Moxalactam in the Therapy of Serious Infections

Transcription

1 ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Apr. 1982, p Vol. 21, No /82/ $02.00/0 Moxalactam in the Therapy of Serious Infections R. L. MARIER,* S. FARO, C. V. SANDERS, W. WILLIAMS, F. DERKS, A. JANNEY, AND K. ALDRIDGE Louisiana State University Medical Center, New Orleans, Louisiana Received 13 August 1981/Accepted 25 January 1982 Sixty-seven patients were treated with moxalactam in a noncomparative trial of hospitalized patients; 32 had endometritis or chorioamnionitis, 12 had skin and soft tissue infections, 5 had osteomyelitis, 5 had pneumonia, 5 had urinary tract infections, 4 had arthritis, 2 had sepsis from an unknown source, 1 had endocarditis, and 1 had peritonitis. Bacteremia was present in 12 of these patients. Patients were given 3 to 12 g of moxalactam per day (mean, 6.24 g/day) in divided doses every 6 to 8 h. Seven patients were given intramuscular treatment for 3 to 20 days for part or all of their therapy. The rest were given intravenous treatment exclusively. Treatment was continued for 2 to 42 days (mean, 10 days). The dose and the duration of therapy were determined by the type of infection and the response of each patient. There were four treatment failures and one enterococcal-clostridial superinfection. Moxalactam was well tolerated. Allergic reactions led to the discontinuation of the antibiotic in three patients. Prolonged prothrombin and partial thromboplastin times were observed in 2 of 11 patients tested; in both instances the patients had severe underlying diseases, including malnutrition and alcoholism. Pain on intramuscular injection was noted in two patients receiving 1,500 mg, but not in five receiving a lower dose; in one case the pain forced the use of intravenous therapy after one dose, and in the other case the pain was mild and the patient was treated for 20 days. We concluded that moxalactam was effective in the treatment of the types of infections included in this study and produced few adverse reactions. Moxalactam is a new oxa-p-lactam derivative with a wide spectrum of activity (2, 4, 6, 11, 12; F. Gudiol, X. Ariza, J. Linares, and C. Dominguez, Program Abstr. Int. Congr. Chemother. 12th, Florence, Italy, abstr. no. 911, 1981). It is more active than presently available cephalosporins against a variety of aerobic gram-negative rods. The present study was designed to determine the safety and efficacy of moxalactam in the treatment of hospitalized patients with serious infections. MATERIALS AND METHODS Antibiotic. Moxalactam was supplied by Eli Lilly & Co Ṡusceptibility testing. Disk susceptibility testing for all aerobic isolates was performed with 30-,ug disks of moxalactam by the method of Bauer et al (3). In addition, the minimum inhibitory concentrations (MICs) of moxalactam for some isolates were determined by the microtiter broth dilution method (5). Calcium- and magnesium-supplemented Mueller-Hinton broth was used for the MIC testing with an inoculum size of 101 colony-forming units per ml. For streptococcal MICs the broth was supplemented with lysed horse blood. We determined minimal bactericidal concentrations by removing a sample of broth from every well showing no visible growth and inoculating it 650 onto sheep blood agar (5). All plates were incubated for 48 h at 35 C. For anaerobic isolates the MICs were determined in groups of 20 by the agar dilution technique (7). Serial twofold dilutions (256 to 0.125,ug/ml) were prepared in Brucella agar (Difco Laboratories) supplemented with 5% sheep blood and vitamin K. All plates were reduced anaerobically overnight before inoculation. Each isolate was inoculated in duplicate onto plates with a Steers replicating device delivering approximately 105 colony-forming units to the agar surface. The plates were placed in an anaerobic chamber for 48 to 72 h at 35 C. MICs for gonococcal isolates were determined by the agar dilution technique in protease no. 3 agar supplemented with 1% hemoglobin and IsoVitaleX (BBL Microbiology Systems). Staphylococcus aureus (ATCC 29213), Escherichia coli (ATCC 25922), and laboratory strains of Bacteroides melaninogenicus subsp. melaninogenicus and Clostridium perfringens were used as controls. For interpretation, organisms with an MIC of.64,ug/ml or a zone size of <14 mm were considered resistant to moxalactam. Clinical studies. Patients included in the study were adults hospitalized at the Charity Hospital of New Orleans, New Orleans, La. Material obtained from the endometrium, skin or soft tissue site, bone, joint fluid, blood, and sputum were cultured aerobically and anaerobically for all patients before entry into the study. Urine cultures with colony counts of 2105/ml in clean catch voided urine were considered positive for

