THE JOURNAL OF INFECTIOUS DISEASES. VOL. 137 • SUPPLEME"T • MAY 1978 © 1978 by the University of Chicago. 0022-1899/78/3725-0020$00.75
Clinical and Laboratory Evaluation of Cefamandole in Infants and Children William J. Rodriguez, Sydney Ross, Waheed N. Khan, and Robin Goldenberg
From the Microbiology Section, Research Foundation ot Children's Hospital National Medical Center, and the Department ot Child Health and Development, George Washington University School ot Medicine, Washington, D.C.
Cefamandole, a new cephalosporin antibiotic, has shown activity against both gram-positive and gram-negative organisms [I, 2]. In addition, the antibiotic has demonstrated excellent in vitro activity against Haemophilus influenzae [3, 4]. The latter finding has assumed increasing importance since the advent of ampicillin-resistant strains of H. influenzae [5-7]. A clinical trial with cefamandole in the treatment of susceptible infections in infants and children was initiated at Children's Hospital National Medical Center in January 1976.
15 years of age were treated with cefamandole. Thirteen (25%) of the patients were younger than one year of age. Forty-seven patients had soft tissue cellulitis, including 12 (23%) with periorbital localization. The remaining six patients had pneumonia that was considered to be bacterial in origin on the basis of laboratory and radiographic evidence. Etiologic agents were isolated from 43 (81 %) of the 53 patients. On admission of the patients to the hospital, samples were obtained for culture from the site of infection. In patients with soft tissue infections, the leading edge of the area of cellulitis was aspirated for smears as well as cultures. Blood samples and throat swabs were obtained from all patients for culture. Stool and urine specimens were cultured when indicated. Additional laboratory studies performed before therapy included a hemogram; urinalysis; determination of levels of serum bilirubin, blood urea nitrogen, serum creatinine, aspartate aminotransferase, and serum alkaline phosphatase; and direct and indirect Coombs' tests. These tests were all repeated at the time of hospital discharge, when treatment with celarnan. dole had been discontinued.
Materials and Methods
Patients. Hospitalized patients with a diagnosis of either soft tissue infection or bacterial pneumonia were included in the present study provided no successful or suppressant antibiotic treatment had been given in the preceding 72 hr. Fifty-three patients between three months and Please address requests for reprints to Dr. 'William J. Rodriguez, Microbiology Research, Children's Hospital Research Foundation, 111 Michigan Avenue N.W., Washington, D.C. 20010.
5150
Downloaded from http://jid.oxfordjournals.org/ at Emory University on August 24, 2015
Fifty-three infants and children, aged three months to 15 years, were treated with an average daily dose of 100 mg of cefamandolejkg intravenously. Of these patients, 47 had soft tissue cellulitis and six had pneumonia. Primary pathogens, including Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, and Haemophilus infiuenzae, were isolated from 43 of the 53 patients. Bacteremia was documented in six of the 53 patients. A satisfactory clinical and bacteriologic response to cefamandole was achieved in all cases except one (98%). The only treatment failure occurred in an infant with both periorbital cellulitis and bacteremia due to H. infiuenzae who developed meningitis while receiving cefamandole; no extravasation of the drug across the blood-brain barrier could be detected in spite of inflamed meninges. In general, the only aberrant effects of cefamandole were the appearance of eosinophilia in 28% of patients and a positive indirect Coombs' test without hemolysis in one patient. Cefamandole showed excellent in vitro activity against 87 ampicillin-resistant strains of H. in{luenzae. Because it has greater activity than any of the other cephalosporins against this important pediatric pathogen, cefamandole may have particular pertinence in the treatment of infections in infants and young children.
