER by The University of Chicago. All rights reserved /84/ $02.00 Cefsulodin Therapy for Osteomyelitis Due to Pseudomonas aeruginosa John C. Pottage, Jr., Peter H. Karakusis, and Gordon M. Trenholme From the Section of Infectious Disease, Department of Medicine, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois The results of treating chronic Pseudomonas aeruginosa osteomyelitis with cefsulodin at Rush-Presbyterian-St. Luke's Medical Center (RPSLMC) and eight other institutions are summarized. Eleven patients whose infections were proven by bone-biopsy culture were treated with cefsulodin at RPSLMC; one received two courses of treatment. Efficacy oftherapy was evaluated for eight patients, all of whom had a polymicrobial infection. The average age of the patients was 52. years (range, 28-85). All had serious underlying illnesses or associated conditions. The mean inhibitory concentration of cefsulodin for the isolates ofp. aeruginosa was.25 ug/rnl (range, O /-lg/ml). Two patients received concomitant therapy with antibiotics not active against P. aeruginosa. Surgical debridement was performed in six of the eight patients. A favorable response was demonstrated in six of the eight patients. Follow-up for seven patients ranged from one week to 2 months, and in the eighth patient follow-up was 2 months. One patient relapsed twice. Seven possible complications of therapy were observed in five of the patients who received cefsulodin; in three of these patients cefsulodin had to be discontinued. In studies of osteomyelitis conducted at other institutions, 0 of 4 patients for whom therapy could be evaluated had a favorable response to cefsulodin. Cefsulodin is a useful agent for the treatment of chronic osteomyelitis associated with P. aeruginosa. The therapy for osteomyelitis due to Pseudomonas aeruginosa presents a challenge. Despite extensive tissue debridement and prolonged antibiotic therapy, treatment is often ineffective or associated with drug-related toxicity. Aminoglycoside antibiotics used either with or without penicillins active against P. aeruginosa have been used most frequently for the treatment of this disease. Results of recent studies evaluating the efficacy of several third-generation cephalosporins for the treatment of infections due to P. aeruginosa have been disappointing [-]. This report summarizes our experience with cefsulodin, a new cephalosporin with selective in vitro activity against P. aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis [, 4], in the therapy for osteomyelitis due to P. aeruginosa. Results of similar studies by eight other investigators also are summarized. Materials and Methods The diagnosis of osteomyelitis due to P. aerugi- Please address requests for reprints to Dr. Gordon M. Trenholrne, Section of Infectious Disease, Department of Medicine, Rush-Presbyterian-St. Luke's Medical Center, 75 West Congress Parkway, Chicago, Illinois nosa was based on roentgenographic and/or bonescan evidence of infection in addition to the isolation of this pathogen from bone-biopsy specimens. Osteomyelitis was considered chronic if the patient had evidence of disease for more than three months. Antimicrobial susceptibility testing of isolates was performed by the broth-dilution method utilizing tryptic soy broth. Each patient was hospitalized. Informed consent was obtained from the patient or closest relative. Parameters assessed before therapy included a complete history, physical examination, and blood and platelet count; urinalysis; and determination of levels of blood urea nitrogen, serum creatinine, total bilirubin, total protein, albumin, glucose, alkaline phosphatase, alanine aminotransferase (SGPT), aspartate aminotransferase (SGOT), and cholesterol. These studies were repeated at least weekly and upon completion of therapy. Cefsulodin was administered by iv infusion in three or four divided doses per day. The total daily dosage was adj usted according to the renal status of the patient and was usually 8 g per day. The response of patients to treatment with cefsulodin was classified as satisfactory or unsatisfactory. A satisfactory response was defined as amelioration of the signs and symptoms of osteomyelitis during Downloaded from at Penn State University (Paterno Lib) on April 8, 206 S728

