ANTicrtoBiAL AGzNTs AND CHmOTHERAPY, Feb. 1977, p. 369-371 Copyright © 1977 American Society for Microbiology

Vol. 11, No. 2 Printed in U.S.A.

Antimicrobial Activity of Cefamandole Against Salmonella typhi SHALOM Z. HIRSCHMAN,* BURT R. MEYERS, AND ALBERT MILLER Division of Infectious Diseases* and Division of Pulmonary Diseases, Department of Medicine, Mount Sinai School of Medicine of the City University of New York, New York, 10029 Received for publication 18 August 1976

A patient with Salmonella typhi bacteremia was sucessfully treated with cefamandole, a new cephalosporin derivative. Infection has not recurred during 6 months of follow-up observation. Minimum inhibitory concentrations and minimum bactericidal concentrations of cefamandole, cephalothin, ampicillin, and chloramphenicol were compared against 26 strains of S. typhi. All the strains were susceptible to cefamandole in vitro. Seven of the strains were resistant to chloramphenicol, and another seven were resistant to both chloramphenicol and ampicillin. Cefamandole appears to warrant further clinical trial for the treatment of typhoid fever.

Cefamandole, 7-D-mandelamido-3-3 {[(1methyl-3-cemethyl-lH-tetrazol-5-yl)-thio] phem-4 carboxylic acid, is a new semisynthetic cephalosporin derivative with a broad spectrum of antimicrobial activity including strains of Haemophilus influenzae (5). Hitherto, the effective agents for therapy of Salmonella typhi infections have been chloramphenicol (4) and ampicillin (4, 8). The similarity of cefamandole to ampicillin in the exquisite susceptibility of strains of H. influenzae to this new cephalosporin prompted us to consider cefamandole therapy in patients with typhoid fever. We report on the susceptibility in vitro ofS. typhi to cefamandole, including strains resistant to ampicillin, and the successful therapy of a typhoid fever patient with this new antimicrobial

ness (without swelling) of the right ankle. Frontal headaches, myalgia, and malaise soon followed. Two weeks before admission, the patient was admitted to another hospital where red spots were noted on his tongue. Blood, stool, and urine cultures were negative. The patient left against medical advice after 4 days. Three days later, the patient developed fever to 104°F (400C) orally, generalized arthralgia and myalgia, severe headache, and shortness of breath. These symptoms were followed by 2 days of watery stools and abdominal pain. The patient had lost 15 pounds (ca. 6.8 kg) of weight since onset ofthe illness. One week before the patient became ill, a friend was admitted to another hospital and treated for "salmonellosis." The patient had been hospitalized with hepatitis in 1964; review of systems was otherwise negative. Physical examination showed a lethargic young man with warm, dry skin. Blood pressure was 140/70 mm of Hg; pulse, 92/min and regular; respirations, 28/min; and rectal temperature, 101°F (38.30C). The tongue was erythematous, with red spots observed along the lateral anterior borders; the neck was supple. Examination of the lungs and heart was negative. There was no hepatosplenomegaly and no abdominal tenderness. Neurological and rectal exams were normal. Laboratory data on admission included a hemoglobin of 13.7 g/dl and a leukocyte count of 3,500/mm3, with a differential count of 25 neutrophils, 29 band forms, 32 lymphocytes, 6 monocytes, and 8 atypical lymphocytes. Urinalysis showed a pH of 5; specific gravity, 1.026; 1+ protein; and 3 to 5 leukocytes per high-power field. Arterial blood gases were normal. The

agent. S. typhi were isolated and identified in the diagnostic microbiology laboratory of The Mount Sinai Hospital by standard methods. The minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) of cefamandole, cephalothin, ampicillin, and chloramphenicol for 26 strains of S. typhi, initially tested for purity by standard techniques, were determined by the twofold tube dilution method in heart infusion broth (Difco) as described previously (5). Seven of the strains carried an R factor mediating resistance to chloramphenicol (2), and seven others carried an R factor conferring resistance to both ampicillin and chloramphenicol (7). Case report. D. L., a 34-year-old black male, entered The Mount Sinai Hospital with complaints of fever and malaise. Illness began 17 days before admission, with pain and tender369