Cejamandole in Infants and Children
47 patients with soft tissue cellulitis; three cases were due to H. influenzae type b, one to S. pneumoniae, and one to S. pyogenes. Of the six patients with pneumonia, two had positive cultures; in one child S. pneumoniae was isolated from a blood culture, and in the second patient S. pneumoniae and Haemophilus species were isolated from a brush biopsy culture from the right upper lobe of the lung. No etiologic agent could be isolated from 10 of the 53 patients; four of the 10 children had pneumonia with a presumed bacterial etiology suggested by clinical, laboratory, and radiographic findings on hospital admission. The 43 bacterial isolates from patients in the present study (including S. aureus, S. pyogenes) S. pneumoniae, and H. influenzac type b) were all sensitive to 30-p,g disks of cefamandole by the standardized Kirby-Bauer method [8]. In vitro bacterial susceptibility studies. Preliminary in vitro studies revealed that 95% of the 87 ampicillin-resistant strains of H. influenzae were inhibited by ~0.78 p,g of cefamandole rml: this activity of cefamandole against H. influenzae closely coincided with the inhibitory effect demonstrated by chloramphenicol (figure I). Of 50 penicillin-resistant stock culture strains of S. aureus) 96% were inhibited by 0.39 p,g of cefamandole/
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Results
Bacterial isolations. Of the 47 patients with soft tissue cellulitis, 21 (45%) had pure cultures of S. aureus isolated from the site of infection by needle aspiration, whereas in seven children (15%) Streptococcus pyogenes was the sale agent for the cellulitis. H. influenzae type b was isolated in four cases (8.5%), and Streptococcus pncumoniae in two. Bacteremia was demonstrated in five of the
...~.
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0.095 0.19 0.39 0.78 1.56 3.12 6.25 12.5 25 50
100
Minimum Inhibition Concentration(ll!I/ml)
Figure 1. In vitro susceptibility of 87 ampicillinresistant strains of Haemophilus influenzae to cefamandole and chloramphenicol.
Downloaded from http://jid.oxfordjournals.org/ at Emory University on August 24, 2015
Clinical assessment of each case was done daily, and response to therapy was carefully calibrated. Cefamandole was administered by iv bolus in a total dosage of 50-150 mg/kg per day (average daily dose, 100 mg/kg; 25-mg/kg bolus every 6 hr), generally for five to seven days while the patient was hospitalized; after discharge, the patients were usually given cephalexin orally on an outpatient basis for an additional three to five days. However, the clinical and bacteriological efficacy of cefamandole was assessed only on the basis of the patient's progress during iv therapy. Pharmacokinetics. Blood samples for determination of cefamandole levels were drawn from 15. patients at zero-time and 0.5, 1,3, and 6 hr after an iv bolus of the drug. In addition, levels of cefamandole in cerebrospinal fluid (CSF) were determined in five patients after an iv bolus of 25 uig] kg. One of the five children had H. influenzae meningitis at the time CSF levels were measured. In vitro studies. Preliminary in vitro studies were performed prior to the clinical trials with cefamandole. By an agar dilution method, appropriate antibiotic concentrations were serially diluted in a microtiter plate system. A 5% Fildes enrichment (Difco, Detroit, Mich.) in brain-heart infusion broth was used. The range of final concentrations was 0.095-100 p,g/ml. Plates were read for MICs after incubation for 12-18 hr at 37 C and were checked again at 48 hr. The inoculum was prepared from an overnight culture of the test organism and was adjusted by dilution to 104 efu/ ml. By this method, 87 strains of H. influenzae resistant to ampicillin were tested for susceptibility to cefamandole and chloramphenicol. In addition, 50 penicillin-resistant stock strains of Staphylococcus aureus and 20 stock strains of group A f3-hemolytic Streptococcus were tested for susceptibility to cefamandole.
S151
Rodriguez et al.
5152
end of 6 hr (figure 2). These levels compared favorably with those of other fi-Iactam antibiotics administered in comparable dosages. When a 25mg/kg bolus of cefamandole was given im, average serum concentrations were 20 JLgjml at I hr and 9 JLg/ml at 2 hr. In five patients cefamandole administered in a 25-mgjkg iv bolus showed poor penetration across the blood-brain barrier; four of these five children had normal meninges. For example, one patient had a level of cefamandole of 38.1 JLg/ml in serum and a concomitant level of 0.14 JLgjml in the CSF. The four other patients had either no detectable level or minimal levels of cefamandole (range, 0.14-0.21 JLgjml) in the CSF 1.5 hr after the bolus. The following case illustrates the failure of ce£amandole to penetrate the meninges even in the presence of bacterial meningitis. An eight-monthold black female infant was admitted to Children's Hospital National Medical Center with a history of an acute onset of periorbital cellulitis of the right eye. On physical examination, the periorbital swelling had an erythematous purplish hue. On admission the patient's temperature was 39.3 C, and a hemogram showed a white blood cell (WBC) count of 17,200jmm3 with 59% polymorphonu-
2
3
4
5
6
Hours After Injection
Figure 2. Levels of cefamandole in serum of 15 patients aged three months to 15 years after a 25-mg/ kg bolus administered iv.