2 Cefsulodin for P. aeruginosa Osteomyelitis S729 therapy. An unsatisfactory response was defined as a. lack of improvement, persistent growth of P. aeruginosa on repeat culture, or relapse of bone infection. Patients were excluded from the analysis of efficacy if they received concomitant therapy with an antibiotic active against P. aeruginosa, were treated with cefsulodin for less than seven days, had an organism isolated that was resistant to cefsulodin, or had malignant external otitis with osteomyelitis of the temporal bone. Toxicity was evaluated for all patients who received cefsulodin. A computerized summary of pertinent data on patients treated by other investigators was available for review. The investigators and their respective hospital affiliations are as follows: Dr. Nelson Gantz, University of Massachusetts Medical Center, Worcester, Mass.; Dr. Joseph F. John, Medical University of South Carolina, Charleston, S.C.; Dr. Peter P. McKellar, Good Samaritan Hospital, Phoenix, Ariz.; Dr. Burt Meyers, Mt. Sinai Hospital, New York, N.Y.; Dr. William J. Mogabgab, Tulane University School of Medicine, New Orleans, La.; Dr. Harold Neu, Columbia Presbyterian Medical Center, New York, N.Y.; Dr. Richard Platt, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass.; Dr. Joel Spalter and Dr. Nelson Zide, Memorial Hospital, Hollywood, Fla.; and Dr. Richard P. Wenzel, University of Virginia Medical Center, Charlottesville, Va. In most instances the original case reports also were examined. Results Rush-Presbyterian-St. Luke's Medical Center. Eleven patients with osteomyelitis associated with P. aeruginosa received 2 courses of cefsulodin. All patients had chronic osteomyelitis. Three patients were excluded from the analysis of efficacy. One of these patients received cefsulodin after four weeks of tobramycin therapy. The aminoglycoside was discontinued because of ototoxicity and progressive azotemia. The patient had a satisfactory response to cefsulodin therapy. Another patient, who had osteomyelitis due to Achromobacter xylosoxidans and P. aeruginosa, was excluded from evaluation because the isolate of A. xylosoxidans was resistant to cefsulodin. The patient had a satisfactory response to gentamicin. The third patient had malignant external otitis, temporal-bone osteomyelitis, and a jugular foramen syndrome, which had progressed despite therapy with tobramycin and ticarcillin. Subsequently she was treated with tobramycin and cefsulodin for 0 days but died after neurosurgical debridement of the basilar osteomyelitis. Eight patients were included in the analysis ofefficacy. The associated conditions in these patients are listed in table. There were six men and two women. The mean age of patients was 52. years (range, years). For four patients, prior therapy with antibiotics active against P. aeruginosa had failed. Patients received 4-2 g of cefsulodin per day (median, 8 g per day). The median duration of therapy was 4 days (range, 7-42 days). Two patients received concomitant therapy with antibiotics not active against P. aeruginosa. One patient received ampicillin; the other received clindamycin. Six (75070) of the eight patients had a satisfactory response to cefsulodin therapy (table 2). In four patients, P. aeruginosa was the only organism that grew in bone cultures; P. aeruginosa was eradicated in two of these patients. Bone cultures for the remaining four patients grew additional organisms; in these cases, cefsulodin therapy resulted in a satisfactory response. The two patients who had unsatisfactory responses to cefsulodin had both failed to respond to prior therapy with gentamicin. The first patient (table 2; patients 2A and 2B) had osteomyelitis of the left tibia. After six weeks of cefsulodin therapy, the patient improved and cultures of wound specimens were sterile. Three months later, the patient relapsed. Cultures of bone specimens revealed P. aeruginosa susceptible to cefsulodin (MIC,.56 g/ml). A second six-week course of cefsulodin was instituted. Despite apparent improvement, Table. Associated conditions in eight patients from Rush-Presbyterian-St. Luke's Medical Center. Condition Diabetes mellitus Organic heart disease Peripheral vascular disease Compound fracture Postoperative state Alcoholism Peripheral neuropathy Pituitary adenoma No. of patients 2 2 Downloaded from at Penn State University (Paterno Lib) on April 8, 206

3 Table 2. Summary of data for eight patients with chronic osteomyelitis due to Pseudomonas aeruginosa who were treated with cefsulodin at Rush-Presbyterian-St. Luke's Medical Center. Patient no. Site of infection Cefsulodin Prior antibiotic MIC Dosage Duration Other Concomitant Surgical therapy (J.tg/ml) (g/day) (days) microorganisms antibiotics therapy Outcome* Length of follow-up 2A 2B Right first phalanx of foot Left calcaneus Left first metatarsal.and phalanx of left foot Sternum Clindamycin Cefsulodin Amikacin Tobramycin Ticarcillin Cefotaxime Ceftazidime Proteus mirabilis Ampicillin Enterococci Staphylococcus aureus, Staphylococcus epidermidis 8 26 S. epidermidis 8 42 S. epidermidis and muscleflap reconstruction and omental flap and skin-graft placement Unsatisfactory Unsatisfactory Unsatisfactory week months (relapse) 4 months (relapse) o months months 2 months 2 months months 2 months * See Materials and Methods for definitions of responses. CIl -.) w o ;0;- r;;. l::l ::: ::: c " :> Downloaded from at Penn State University (Paterno Lib) on April 8, 206

