Journal of Antimicrobial Chemotherapy (1978) 4 (Suppl. E), 203-208
Evaluation of cefoxitin sodium therapy in anaerobic infections
H. Thadepalli, D. Webb, I. Roy and V. Bach
Division of Infectious Diseases, Department of Internal Medicine, Charles R. Drew Postgraduate School of Medicine, University of Southern California School of Medicine, and Martin Luther King, Jr., General Hospital, Los Angeles, California, U.S.A. Fifteen patients were treated with cefoxitin sodium intravenously. Infections included lung abscess (4), empyema of the chest (4), liver abscess (3), osteomyelitis (3), and pancreatic abscess (1). Seven patients had exclusively anaerobic infections and 8 had an aerobic infection in addition. The only patients not cured were 2 with osteomyelitis of the mandible. Cefoxitin appears to be effective in the treatment of anaerobic infections. Introduction Wallick & Hendlin (1974), Sutter & Finegold (1975) and Bach, Roy & Thadepalli (1977) reported that cefoxitin sodium, a cephamycin derivative, was effective in vitro against certain clinically important aerobic and anaerobic bacteria. Onishi et al. (1974) and Neu (1974) observed that cefoxitin was uniquely resistant to cephalosporinase produced by Staphylococcus aureus and by certain Gram-negative bacilli. Since infections by anaerobic bacteria are often associated with infections by aerobes, a single antibiotic effective against both aerobic and anaerobic bacteria would be very desirable. Cefoxitin was tested against both anaerobic and aerobic mixed infections in this study. Materials and methods All patients were adults admitted to Martin Luther King, Jr., General Hospital in Los Angeles. Informed, written consent was obtained from each patient entering the study. Material for microbiological culture was obtained, preferably on two occasions for each patient, by transtracheal aspiration or thoracentesis, or surgically drained or needleaspirated pus was used. Blood cultures were obtained from each patient. The initial dose of cefoxitin was 4 to 8 g/day in divided doses administered i.v. every 4 to 6 h. Thirteen patients were treated with cefoxitin alone, but 2 others also received gentamicin for 2 to 3 days. The methods used to collect specimens and to transport, process, isolate, and identify anaerobic bacteria were those described by Holdeman & Moore (1975). Aerobic bacteria were identified in the conventional manner. Minimum inhibitory concentrations (MlCs) of anaerobic bacteria were assayed in an anaerobic glove box by the agar-dilution method, details of which have been published elsewhere (Sutter & Finegold, 1975). Cefoxitin levels in the serum and in pleural fluids were assayed against a susceptible strain of Staph. aureus, ATCC 2786, with appropriate controls. 03O5-7453/78/07OI-B2O3 SOI .00/0
203 © (1978) The British Society for Antimicrobial Chemotherapy
204
H. ThadepaJli, D. Webb, I. Roy and V. Bach
Therapeutic responses were assessed according to the following criteria: cure— complete clinical resolution of infection, without relapse; improvement—significant improvement of infection, but with incomplete resolution or with subsequent relapse; failure—failure to respond despite adequate therapeutic trial; unevaluable—no pathogenic organism grown, or course of therapy not completed. Results Fifteen patients proven to have an anaerobic infection were treated with cefoxitin i.v. In 7 patients, the infection was exclusively anaerobic; 8 other patients were infected by aerobic bacteria as well. The 15 infections included 4 lung abscesses, 4 cases of empyema, 3 liver abscesses, 3 cases of osteomyelitis, and 1 pancreatic abscess. Table I summarizes the bacteriologic and clinical results of cefoxitin therapy. Two seriously ill patients (nos. 1 and 6) received both cefoxitin and gentamicin because they were infected additionally with Pseudomonas, known to be resistant to cefoxitin. Four patients had blood cultures positive for aerobic organisms. Serum levels of cefoxitin 1 h after administration of 2 g of cefoxitin i.v. ranged from 16 to 32/xg/ml. In 4 patients for whom cefoxitin levels in pleural fluid were measured, the serum:pleural fluid ratio was 1:0-5 + 0-25. Cefoxitin inhibited the growth of all but two strains of anaerobic bacteria isolated in this study when its concentration was < 2/zg/ml. One of these strains was inhibited when the concentration of cefoxitin