Downloaded from http://jid.oxfordjournals.org/ at Emory University on August 24, 2015
ml, whereas all of the 20 stock strains of S. pyagenes were inhibited by~1.56 JLg of the drug/ml. Clinical efficacy oi ceiamandole. Sojt tissue cellulitis. Prompt defervescence occurred after initiation of iv treatment with cefamandole; the mean duration of fever was 32 hr. In 46 of 47 patients, the local erythema, warmth, and tenderness receded rather quickly within three to five days. The one treatment failure occurred in an eightmonth-old infant with periorbital cellulitis and bacteremia due to H. influenzae type b who developed meningitis while receiving cefamandole (see below). Pneumonia. After initiation of treatment with ce£amandole, each of the six patients with pneumonia became afebrile within 24-72 hr (mean, 40 hr), with a prompt diminution in rales. The iv regimen was continued for five to seven days during hospitalization followed by step-down treatment with cephalexin given orally (50-75 mg/kg daily) after discharge of the patient from the hospital, for a total of 10-14 days of therapy. At the time parenteral cefamandole was discontinued, all six patients were clinically asymptomatic and improved according to radiographic evidence. Toxicity. Eosinophilia (6%-25% eosinophils) was noted in 15 (28%) of 53 patients. Eosinophil counts, with the exception of that in one patient, returned to normal shortly after discontinuation of cefamandole therapy. There was no clinical counterpart of hypersensitvity in any patient with eosinophilia induced by the drug. Results of direct and indirect Coombs' tests for all 53 patients revealed no abnormalities attributable to cefamandole except in one case in which results of the indirect Coombs' test became positive during therapy. No evidence of hemolysis or other adverse hematopoietic effects were observed in this patient. Results of hepatic and renal studies similarly revealed no abnormalities in any patient in the study. No evidence of thrombophlebitis was observed after iv administration of cefamandole, although our patients only received relatively brief iv courses of the drug. Pharmacokinetics. Serial determinations of levels of cefamandole in serum were performed in 15 patients. Following administration of a 25- mgj kg iv bolus, the average concentration of the drug in serum was 33 JLg/ml after 0.5 hr, 13.8 JLg/ml after I hr, 2.9 JLg/ml at 3 hr, and 0.3 JLg/ml at the
Cefamandole in Infants and Children
chloramphenicol, cephalexin, cephaloridine, and ampicillin against 100 sensitive strains of H. infiuenzae. In addition, cefamandole showed good activity against the gram-positive organisms that most frequently cause skin and soft tissue infections as well as bacterial pneumonia in children. The drug was well tolerated clinically in all 53 patients in the present study. The only untoward reaction was transitory eosinophilia occurring in 28% of patients without any associated evidence of clinical hypersensitivity. These preliminary results would suggest that cefamandole is an effective parenteral cephalosporin in treatment of soft tissue cellulitis and bacterial pneumonia due to gram-positive coccal organisms in infants and children. Cefamandole has the additional advantage of being the most active of the cephalosporins against H. in[luenzae and produces salutary clinical results when used in treatment of infections due to this organism. Because of the prime importance of H. influenzae as a causative agent in bacterial infections in infants and young children, cefamandole may have particular pertinence for the pediatrician. For example, in instances of cellulitis in infants in which the most likely infecting organisms may be S. aureus (usually penicillin-resistant), S. pyogenes, or H. infiuenzae, it would be possible to initiate 100
Discussion
Ninety-eight percent of our patients responded favorably to therapy with cefamandole. The only failure was the case discussed above of an infant with H. infiuenzae periorbital cellulitis with bacteremia who developed meningitis while receiving cefamandole. This failure was thought to be due to the inadequate extravasation of the antibiotic even across the inflamed meninges. Parenthetically, two other patients with cellulitis due to H. influenzae with associated bacteremia defervesced rapidly and had uncomplicated recoveries. The fourth patient with cellulitis due to H. infiuenzae (but without bacteremia) also fared well. Cefamandole showed excellent in vitro activity against ampicillin-resistant H. iniiuenzac (figure 1). All previous cephalosporins have been only mildly active against H. infiuenzae as shown in figure 3, which compares the inhibitory activity of
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0.095 0.19 0.39 0.78 1.56 3.12 6.25 12.5 25 50 100 Minimum Inhibition Concentration Ill!I/mll
Figure 3. In vitro susceptibility of 100 ampicillinsensitive strains of Haemophilus injluenzae to four antibiotics.