4 Cefsulodinfor P. aeruginosa Osteomyelitis S7 Table. Possible complications ofcefsulodin therapy in patients from Rush-Presbyterian-St. Luke's Medical Center. Complication Renal failure Nausea Parasthesias Elevated transaminase levels Eosinophilia No. of patients bone infection recurred four months after completion of therapy. The second patient with an unsatisfactory response (table 2; patient ) had osteomyelitis of the left calcaneus. After two weeks of cefsulodin therapy, the patient died of a myocardial infarction. An antemortem culture of a specimen from the sinus tract grew P. aeruginosa. Seven possible complications of therapy were noted in five of the patients who received cefsulodin (table ). In three patients complications necessitated discontinuation of the drug. Cefsulodin was discontinued in a patient with osteomyelitis of the left tibia who developed paresthesias in all extremities during infusion of the antibiotic. The antibiotic also was discontinued in two of three patients who developed renal failure during treatment. One of these patients (table 2; patient ) was a 60-year-old man with diabetes mellitus and severe peripheral vascular disease who developed nonoliguric renal failure while being treated for osteomyelitis of the right great toe. The patient received 4 g of cefsulodin per day in conjunction with large doses of furosemide. Cefsulodin therapy was discontinued when the patient's serum creatinine level rose to 5 mg/dl. Examination of the urinary sediment did not reveal eosinophils or casts. One week after cefsulodin therapy was discontinued the patient died of a ventricular arrhythmia. The second patient (table 2; patient ) was an 82-year-old man who developed nonoliguric renal failure while receiving cefsulodin for treatment of osteomyelitis of the left heel. This patient had received gentamicin immediately before receiving cefsulodin, and his serum creatinine level had risen to.2 mg/dl by the time cefsulodin therapy was started. Cefsulodin therapy was discontinued after 4 days of therapy, at which time the patient's serum creatinine level had reached 5.2 mg/dl. A count of eosinophils in urine was not performed, I but urinalysis indicated proteinuria and pyuria. One day after cessation of cefsulodin therapy, the patient had a fatal myocardial infarction. Another patient, who was not included in the analysis of efficacy, developed nonoliguric renal failure while receiving cefsulodin for osteomyelitis of the right tibia. Before receiving treatment with cefsulodin, she had received tobramycin for four weeks; the aminoglycoside was discontinued because of increasing azotemia (serum creatinine level,.8 mg/dl) and ototoxicity. Cefsulodin (8 g per day) was administered for two weeks to complete the prescribed six-week course of antibiotic therapy. During treatment, the patient's serum creatinine level rose to 5.5 mg/dl. After cefsulodin therapy was completed, serum creatinine levels gradually returned to base-line levels. Urinalysis during cefsulodin therapy revealed minimal proteinuria and three to four hyaline casts per highpower microscopic field. Case reports from multicenter study. Sixteen patients with P. aeruginosa osteomyelitis were treated by investigators at other institutions. One of these patients received two courses of cefsulodin therapy. Two patients were excluded from the analysis of efficacy because either pretreatment cultures were negative or only six days of cefsu Iodin therapy were given. For fourteen patients (0 men and four women), clinical efficacy was evaluated. Their median age was 44.8 years, with a range of -82 years. All patients had associated conditions. The median therapeutic dose of cefsulodin was 6 g per day (range, 2-8 g per day), and the median MIC of cefsulodin for P. aeruginosa was. ug/rnl (range, ug/rnl). The median duration of therapy was 7 days (range, 9-20 days). Five patients received concomitant therapy with antibiotics not active against P. aeruginosa. Ten (79070) of 4 patients whose treatment could be evaluated had a satisfactory response to cefsu Iodin. In eight of these patients, a bacteriologic diagnosis of P. aeruginosa osteomyelitis was predicated on the basis of results of cultures of wound or sinus tract specimens alone. In the remaining two patients, P. aeruginosa was isolated from bone-biopsy specimens. One of these patients acquired a superinfection with Pseudomonas maltophilia that required concomitant therapy with trimethoprim-sul famethoxazole. Downloaded from at Penn State University (Paterno Lib) on April 8, 206

5 S72 Pottage, Karakusis, and Trenholme Four patients had unsatisfactory responses to cefsulodin. In two of these patients, therapy was based on results of cultures of sinus tract specimens alone, and in the third patient, P. aeruginosa osteomyelitis was documented by bonebiopsy cultures. In the latter case, P. aeruginosa persistently grew from a draining sinus tract, despite extensive surgical debridement and a sevenmonth course of cefsulodin. The patient subsequently was treated with a five week course of cefsulodin and ticarcillin. P. aeruginosa was isolated from sinus tract drainage after completion of therapy. The fourth patient received 8 days of cefsu Iodin for osteomyelitis of the distal tibia proven by bone-biopsy culture. Therapy was terminated because