erythrocyte sedimentation rate

was 23 mm/h (Westergren). The blood urea nitrogen was 18 mg/dl, and fasting blood sugar was 115 mg/dl. The serum amylase was 136 units; phosphorus, 2.7 mg/dl; cholesterol 123 mg/dl (lower limit of normal, 140 mg/dl); total bilirubin, 0.8 mg/dl; alkaline phosphatase, 62 I,uU/ml; glutamic pyruvic transaminase, 50 I,U/ml; oxaloacetic transaminase, 98 I,uU/ml (upper limit of normal, 50 I,uU/ml); albumin, 4 g/dl; globulin, 4 g/ dl; creatine phosphokinase, 419 I,uU/ml (upper limit of normal, 145 IIuU/ml); and creatinine, 1.4 g/dl. Urinary urobilinogen was positive at a 1:20 dilution. The prothrombin time was 15.4 s, with a control value of 12 s. The slide test for infectious mononucleosis was negative. Stool examination for ova and parasites was negative. The VDRL test for syphilis and the intermediate-strength purified protein derivative skin test were negative. S. typhi 0 and H agglutinins were 1:160 and 1:200, respectively. Electrocardiogram, chest X-ray, and oral cholangiography were normal. Liver-spleen scintigraphy showed patchy hepatic uptake. Blood cultures taken on admission grew S. typhi susceptible to ampicillin, chloramphenicol, gentamicin, tobramycin, kanamycin, and cefamandole by tube dilution test. Stool and urine culture were negative for S. typhi. The patient was treated with cefamandole, 2 g intravenously every 6 h for 14 days. The MIC and MBC of cefamandole for the isolate were 0.78 and 1.56 ,ug/ml, respectively. Defervescence occurred with 24 h after beginning therapy, and within 48 h the patient reported return of his sense of well-being. Blood cultures taken 24 h after beginning therapy were negative for S. typhi, and blood cultures remained negative

during the hospital stay. One week after therapy was initiated, laboratory data included a hemoglobin of 12.5 g/dl and leukocyte count of 4,600 mm3, with a differential count of 48 neutrophils, 3 band forms, 36 lymphocytes, 10 monocytes, 2 eosinophils, and 1 basophil. Serum chemistries showed an alkaline phosphatase of 99 I,uU/ml; total bilirubin, 0.2 mg/dl; glutamic pyruvic transaminase, 47 IuU/ml; oxaloacetic transaminase, 47 IuU/ml; creatinine phosphokinase, 177 I,tU/ml; albumin, 3.9 gm/dl; and globulin, 4.4 g/dl. The patient felt well upon discharge 18 days after admission. Stool cultures have remained negative for S. typhi during the 6 months after discharge. RESULTS All 19 strains of S. typhi tested that were susceptible to ampicillin were very suceptible to cefamandole (Table 1), with 63.2 and 100% of strains inhibited by concentrations of cefamandole of 1.56 and 2.5 ug/ml, respectively. The MBCs were only slightly higher than the MICs; all the strains were killed at a concentration of 5 ,ug/ml. These strains were inhibited and killed by concentrations of cephalothin and ampicillin of 12.5 and 6.25 ug/ml, respectively (Table 1); seven of the strains tested were resistant to choramphenicol (MIC > 25 ,ug/ml). During an epidemic of S. typhi infection in Mexico with strains carrying an R factor mediating resistance to chloramphenicol, tetracycline, streptomycin, and sulfonamides, Olarte and Galindo (7) encountered seven strains additionally resistant to ampicillin. The MIC and MBC of cefamandole for these ampicillin- and chloramphenicol-resistant strains are shown in

TABLE 1. Cumulative percentage of 19 strains of S. typhi inhibited (I) and killed (K) by cefamandole, cephalothin, ampicillin, and chloramphenicol % Strains inhibited and killed by: Conen (lgg Cefamandole Cephalothin Ampicillin Chloramphenicol 0.39 0.78 1.25 1.56 2.50 3.12 5.00 6.25 12.5 25 50 (>50)a a






10.5 36.9 52.6 63.2 100

0 31.6 42.1 52.6 73.7 79 100

0 15.8

0 5.3

0 10.5










94.7 100

84.2 100


strains of S. typhi.