Downloaded from http://jid.oxfordjournals.org/ at Emory University on August 24, 2015
clear leukoctyes. Cultures of blood and the right eye obtained on admission subsequently yielded H. in[luenzae type b. CSF obtained at the time of hospitalization showed 1 'VBC/mm3 and, on cytocentrifugation, only lymphocytes were seen; culture and smear of CSF were negative. Treatment with cefamandole was initiated shortly after admission in a daily dose of 100 mg/ kg administered iv in a 6-hr divided dosage schedule. Within 36 hr after admission, the periorbital swelling improved substantially, although the infant remained febrile. The temperature suddenly spiked to 40 C 12 hr later, and a repeat lumbar puncture was performed. The WBC count in the, CSF had risen to 548 leukocytesymm" with 74% polymorphonuclear cells; a smear suggested and a culture confirmed the presence of H. influenzae type b. The MIC of cefamandole was 0.78 /1-g/ml, which was the same MIC noted for the strains of H. influenzae isolated from blood and eye cultures on admission of the patient. Parenthetically, a repeat blood culture obtained at the time of the second lumbar puncture was sterile. Carbenicillin was substituted for cefamandole, and within 12 hr the patient was afebrile. The infant subsequently recovered uneventfully. A specimen of CSF obtained at the time of diagnosis of meningitis (3.5 hr after a 25-mg/kg iv bolus) contained no detectable cefamandole.
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References I. Jones, R. N., Fuchs, P. C. Comparison of in vitro antimicrobial activity of cefamandole and cefazolin with
2.
3.
4. 5.
6.
7. 8.
cephalothin against over 8,000 clinical bacterial isolates. Antimicrob. Agents Chemother. 9:1066-1069, 1976. Sande, M. A., Minor, M. R., Dilworth, J. A., Mandell, G. L. Cefamandole treatment of pulmonary infections caused by grarn-ncgat ive rods. J. Antimicrob. Chemother, 2:49-53, 1976. Kammer, R. B., Preston, D. A., Turner, J. R., Hawley, L. C. Rapid detection of ampicillin-resistant Hemophilus influenzae and their susceptibility to sixteen antibiotics. Antimicrob. Agents Chemother, 8:91-94, 1975. Williams, J. D., Andrews, J. Sensitivity of Hemophilus influenzae to antibiotics. Br. Med. J. 1:134-137, 1974. Khan, W., Ross, S., Rodriguez, W., Controni, G., Saz, A. Hemophilus injluenzae type b resistant to ampicillin. A report of two cases. J.A.M.A. 229:298-301, 1974. Tomeh, M. 0., Starr, S. E., McGowan, J. E., Jr., Terry, P. M., Nahmias, A. J. Ampicillin resistant Hemophilus influenzae type b infections. J.A.M.A. 229:295-297, 1974. Katz, S. L. Ampicillin-resistant Hemophilus injluenzae type b: a status report. Pediatrics 55:6-8,1975. Bauer, A. W., Kirby, W. M. M., Sherris, J. C., Turck, M. Antibiotic susceptibility testing by a standardized single disc method. Am. J. Clin. Pathol. 45:493-496, 1966.
Downloaded from http://jid.oxfordjournals.org/ at Emory University on August 24, 2015
treatment with cefamandole rather than the usual combination of ampicillin and oxacillin. Cefamandole would provide the required broad-spec. trum coverage when used alone in such instances. In addition, cefamandole would have the advantage of being efficacious if the causative organism were found to be an ampicillin-resistant strain of H. influenzae. This drug would similarly provide good coverage (prior to the availability of culture reports) in other infections in which H. influenzae is a potential causative agent, i.e., epiglottitis, pyogenic arthritis, and, to a lesser extent, bacterial pneumonia. It is important to emphasize that in cases of bacteremia due to H. influenzae, a lumbar pun£ture should be done to ascertain the concomitant meningeal status of the patient. The relatively poor extravasation of cefamandole across the blood-brain barrier, when currently recommended therapeutic doses of the drug are used, might render cefamandole of dubious value if meningitis had supervened sequential to the bacteremia.