was 8/xg/ml; the other, a species of Bacteroides (not fragilis), proved resistant to cefoxitin, i.e., the MIC was > 32/ng/ml. The MIC to cefoxitin for each of the two strains of B. fragilis isolated in this study was < 2 /xg/ml. Tolerance and toxicity In general, cefoxitin administered i.v. was well tolerated. Three patients developed leukocytosis (leukocyte count between 10,000 and 26,000/mm3) that could not be attributed to eosinophilia; it persisted even after the infection had been brought under control. In all instances, the leukocytosis was resolved after the course of cefoxitin therapy had been completed. In no case was the leukocytosis considered severe enough to warrant discontinuation of cefoxitin therapy. The following case histories summarize some of the successes and failures encountered with cefoxitin therapy. Patient no. 4: lung abscess This 39-year-old man, a heroin addict, was admitted because of right-sided pleuritic pain, chills, and fever of 2 weeks' duration. On admission, he was febrile (102°F); the physical examination was otherwise unremarkable. The chest roentgenogram showed a large cavity with an air/fluid meniscus in the right upper lobe. Peptostreptococcus intermedius was isolated from material obtained by transtracheal aspiration. Cultures failed to yield Mycobacterium tuberculosis. The patient was treated with cefoxitin i.v., 8 g/day. After 96 h of therapy, he became afebrile. Weekly chest roentgenograms showed gradual resolution of the lung abscess. After 14 days of therapy, the cavitary lesion had closed completely and cefoxitin therapy was discontinued. The organism isolated was susceptible to cefoxitin at < 2 jig/ml. Serum levels of cefoxitin were 21 -6 and 11 -6/xg/ml at 1 and 5 h, respectively, after 2 g of the antibiotic had been infused i.v.
Proteus Staph. aureust Proteus vulgaris
Empyema Empyema Liver abscess Liver abscess
Liver abscess
Pancreatic abscess Osteomyelitis of phalanx Osteomyelitis of mandible Osteomyelitis of mandible
6*
7 8 9 10
11
12
Anaerobes
failure failure
drainage drainage B. fragilis Bacteroides spp.
Enterococcus
cure
B. fragilis
pus
non-haemolytic
Group D strept
cure
pleural fluid pleural fluid pleural fluid pus pus
pus
cure cure cure cure
fluid fluid
cure
cure cure cure cure
cure
TTA TTA pleural pleural
cure
aspiration (TTA) TTA
Outcome
transtracheal
Source of culture
pus
Peptostreptococcus (Ps.) intermedius Peptococcus (Pc.) magnus Ps. intermedius Ps. intermedius Gram-negative anaerobic bacilli
Eubacterium lentum
Culture results
Propionibacterium acnes Pc. magnus Pc. prevotii Fusobacterium nucleatum Bacteroides spp. Clostridium butyricum Butyrivibrio fibrisolvens Bacteroides spp. Propionibacterium acidipropionici Bacteroides (B.) fragilis Eubacterium lentum Pseudomonas B. corrodens
• Patients nos. 1 and 6 received gentamicin as well as cefoxitin. t Also isolated from blood cultures.
15
14
13
Klebsiella pneumoniae\ Escherichia coli
Lung abscess Lung abscess Empyema Empyema
3 4 5
Staphylococcus (Staph.) aureus Pseudomonas
Lung abscess
2
Klebisella (Pseudomonas)
Aerobes
Lung abscess
Diagnosis
1*
number
Patient
Table I. Microbiologic and clinical results of cefoxitin therapy
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H. Thadepalli, D. Webb, I. Roy and V. Bach
Patient no. 9: liver abscess This 30-year-old Mexican woman was admitted because of fever and chills with progressive jaundice of 2 weeks' duration. She was febrile (103°F). Abdominal examination revealed tenderness in the right upper quadrant. Laboratory values were consistent with a diagnosis of obstructive jaundice. Oral cholecystography revealed cholelithiasis. A Tc-99m colloid scan of liver and spleen showed three filling defects in the right lobe of the liver, and a Ga-67 scan showed increased uptake in all three areas. The patient was diagnosed as having a pyogenic liver abscess, and underwent cholecystectomy; the liver abscesses each 2 inches in diameter, were drained. Therapy with cefoxitin i.v., 4 g/day, was started. The patient's clinical response was excellent; she became afebrile within 3 days. Cefoxitin therapy was continued for 4 weeks. Although therapy was well tolerated, the patient developed a persistent leukocytosis (leukocyte count up to 26,000/mm3) that resolved after cefoxitin therapy had been completed. Culture of pus drained surgically from the liver revealed the presence of Peptococcus prevotii (MIC to cefoxitin