2 VOL. 21, 1982 MOXALACTAM THERAPY 651 TABLE 1. Case summaries Treatment Infection patientsa Dose (g/day) Duration (days) Mean Range Mean Range Endomyometritis/choriamnionitis 32 (6) Skin/soft tissue infection 12 (1) Osteomyelitis Arthritis Pneumonia Urinary tract infection 5 (2) Sepsis-source unknown 2 (2) Endocarditis 1 (1) 6 28 Peritonitis a Numbers in parentheses indicate bacteremic patients. urinary tract infection. In patients with urinary tract infection, repeat cultures were obtained 5 to 9 days after the completion of therapy. In patients with bacteremia, repeat cultures were obtained 2 to 4 days after the beginning of therapy and 1 to 2 days after the completion of therapy. Other pretreatment studies included complete blood count, platelet estimate, direct Coombs test, renal function test, liver function studies, and urinalysis. These studies were repeated every 4 to 7 days during treatment and 1 to 3 days posttreatment. Criteria for judging responses. We defined clinical cure as findings resolved with no evidence of infection at the time treatment was discontinued and during the follow-up period. We defined clinical failure as an unsatisfactory clinical response. Superinfection was the appearance of a new pathogen associated with signs and symptoms of a new infection at any site. RESULTS Of 82 patients entered into this study, 15 were considered non-evaluable; 9 of these showed no pretreatment pathogen, 1 yielded inadequate data, 1 required premature termination due to adverse experience, 1 had a resistant pretreatment isolate, and 3 had received concomitant administration of other antibiotics. The adverse experience occurred in a patient with chronic osteomyelitis secondary to infection with Alcaligenes faecalis, Staphylococcus epidermidis and B. melaninogenicus. The patient received 2 g of moxalactam intravenously (i.v.) every 8 h (q8h). On day 7 he developed a rash and fever, and the moxalactam was discontinued. He was improving at this time. The resistant pretreatment isolate was recovered from a patient with Pseudomonas aeruginosa osteomyelitis. The patient was begun on 3 g of moxalactam i.v. q8h at the time of surgical debridement. On day 2 the moxalactam was discontinued, when a resistant P. aeruginosa strain (MIC, 64,ug/ml) was identified in the bone specimen. The patient was not responding clinically at this time. We considered 67 patients to be evaluable. There were 17 males and 50 females. Age ranged from 16 to 88 (median, 25 years). Infection diagnosis and treatment are summarized in Table 1. A total of 32 patients had endometritis or chorioamnionitis. These infections followed Cesarean sections or premature rupture of the membranes. Clinical diagnosis was based on fever, uterine tenderness, and, in some cases, foul-smelling vaginal discharge. Bacteriological diagnosis was based on cultures of endometrium, amniotic fluid, vaginal discharge, or peritoneal fluid. Bacteria isolated from these patients included 83 aerobes and 67 anaerobes. The leading aerobic isolates were group B streptococci (5 isolates), enterococci (5 isolates), and other streptococci (20 isolates). The leading anaerobic isolates were B. melaninogenicus (14 isolates) and other Bacteroides species (30 isolates). Six patients were bacteremic. Blood culture isolates included two of streptococci, two of peptococci, one of Sarcina ventriculi, and one of Fusobacterium sp. There was an average of two anaerobic and two aerobic isolates per patient. All patients were treated with 2 g of moxalactam i.v. q8h except for two who received 1 g intramuscularly q8h. Treatment was continued for 3 to 8 days (mean, 5.8 days). There were 31 clinical cures and 1 failure. The failure was a 36- year-old female with endometritis. Endometrial cultures were positive only for diphtheroids. There was no response to moxalactam (3 g/day for 5 days). Persistence of lower abdominal pain led to discontinuation of moxalactam and treatment with other antibiotics and subsequent slow recovery. A total of 12 patients had skin or soft tissue infections. Of these, six had cellulitis, two had soft tissue abscesses, one had a decubitus ulcer with sepsis, one had periorbital cellulitis, one had fasciitis, and one had a wound infection. These infections were caused by group A betahemolytic streptococci (five isolates), S. aureus