Clinical and Laboratory Evaluation of Cefamandole in Infants and Children William J. Rodriguez, Sydney Ross, Waheed N. Khan, and Robin Goldenberg
From the Microbiology Section, Research Foundation ot Children's Hospital National Medical Center, and the Department ot Child Health and Development, George Washington University School ot Medicine, Washington, D.C.
Cefamandole, a new cephalosporin antibiotic, has shown activity against both gram-positive and gram-negative organisms [I, 2]. In addition, the antibiotic has demonstrated excellent in vitro activity against Haemophilus influenzae [3, 4]. The latter finding has assumed increasing importance since the advent of ampicillin-resistant strains of H. influenzae [5-7]. A clinical trial with cefamandole in the treatment of susceptible infections in infants and children was initiated at Children's Hospital National Medical Center in January 1976.
15 years of age were treated with cefamandole. Thirteen (25%) of the patients were younger than one year of age. Forty-seven patients had soft tissue cellulitis, including 12 (23%) with periorbital localization. The remaining six patients had pneumonia that was considered to be bacterial in origin on the basis of laboratory and radiographic evidence. Etiologic agents were isolated from 43 (81 %) of the 53 patients. On admission of the patients to the hospital, samples were obtained for culture from the site of infection. In patients with soft tissue infections, the leading edge of the area of cellulitis was aspirated for smears as well as cultures. Blood samples and throat swabs were obtained from all patients for culture. Stool and urine specimens were cultured when indicated. Additional laboratory studies performed before therapy included a hemogram; urinalysis; determination of levels of serum bilirubin, blood urea nitrogen, serum creatinine, aspartate aminotransferase, and serum alkaline phosphatase; and direct and indirect Coombs' tests. These tests were all repeated at the time of hospital discharge, when treatment with celarnan. dole had been discontinued.
Materials and Methods
Patients. Hospitalized patients with a diagnosis of either soft tissue infection or bacterial pneumonia were included in the present study provided no successful or suppressant antibiotic treatment had been given in the preceding 72 hr. Fifty-three patients between three months and Please address requests for reprints to Dr. 'William J. Rodriguez, Microbiology Research, Children's Hospital Research Foundation, 111 Michigan Avenue N.W., Washington, D.C. 20010.
5150
Downloaded from http://jid.oxfordjournals.org/ at Emory University on August 24, 2015
Fifty-three infants and children, aged three months to 15 years, were treated with an average daily dose of 100 mg of cefamandolejkg intravenously. Of these patients, 47 had soft tissue cellulitis and six had pneumonia. Primary pathogens, including Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, and Haemophilus infiuenzae, were isolated from 43 of the 53 patients. Bacteremia was documented in six of the 53 patients. A satisfactory clinical and bacteriologic response to cefamandole was achieved in all cases except one (98%). The only treatment failure occurred in an infant with both periorbital cellulitis and bacteremia due to H. infiuenzae who developed meningitis while receiving cefamandole; no extravasation of the drug across the blood-brain barrier could be detected in spite of inflamed meninges. In general, the only aberrant effects of cefamandole were the appearance of eosinophilia in 28% of patients and a positive indirect Coombs' test without hemolysis in one patient. Cefamandole showed excellent in vitro activity against 87 ampicillin-resistant strains of H. in{luenzae. Because it has greater activity than any of the other cephalosporins against this important pediatric pathogen, cefamandole may have particular pertinence in the treatment of infections in infants and young children.