Evaluation of cefoxitin sodium therapy in anaerobic infections
H. Thadepalli, D. Webb, I. Roy and V. Bach
Division of Infectious Diseases, Department of Internal Medicine, Charles R. Drew Postgraduate School of Medicine, University of Southern California School of Medicine, and Martin Luther King, Jr., General Hospital, Los Angeles, California, U.S.A. Fifteen patients were treated with cefoxitin sodium intravenously. Infections included lung abscess (4), empyema of the chest (4), liver abscess (3), osteomyelitis (3), and pancreatic abscess (1). Seven patients had exclusively anaerobic infections and 8 had an aerobic infection in addition. The only patients not cured were 2 with osteomyelitis of the mandible. Cefoxitin appears to be effective in the treatment of anaerobic infections. Introduction Wallick & Hendlin (1974), Sutter & Finegold (1975) and Bach, Roy & Thadepalli (1977) reported that cefoxitin sodium, a cephamycin derivative, was effective in vitro against certain clinically important aerobic and anaerobic bacteria. Onishi et al. (1974) and Neu (1974) observed that cefoxitin was uniquely resistant to cephalosporinase produced by Staphylococcus aureus and by certain Gram-negative bacilli. Since infections by anaerobic bacteria are often associated with infections by aerobes, a single antibiotic effective against both aerobic and anaerobic bacteria would be very desirable. Cefoxitin was tested against both anaerobic and aerobic mixed infections in this study. Materials and methods All patients were adults admitted to Martin Luther King, Jr., General Hospital in Los Angeles. Informed, written consent was obtained from each patient entering the study. Material for microbiological culture was obtained, preferably on two occasions for each patient, by transtracheal aspiration or thoracentesis, or surgically drained or needleaspirated pus was used. Blood cultures were obtained from each patient. The initial dose of cefoxitin was 4 to 8 g/day in divided doses administered i.v. every 4 to 6 h. Thirteen patients were treated with cefoxitin alone, but 2 others also received gentamicin for 2 to 3 days. The methods used to collect specimens and to transport, process, isolate, and identify anaerobic bacteria were those described by Holdeman & Moore (1975). Aerobic bacteria were identified in the conventional manner. Minimum inhibitory concentrations (MlCs) of anaerobic bacteria were assayed in an anaerobic glove box by the agar-dilution method, details of which have been published elsewhere (Sutter & Finegold, 1975). Cefoxitin levels in the serum and in pleural fluids were assayed against a susceptible strain of Staph. aureus, ATCC 2786, with appropriate controls. 03O5-7453/78/07OI-B2O3 SOI .00/0
203 © (1978) The British Society for Antimicrobial Chemotherapy
204
H. ThadepaJli, D. Webb, I. Roy and V. Bach
Therapeutic responses were assessed according to the following criteria: cure— complete clinical resolution of infection, without relapse; improvement—significant improvement of infection, but with incomplete resolution or with subsequent relapse; failure—failure to respond despite adequate therapeutic trial; unevaluable—no pathogenic organism grown, or course of therapy not completed. Results Fifteen patients proven to have an anaerobic infection were treated with cefoxitin i.v. In 7 patients, the infection was exclusively anaerobic; 8 other patients were infected by aerobic bacteria as well. The 15 infections included 4 lung abscesses, 4 cases of empyema, 3 liver abscesses, 3 cases of osteomyelitis, and 1 pancreatic abscess. Table I summarizes the bacteriologic and clinical results of cefoxitin therapy. Two seriously ill patients (nos. 1 and 6) received both cefoxitin and gentamicin because they were infected additionally with Pseudomonas, known to be resistant to cefoxitin. Four patients had blood cultures positive for aerobic organisms. Serum levels of cefoxitin 1 h after administration of 2 g of cefoxitin i.v. ranged from 16 to 32/xg/ml. In 4 patients for whom cefoxitin levels in pleural fluid were measured, the serum:pleural fluid ratio was 1:0-5 + 0-25. Cefoxitin inhibited the growth of all but two strains of anaerobic bacteria isolated in this study when its concentration was < 2/zg/ml. One of these strains was inhibited when the concentration of cefoxitin was 8/xg/ml; the other, a species