3 652 MARIER ET AL. (four isolates), Proteus mirabilis (three isolates), non-a, non-b, non-d streptococci (three isolates), and one isolate each of Klebsiella pneumoniae, E. coli, P. aeruginosa, Peptococcus magnus, and Peptostreptococcus anaerobius. Three of these patients had diabetes mellitus. Alcoholism or illicit-drug abuse or both were present in three patients as well. These patients received 1 to 2 g of moxalactam i.v. q8h each day for 2 to 41 days (mean, 9.3 days). The patient treated for 41 days was a diabetic with a severe polymicrobial infection of the foot. All patients were clinically cured except for an 88- year-old female with diabetes mellitus who had a group A streptococcal (zone, 23 mm; MIC, 4,ug/ ml) fasciitis. The patient was started on 2 g of moxalactam i.v. q6h. Progression of the infection led to extensive surgical debridement 2 days after the start of therapy. At this time the moxalactam was discontinued, and the patient was started on penicillin G. Repeat cultures remained positive. The failure of this patient to respond to treatment was attributed in part to inadequate surgical management. There were five patients with osteomyelitis; all had chronic infection and were managed with a combination of surgical debridement and antibiotics. Isolates included one of Serratia marcescens, one ofe. coli, one ofacinetobacter calcoaceticus, one of P. mirabilis, and two of P. aeruginosa. The moxalactam dose in these cases was 6 to 12 g/day (mean, 8.6 g/day) given i.v. in divided doses every 6 to 8 h for 28 to 42 days (mean, 39.4 days). All patients were cured clinically. Four patients had gonococcal arthritis. They were given 1 to 2 g of moxalactam i.v. q8h for 6 to 10 days (mean, 8 days). All of these patients were cured clinically. Five patients had pneumonia. Two patients with pneumococcal infection were treated with 3 g of moxalactam per day for 7 and 14 days, respectively, and cured. One patient with pneumococcal (MIC, 2,ug/ml; zone, 26 mm) pneumonia failed to respond to therapy. He was a 74- year-old male with chronic obstructive pulmonary disease, congestive heart failure, and extensive pneumonia. On admission he was begun on 2 g of moxalactam i.v. q8h. He died 3 days later of progressive respiratory failure. At autopsy, extensive pneumonia was identified. No cultures were obtained. There was one patient with lung abscess and empyema. B. melaninogenicus, Bacteroides oralis, P. mirabilis, group A beta-hemolytic streptococci, and a non- A, non-b streptococci were isolated from empyema fluid. He was given 3 g of moxalactam i.v. q8h for 28 days and underwent chest tube drainage. His infection was cured. Finally, there was a 32-year-old male with hypertension, status post-cerebrovascular accident with pneumonia ANTIMICROB. AGENTS CHEMOTHER. secondary to infection with P. mirabilis (zone, 30 mm; MIC, 32,ug/ml), P. aeruginosa (zone, 17 mm; MIC, 16,ug/ml), and S. marcescens (zone, 26 mm; MIC, 4,ug/ml). He was started on 2 g of moxalactam i.v. q8h. He died unexpectedly 4 days later. Autopsy revealed extensive pneumonia. Cultures were not obtained from the lungs at the time of death. There were five patients with urinary tract infections. Two were bacteremic. These two patients were given 1 and 2 g of moxalactam i.v. q8h for 12 and 14 days, respectively. The patients without bacteremia were given 1 g of moxalactam i.v. q8h for 7 to 14 days. Urine isolates included E. coli in four cases and E. coli and Hafnia alvei in one case. Follow-up urine cultures 5 to 9 days later were negative in all patients. There were two patients with bacteremia from an unknown source. One of these patients had metastatic hepatocellular carcinoma. K. pneumoniae was isolated from the blood over a 3-day period. The patient continued to be bacteremic on penicillin G