Cejamandole in Infants and Children
47 patients with soft tissue cellulitis; three cases were due to H. influenzae type b, one to S. pneumoniae, and one to S. pyogenes. Of the six patients with pneumonia, two had positive cultures; in one child S. pneumoniae was isolated from a blood culture, and in the second patient S. pneumoniae and Haemophilus species were isolated from a brush biopsy culture from the right upper lobe of the lung. No etiologic agent could be isolated from 10 of the 53 patients; four of the 10 children had pneumonia with a presumed bacterial etiology suggested by clinical, laboratory, and radiographic findings on hospital admission. The 43 bacterial isolates from patients in the present study (including S. aureus, S. pyogenes) S. pneumoniae, and H. influenzac type b) were all sensitive to 30-p,g disks of cefamandole by the standardized Kirby-Bauer method [8]. In vitro bacterial susceptibility studies. Preliminary in vitro studies revealed that 95% of the 87 ampicillin-resistant strains of H. influenzae were inhibited by ~0.78 p,g of cefamandole rml: this activity of cefamandole against H. influenzae closely coincided with the inhibitory effect demonstrated by chloramphenicol (figure I). Of 50 penicillin-resistant stock culture strains of S. aureus) 96% were inhibited by 0.39 p,g of cefamandole/
100
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Results
Bacterial isolations. Of the 47 patients with soft tissue cellulitis, 21 (45%) had pure cultures of S. aureus isolated from the site of infection by needle aspiration, whereas in seven children (15%) Streptococcus pyogenes was the sale agent for the cellulitis. H. influenzae type b was isolated in four cases (8.5%), and Streptococcus pncumoniae in two. Bacteremia was demonstrated in five of the
...~.
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0.095 0.19 0.39 0.78 1.56 3.12 6.25 12.5 25 50
100
Minimum Inhibition Concentration(ll!I/ml)
Figure 1. In vitro susceptibility of 87 ampicillinresistant strains of Haemophilus influenzae to cefamandole and chloramphenicol.
Downloaded from http://jid.oxfordjournals.org/ at Emory University on August 24, 2015
Clinical assessment of each case was done daily, and response to therapy was carefully calibrated. Cefamandole was administered by iv bolus in a total dosage of 50-150 mg/kg per day (average daily dose, 100 mg/kg; 25-mg/kg bolus every 6 hr), generally for five to seven days while the patient was hospitalized; after discharge, the patients were usually given cephalexin orally on an outpatient basis for an additional three to five days. However, the clinical and bacteriological efficacy of cefamandole was assessed only on the basis of the patient's progress during iv therapy. Pharmacokinetics. Blood samples for determination of cefamandole levels were drawn from 15. patients at zero-time and 0.5, 1,3, and 6 hr after an iv bolus of the drug. In addition, levels of cefamandole in cerebrospinal fluid (CSF) were determined in five patients after an iv bolus of 25 uig] kg. One of the five children had H. influenzae meningitis at the time CSF levels were measured. In vitro studies. Preliminary in vitro studies were performed prior to the clinical trials with cefamandole. By an agar dilution method, appropriate antibiotic concentrations were serially diluted in a microtiter plate system. A 5% Fildes enrichment (Difco, Detroit, Mich.) in brain-heart infusion broth was used. The range of final concentrations was 0.095-100 p,g/ml. Plates were read for MICs after incubation for 12-18 hr at 37 C and were checked again at 48 hr. The inoculum was prepared from an overnight culture of the test organism and was adjusted by dilution to 104 efu/ ml. By this method, 87 strains of H. influenzae resistant to ampicillin were tested for susceptibility to cefamandole and chloramphenicol. In addition, 50 penicillin-resistant stock strains of Staphylococcus aureus and 20 stock strains of group A f3-hemolytic Streptococcus were tested for susceptibility to cefamandole.
S151
Rodriguez et al.
5152
end of 6 hr (figure 2). These levels compared favorably with those of other fi-Iactam antibiotics administered in comparable dosages. When a 25mg/kg bolus of cefamandole was given im, average serum concentrations were 20 JLgjml at I hr and 9 JLg/ml at 2 hr. In five patients cefamandole administered in a 25-mgjkg iv bolus showed poor penetration across the blood-brain barrier; four of these five children had normal meninges. For example, one patient had a level of cefamandole of 38.1 JLg/ml in serum and a concomitant level of 0.14 JLgjml in the CSF. The four other patients had either no detectable level or minimal levels of cefamandole (range, 0.14-0.21 JLgjml) in the CSF 1.5 hr after the bolus. The following case illustrates the failure of ce£amandole to penetrate the meninges even in the presence of bacterial meningitis. An eight-monthold black female infant was admitted to Children's Hospital National Medical Center with a history of an acute onset of periorbital cellulitis of the right eye. On physical examination, the periorbital swelling had an erythematous purplish hue. On admission the patient's temperature was 39.3 C, and a hemogram showed a white blood cell (WBC) count of 17,200jmm3 with 59% polymorphonu-
2
3
4
5
6
Hours After Injection
Figure 2. Levels of cefamandole in serum of 15 patients aged three months to 15 years after a 25-mg/ kg bolus administered iv.