the patient decided to undergo amputation. Cultures of the wound at the end of the therapy grew P. aeruginosa. Six possible adverse reactions to cefsulodin occurred in five patients. These included diarrhea (one patient), elevation of transaminase level (one), eosinophilia (one), Coombs-positive hemolytic anemia (one), thrombocytopenia (one), and azotemia (one). Cefsulodin therapy was terminated in one patient who had chronic osteomyelitis of the right index finger. After six days of therapy with cefsulodin and nafcillin the patient's creatinine level rose to 2 mg/dl. Urinalysis revealed proteinuria but no eosinophils or casts. The patient's creatinine level returned to normal five days after discontinuation of therapy with cefsulodin and nafcillin. Discussion Osteomyelitis due to P. aeruginosa is commonly associated with penetrating trauma, compound fractures, previous surgery, and parenteral drug addiction [5]. In most instances, infection is insidiously progressive. Effective treatment for P. aeruginosa osteomyelitis includes radical surgical excision of necrotic bone and prolonged treatment with parenteral antibiotics. Despite medical and surgical therapy, many patients with bone infections due to P. aeruginosa relapse. Suppressive oral antibiotics are not available for the treatment of this infection. This report examined the effectiveness of cefsu Iodin alone in the treatment of osteomyelitis proven to be due to P. aeruginosa by results of bone-biopsy culture. In studies carried out at Rush-Presbyterian-St. Luke's Medical Center, isolation of P. aeruginosa from wound or sinus tract specimens was not considered adequate proof of bone infection with this organism. If these criteria are applied to the overall study, only four patients can be included in the assessment. Thus, if the overall study is combined with our study, eight of 2 patients with osteomyelitis proven by bonebiopsy culture had a satisfactory response to therapy. Two of these patients had complications associated with administration of cefsulodin that necessitated discontinuation of therapy. Four patients who had P. aeruginosa isolated from bone specimens had unsatisfactory responses to cefsu Iodin. In three of these patients, the necrotic bone could not be adequately resected, a difficulty that resulted in persistent or relapsing infection. Two patients with satisfactory responses underwent microvascular transfer of tissue that utilized muscle flaps, a procedure shown to be helpful in the treatment of chronic osteomyelitis [6]. We pooled our experience with that of other medical centers to evaluate adverse reactions. Possible complications of therapy occurred in 0 of 27 patients who received cefsulodin therapy for P. aeruginosa osteomyelitis. Treatment with cefsu Iodin had to be discontinued in four patients. Four patients developed reversible azotemia or nonoliguric renal failure; none had eosinophiluria. It is of interest that the molecular structure of cefsulodin is similar to that of cephaloridine; both have a pyridine side chain at the -position ofthe cephalosporanic acid nucleus []. While cephaloridine has been implicated in the development of acute tubular necrosis during therapy, no association between the presence of the pyridine side chain and renal failure has been documented. There is a paucity of data on the therapy of chronic P. aeruginosa osteomyelitis, and followup information in many studies has often been inadequate. The latter criticism can be applied to the results of the series we have summarized, which is one of the largest of its kind in which a single therapeutic agent was employed for treatment of chronic bone infection due to P. aeruginosa. These results suggest that cefsulodin is a useful agent in the treatment of patients with osteomyelitis associated with P. aeruginosa. Prolonged follow-up of patients is needed before the true efficacy of cefsu- Downloaded from at Penn State University (Paterno Lib) on April 8, 206

6 Cefsulodinfor P. aeruginosa Osteomyelitis S7 Iodin can be known. A possible relationship between the use of cefsulodin and development of renal insufficiency requires clarification. References. Neu He. The new beta-lactarnase-stable cephalosporins. Ann Intern Med 982;97: Karakusis PH, Feczko JM, Goodman LJ, Hanlon OM, Harris AA, Levin S, Trenholme GM. Clinical efficacy of cefotaxime in serious infections. Antimicrob Agents Chemother 982;2: Mathisen GE, Meyer RD, Thompson JM, Finegold SM. Clinical evaluation of moxalactam. Antimicrob Agents Chemother 982;2: Smith OJ, Kaplan RL, Landau W l Trenholme GM. Speciation and antibiotic susceptibility patterns of coagulase negative staphylococci. Eur J Clin Microbiol 982;: Bodey GP, Bolivar R, Fainstein V, Jadeja L. Infections caused by Pseudomonas aeruginosa. Rev Infect Dis 98;5: May JW Jr, Gallico GG III, Lukash FN. Microvascular transfer of free tissue for closure of bone wounds of the distal lower extremity. N Engl J Med 982;06:25-7 Downloaded from at Penn State University (Paterno Lib) on April 8, 206