and tobramycin. He was treated with 4 g of moxalactam i.v. q8h for 8 days. Follow-up blood cultures were negative. The second patient was a 64-year-old paraplegic with multiple chronic severe decubiti and bacteremia secondary to S. epidermidis infection (MIC, 16,ug/ml). Multiple blood cultures were positive. He was treated with 2 g of moxalactam i.v. q8h for 21 days. At this time he developed signs of sepsis. Enterococcus (MIC, >128,ug/ml) and Clostridium tertium (MIC, 8,ug/ml) were isolated from the blood. The patient was switched to ampicillin and recovered. The patient with endocarditis had multiple blood cultures positive for S. aureus (MIC, 2,ug/ ml). She was a 17-year-old with mental retardation and possible rheumatic heart disease. She was treated with 2 g of moxalactam i.v. q8h for 28 days. Follow-up blood cultures 2 and 6 months after the completion of therapy were negative. The patient with peritonitis had mixed flora, including an enterococcus, non-a, non-b, non-d streptococci, P. aeruginosa, Klebsiella oxytoca, Bacteroides fragilis, Fusobacterium nucleatum, and Veillonella spp., isolated from peritoneal fluid. The infection followed rupture of a retrocecal appendix. He was treated with surgical drainage and 4 g of moxalactam i.v. q8h for 11 days, with complete resolution of the infection. The results of susceptibility testing are shown in Table 2. An MIC of.64 (resistant) was seen in 6 of 125 (5%) isolates tested. The resistant anaerobes were all isolated from endometritis cases as part of mixed flora. All of these patients were cured clinically. The resistant S. aureus was isolated from a patient with periorbital cellulitis. Aspirates of material from this area

4 VOL. 21, 1982 MOXALACTAM THERAPY 653 TABLE 2. Susceptibility to moxalactam Total No. of isolates with MIC (p.g/ml) of: Isolate no. of isolates s Aerobes Group A streptococci Enterococcus 1 1 Streptococcus pneumoniae Other streptococci Staphylococcus aureus Staphylococcus epidermidis 1 1 Escherichia coli Proteus mirabilis Pseudomonas aeruginosa 5 5 Klebsiella pneumoniae Hafnia alvei 1 1 Eikenella corrodens 1 1 Serratia marcescens Acinetobacter sp. 1 1 Neisseria gonorrhoeae 2 2 Klebsiella oxytoca 1 1 Anaerobes Bacteroides melaninogenicus Bacteroides capillosus Bacillus brevis Bacteroides distasonis 1 1 Bacteroides furcosus 1 1 Bacteroides oralis 2 2 Bacteroides fragilis Bacteroides spp. other Capnocytophaga sp. 2 2 Peptococcus spp. 8 8 Peptostreptococcus spp Sarcina ventriculi 2 2 Fusobacterium spp Gaffkya spp. 6 6 were positive for K. pneumoniae, E. coli, group A streptococci, and the resistant S. aureus. The patient was treated with 2 g of moxalactam i.v. q8h for 11 days and was cured clinically. The susceptibility of aerobic isolates from the patients with endometritis and chorioamnionitis was measured by disk diffusion testing only. A zone of inhibition of <14 mm (resistant) was seen in 5 of 63 (8%) isolates tested. All of these resistant isolates were enterococci. They were isolated as part of mixed endometrial flora. All of the patients were cured. A zone of inhibition of 15 to 17 mm (intermediate) was seen in 2 of 63 (3.1%) isolates tested. These isolates included a Streptococcus strain and an S. epidermidis strain. A zone of inhibition of.18 mm (susceptible) was seen for the remaining isolates, iricluding P. mirabilis (6 isolates), E. coli (5 isolates), K. pneumoniae (2 isolates), P. aeruginosa (2 isolates), Enterobacter cloacae (1 isolate), H. alvei (1 isolate), group B streptococci (5 isolates), other streptococci (18 isolates), and S. epidermidis (16 isolates). Adverse experiences were minor. Of 82 patients receiving moxalactam (evaluable and nonevaluable cases), 7 (9%) had mild to moderate thrombophlebitis 1 to 34 days after beginning i.v. moxalactam. Information about the types of i.v. lines and duration of i.v. placement before the appearance of thrombophlebitis is not available. Three patients developed rashes which necessitated the discontinuation of the study drug. Two of seven (29%) patients receiving i.m. treatment for 3 to 20 days as part or all of their therapy developed some pain at the injection site. Both of these patients received 1,500 mg of moxalactam i.m. q8h. No pain was noted in patients receiving lower i.m. doses of moxalactam. In one case the pain forced the use of i.v. therapy after one i.m. dose. Prolonged prothrombin and partial thromboplastin times were observed in 2 of 11 patients tested. Both of these patients had severe underlying diseases, including malnutrition and renal failure. Both patients received 2 g of moxalactam i.v. q8h, and the abnormalities appeared 10 and 11 days, respectively, after the institution of therapy. The incidence of abnormal clotting cannot be ascertained, however, since studies were not obtained on all patients. Minimal increases in