Downloaded from http://jid.oxfordjournals.org/ at Emory University on August 24, 2015
ml, whereas all of the 20 stock strains of S. pyagenes were inhibited by~1.56 JLg of the drug/ml. Clinical efficacy oi ceiamandole. Sojt tissue cellulitis. Prompt defervescence occurred after initiation of iv treatment with cefamandole; the mean duration of fever was 32 hr. In 46 of 47 patients, the local erythema, warmth, and tenderness receded rather quickly within three to five days. The one treatment failure occurred in an eightmonth-old infant with periorbital cellulitis and bacteremia due to H. influenzae type b who developed meningitis while receiving cefamandole (see below). Pneumonia. After initiation of treatment with ce£amandole, each of the six patients with pneumonia became afebrile within 24-72 hr (mean, 40 hr), with a prompt diminution in rales. The iv regimen was continued for five to seven days during hospitalization followed by step-down treatment with cephalexin given orally (50-75 mg/kg daily) after discharge of the patient from the hospital, for a total of 10-14 days of therapy. At the time parenteral cefamandole was discontinued, all six patients were clinically asymptomatic and improved according to radiographic evidence. Toxicity. Eosinophilia (6%-25% eosinophils) was noted in 15 (28%) of 53 patients. Eosinophil counts, with the exception of that in one patient, returned to normal shortly after discontinuation of cefamandole therapy. There was no clinical counterpart of hypersensitvity in any patient with eosinophilia induced by the drug. Results of direct and indirect Coombs' tests for all 53 patients revealed no abnormalities attributable to cefamandole except in one case in which results of the indirect Coombs' test became positive during therapy. No evidence of hemolysis or other adverse hematopoietic effects were observed in this patient. Results of hepatic and renal studies similarly revealed no abnormalities in any patient in the study. No evidence of thrombophlebitis was observed after iv administration of cefamandole, although our patients only received relatively brief iv courses of the drug. Pharmacokinetics. Serial determinations of levels of cefamandole in serum were performed in 15 patients. Following administration of a 25- mgj kg iv bolus, the average concentration of the drug in serum was 33 JLg/ml after 0.5 hr, 13.8 JLg/ml after I hr, 2.9 JLg/ml at 3 hr, and 0.3 JLg/ml at the
Cefamandole in Infants and Children
chloramphenicol, cephalexin, cephaloridine, and ampicillin against 100 sensitive strains of H. infiuenzae. In addition, cefamandole showed good activity against the gram-positive organisms that most frequently cause skin and soft tissue infections as well as bacterial pneumonia in children. The drug was well tolerated clinically in all 53 patients in the present study. The only untoward reaction was transitory eosinophilia occurring in 28% of patients without any associated evidence of clinical hypersensitivity. These preliminary results would suggest that cefamandole is an effective parenteral cephalosporin in treatment of soft tissue cellulitis and bacterial pneumonia due to gram-positive coccal organisms in infants and children. Cefamandole has the additional advantage of being the most active of the cephalosporins against H. in[luenzae and produces salutary clinical results when used in treatment of infections due to this organism. Because of the prime importance of H. influenzae as a causative agent in bacterial infections in infants and young children, cefamandole may have particular pertinence for the pediatrician. For example, in instances of cellulitis in infants in which the most likely infecting organisms may be S. aureus (usually penicillin-resistant), S. pyogenes, or H. infiuenzae, it would be possible to initiate 100
Discussion
Ninety-eight percent of our patients responded favorably to therapy with cefamandole. The only failure was the case discussed above of an infant with H. infiuenzae periorbital cellulitis with bacteremia who developed meningitis while receiving cefamandole. This failure was thought to be due to the inadequate extravasation of the antibiotic even across the inflamed meninges. Parenthetically, two other patients with cellulitis due to H. influenzae with associated bacteremia defervesced rapidly and had uncomplicated recoveries. The fourth patient with cellulitis due to H. infiuenzae (but without bacteremia) also fared well. Cefamandole showed excellent in vitro activity against ampicillin-resistant H. iniiuenzac (figure 1). All previous cephalosporins have been only mildly active against H. infiuenzae as shown in figure 3, which compares the inhibitory activity of
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0.095 0.19 0.39 0.78 1.56 3.12 6.25 12.5 25 50 100 Minimum Inhibition Concentration Ill!I/mll
Figure 3. In vitro susceptibility of 100 ampicillinsensitive strains of Haemophilus injluenzae to four antibiotics.