of Bacteroides (not fragilis), proved resistant to cefoxitin, i.e., the MIC was > 32/ng/ml. The MIC to cefoxitin for each of the two strains of B. fragilis isolated in this study was < 2 /xg/ml. Tolerance and toxicity In general, cefoxitin administered i.v. was well tolerated. Three patients developed leukocytosis (leukocyte count between 10,000 and 26,000/mm3) that could not be attributed to eosinophilia; it persisted even after the infection had been brought under control. In all instances, the leukocytosis was resolved after the course of cefoxitin therapy had been completed. In no case was the leukocytosis considered severe enough to warrant discontinuation of cefoxitin therapy. The following case histories summarize some of the successes and failures encountered with cefoxitin therapy. Patient no. 4: lung abscess This 39-year-old man, a heroin addict, was admitted because of right-sided pleuritic pain, chills, and fever of 2 weeks' duration. On admission, he was febrile (102°F); the physical examination was otherwise unremarkable. The chest roentgenogram showed a large cavity with an air/fluid meniscus in the right upper lobe. Peptostreptococcus intermedius was isolated from material obtained by transtracheal aspiration. Cultures failed to yield Mycobacterium tuberculosis. The patient was treated with cefoxitin i.v., 8 g/day. After 96 h of therapy, he became afebrile. Weekly chest roentgenograms showed gradual resolution of the lung abscess. After 14 days of therapy, the cavitary lesion had closed completely and cefoxitin therapy was discontinued. The organism isolated was susceptible to cefoxitin at < 2 jig/ml. Serum levels of cefoxitin were 21 -6 and 11 -6/xg/ml at 1 and 5 h, respectively, after 2 g of the antibiotic had been infused i.v.
Proteus Staph. aureust Proteus vulgaris
Empyema Empyema Liver abscess Liver abscess
Liver abscess
Pancreatic abscess Osteomyelitis of phalanx Osteomyelitis of mandible Osteomyelitis of mandible
6*
7 8 9 10
11
12
Anaerobes
failure failure
drainage drainage B. fragilis Bacteroides spp.
Enterococcus
cure
B. fragilis
pus
non-haemolytic
Group D strept
cure
pleural fluid pleural fluid pleural fluid pus pus
pus
cure cure cure cure
fluid fluid
cure
cure cure cure cure
cure
TTA TTA pleural pleural
cure
aspiration (TTA) TTA
Outcome
transtracheal
Source of culture
pus
Peptostreptococcus (Ps.) intermedius Peptococcus (Pc.) magnus Ps. intermedius Ps. intermedius Gram-negative anaerobic bacilli
Eubacterium lentum
Culture results
Propionibacterium acnes Pc. magnus Pc. prevotii Fusobacterium nucleatum Bacteroides spp. Clostridium butyricum Butyrivibrio fibrisolvens Bacteroides spp. Propionibacterium acidipropionici Bacteroides (B.) fragilis Eubacterium lentum Pseudomonas B. corrodens
• Patients nos. 1 and 6 received gentamicin as well as cefoxitin. t Also isolated from blood cultures.
15
14
13
Klebsiella pneumoniae\ Escherichia coli
Lung abscess Lung abscess Empyema Empyema
3 4 5
Staphylococcus (Staph.) aureus Pseudomonas
Lung abscess
2
Klebisella (Pseudomonas)
Aerobes
Lung abscess
Diagnosis
1*
number
Patient
Table I. Microbiologic and clinical results of cefoxitin therapy
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H. Thadepalli, D. Webb, I. Roy and V. Bach
Patient no. 9: liver abscess This 30-year-old Mexican woman was admitted because of fever and chills with progressive jaundice of 2 weeks' duration. She was febrile (103°F). Abdominal examination revealed tenderness in the right upper quadrant. Laboratory values were consistent with a diagnosis of obstructive jaundice. Oral cholecystography revealed cholelithiasis. A Tc-99m colloid scan of liver and spleen showed three filling defects in the right lobe of the liver, and a Ga-67 scan showed increased uptake in all three areas. The patient was diagnosed as having a pyogenic liver abscess, and underwent cholecystectomy; the liver abscesses each 2 inches in diameter, were drained. Therapy with cefoxitin i.v., 4 g/day, was started. The patient's clinical response was excellent; she became afebrile within 3 days. Cefoxitin therapy was continued for 4 weeks. Although therapy was well tolerated, the patient developed a persistent leukocytosis (leukocyte count up to 26,000/mm3) that resolved after cefoxitin therapy had been completed. Culture of pus drained surgically from the liver revealed the presence of Peptococcus prevotii (MIC to cefoxitin