5 654 MARIER ET AL. serum glutamic oxalacetic transaminase were observed in two patients 3 and 7 days after the institution of therapy with 2 g of moxalactam i.v. q6h and 4 g i.v. q8h, respectively. In neither case did the abnormalities lead to a discontinuation of therapy. Finally, there was one patient with pyelonephritis treated with 1 g of moxalactam i.v. q8h who developed anemia (hematocrit falling from 31.9 to 21.6), leukocytosis (leukocyte count rising from 14.7 to 20.7), and monocytosis (monocytes rising from 0 to 8%) 5 days after the institution of therapy. Hemoglobin electrophoresis, direct Coombs test, and haptoglobin results were all within normal limits. There was no eosinophilia. The treatment was discontinued for these reasons, with subsequent improvement in these abnormalities. One of the patients with liver function abnormalities developed eosinophilia 19 days after beginning therapy with 2 g of moxalactam i.v. q6h for mixed aerobic (A. calcoaceticus and P. mirabilis) osteomyelitis. Moxalactam was not discontinued. The patient completed 40 days of therapy. Subsequently, the eosinophilia and minimal abnormalities of the serum glutamic oxalacetic transaminase resolved. DISCUSSION The results of the present study indicate that moxalactam is effective in the therapy of a variety of serious infections, as has been noted by others (8-10; A. Lentnek, Abstr. Int. Cong. Chemother. 12th, Florence, Italy, abstr. no. 917, 1981). Moxalactam was active against most isolates recovered from these patients. MICs were 264,ug/ml (resistant) for 6 of 125 (5%) isolates tested. Emergence of resistance on therapy was not observed. In general, moxalactam was well tolerated. There were two patients with prolonged prothrombin times, both of whom had severe underlying diseases. Prolonged prothrombin times with or without clinically apparent bleeding have been observed by others in the present clinical trials of moxalactam and have been attributed to biliary excretion of moxalactam with suppression of gastrointestinal flora which synthesize vitamin K (N. U. Band, S. S. Tessler, R. L. Heindenreich, C. A. Marks, and L. E. Mattler, Moxalactam Symp., London, abstract, 1981). This phenomenon has been associated with general debility, malnutrition, liver or biliary duct disease, coagulopathies, and severe reduced renal function which leads to excessive serum ANTIMICROB. AGENTS CHEMOTHER. levels. The prophylactic administration of vitamin K to high-risk patients has been recommended by the Lilly Research Laboratories (personal communication). There was one patient with enterococcal and clostridial superinfection. Enterococcal superinfection has been noted by others in the present clinical trials of moxalactam (11, 12; R. C. Moellering, Jr., Moxalactam Symp., London, abstract, 1981). Enterococci are resistant to moxalactam and all cephalosporins and may cause superinfection in patients treated with any of these antibiotics. The overall risk, based on preliminary data, is low. We conclude that moxalactam is an effective and safe antibiotic and can be used in a variety of serious infections. ACKNOWLEDGMENTS We acknowledge the financial support of Eli Lilly & Co. We also acknowledge the administrative and technical support of P. Moise, V. Pirolozzi, D. Schiro, L. Shaik, D. Martin, and J. Mitchell and the cooperation of the nursing and medical services of the Charity Hospital of New Orleans, with special thanks to S. Wolfs. LITERATURE CITED 1. Bartlett, J. G Therapeutic trial of moxalactam in intraabdominal sepsis and gynecological infections, p In P. Periti and G. G. Grassi (ed.), Current chemotherapy and immunotherapy. American Society for Microbiology, Washington, D.C. 2. Barza, M., F. P. Tally, N. V. 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