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clear leukoctyes. Cultures of blood and the right eye obtained on admission subsequently yielded H. in[luenzae type b. CSF obtained at the time of hospitalization showed 1 'VBC/mm3 and, on cytocentrifugation, only lymphocytes were seen; culture and smear of CSF were negative. Treatment with cefamandole was initiated shortly after admission in a daily dose of 100 mg/ kg administered iv in a 6-hr divided dosage schedule. Within 36 hr after admission, the periorbital swelling improved substantially, although the infant remained febrile. The temperature suddenly spiked to 40 C 12 hr later, and a repeat lumbar puncture was performed. The WBC count in the, CSF had risen to 548 leukocytesymm" with 74% polymorphonuclear cells; a smear suggested and a culture confirmed the presence of H. influenzae type b. The MIC of cefamandole was 0.78 /1-g/ml, which was the same MIC noted for the strains of H. influenzae isolated from blood and eye cultures on admission of the patient. Parenthetically, a repeat blood culture obtained at the time of the second lumbar puncture was sterile. Carbenicillin was substituted for cefamandole, and within 12 hr the patient was afebrile. The infant subsequently recovered uneventfully. A specimen of CSF obtained at the time of diagnosis of meningitis (3.5 hr after a 25-mg/kg iv bolus) contained no detectable cefamandole.
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cephalothin against over 8,000 clinical bacterial isolates. Antimicrob. Agents Chemother. 9:1066-1069, 1976. Sande, M. A., Minor, M. R., Dilworth, J. A., Mandell, G. L. Cefamandole treatment of pulmonary infections caused by grarn-ncgat ive rods. J. Antimicrob. Chemother, 2:49-53, 1976. Kammer, R. B., Preston, D. A., Turner, J. R., Hawley, L. C. Rapid detection of ampicillin-resistant Hemophilus influenzae and their susceptibility to sixteen antibiotics. Antimicrob. Agents Chemother, 8:91-94, 1975. Williams, J. D., Andrews, J. Sensitivity of Hemophilus influenzae to antibiotics. Br. Med. J. 1:134-137, 1974. Khan, W., Ross, S., Rodriguez, W., Controni, G., Saz, A. Hemophilus injluenzae type b resistant to ampicillin. A report of two cases. J.A.M.A. 229:298-301, 1974. Tomeh, M. 0., Starr, S. E., McGowan, J. E., Jr., Terry, P. M., Nahmias, A. J. Ampicillin resistant Hemophilus influenzae type b infections. J.A.M.A. 229:295-297, 1974. Katz, S. L. Ampicillin-resistant Hemophilus injluenzae type b: a status report. Pediatrics 55:6-8,1975. Bauer, A. W., Kirby, W. M. M., Sherris, J. C., Turck, M. Antibiotic susceptibility testing by a standardized single disc method. Am. J. Clin. Pathol. 45:493-496, 1966.
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treatment with cefamandole rather than the usual combination of ampicillin and oxacillin. Cefamandole would provide the required broad-spec. trum coverage when used alone in such instances. In addition, cefamandole would have the advantage of being efficacious if the causative organism were found to be an ampicillin-resistant strain of H. influenzae. This drug would similarly provide good coverage (prior to the availability of culture reports) in other infections in which H. influenzae is a potential causative agent, i.e., epiglottitis, pyogenic arthritis, and, to a lesser extent, bacterial pneumonia. It is important to emphasize that in cases of bacteremia due to H. influenzae, a lumbar pun£ture should be done to ascertain the concomitant meningeal status of the patient. The relatively poor extravasation of cefamandole across the blood-brain barrier, when currently recommended therapeutic doses of the drug are used, might render cefamandole of dubious value if meningitis had supervened sequential to the bacteremia.