0 57.9 63.2

0 5.3 36.8



VOL. 11, 1977



though the MICs of cefamandole for the ampicillin-resistant strains (c25 Ag/ml) were higher than those for the ampicillin-susceptible strains, the required inhibitory and bactericidal concentrations are easily achieved in seMI) Strain rum with intravenous cefamandole therapy (6). MBC MIC MIC MBC Some patients with typhoid fever do recover 50 >50 P-12 25 25 spontaneously. However, the patient reported 50 50 JRR 12.5 12.5 here had been ill for almost 3 weeks before 6.25 JM 3.12 3.12 6.25 admission, and the response to therapy was 50 50 25 H-185 25 prompt and marked. Furthermore, illness did 50 25 >50 LA 25 not recur after therapy. It would appear that 50 50 12.5 25 LAR I 50 50 LAR II 25 25 cefamandole warrants clinical trial for the therapy of S. typhi infections in areas where this organism is more prevalent. Table 2. The seven ampicillin-resistant strains of S. typhi were less susceptible to cefamandole We thank G. Brier of Eli Lilly and Co. for providing than the 19 ampicillin-susceptible strains, but strains of ampicillin-susceptible S. typhi, G. T. Keusch and still were inhibited by concentrations of cefa- S. Formal for chloramphenicol-resistant organisms, and J. < mandole 25 ,ug/ml. The ampicillin-resistant Olarte for his kindness in providing ampicillin-chloramstrains. The technical assistance of Z. strains were less susceptible to cephalothin phenicol-resistant (Table 2) and were highly resistant to both Sadka is appreciated. ampicillin and chloramphenicol (MICs > 50 ,ug/

TABLE 2. Susceptibility to cefamandole in vitro of seven strains of S. typhi resistant to both ampicillin and chloramphenicol Cefamandole (,.g/ Cephalothin (Ag/ml)

ml). The patient's clinical response to cefamandole therapy was prompt and complete after almost 3 weeks of continued illness. Defervescence occurred in 24 h and the patient was out ofbed within 48 h. Blood cultures became negative within 24 h, and the patient has remained well during 6 months of follow-up observation. Outbreaks of S. typhi infection with organisms resistant to chloramphenicol (1, 2) or to both chloramphenicol and ampicillin (7) have occurred. Although recent reports of the use of the combination of trimethoprim and sulfamethoxazole for the treatment of infections due to chloramphenicol-resistant S. typhi are encouraging (3), alternative effective parenteral therapy has hitherto not been available, especially in patients hypersensitive to ampicillin. Cephalothin has not proved clinically reliable despite the susceptibility of S. typhi to this antimicrobial agent in vitro (4). Cefamandole appears to be extremely effective against S. typhi in vitro and, furthermore, shares a property of ampicillin in its effectiveness in vitro against strains of H. influenzae. It is interesting to note that the ampicillin-resistant strains ofS. typhi isolated by Olarte and Galindo (7) in Mexico were susceptible to cefamandole. Al-


1. Anderson, S., and H. R. Smith. 1972. Chloramphenicol resistance in the typhoid bacillus. Br. Med. J. 3:329331. 2. Datta, N., and J. Olarte. 1974. R factors in strains of Salmonella typhi and Shigella dysenteriae 1 isolated during epidemics in Mexico: classification by compat-

ibility. Antimicrob. Agents Chemother. 5:310-317. 3. Gilman, R. H., M. Terminel, M. Levine, P. HernandezMendosa, E. Calderone, E. Vasquez, E. Martinez, M. J. Snyder, and R. B. Hornick. 1975. Comparison of trimethoprim-sulfamethoxazole and amoxicillin in therapy of chloramphenicol resistant and chloramphenicol sensitive typhoid fever. J. Infect. Dis.

132:630-635. 4. Hook, E. W., and W. D. Thompson. 1972. Typhoid fever, p. 593-601. In P. D. Hoeprich, (ed.), Infectious diseases. Harper and Row, New York. 5. Meyers, B. R., B. Leng, and S. Z. Hirschman. 1975. Cefamandole: antimicrobial activity in vitro of a new cephalosporin. Antimicrob. Agents Chemother. 8:734-741. 6. Meyers, B. R., B. Ribner, S. Yancovitz, and S. Z. Hirschman. 1976. Pharmacological studies with cefamandole in humans volunteers. Antimicrob. Agents Chemother. 9:140-144. 7. Olarte, J., and E. Galindo. 1973. Salmonella typhi resistant to chloramphenicol, ampicillin, and other antimicrobial agents: strains isolated during an extensive typhoid fever epidemic in Mexico. Antimicrob. Agents Chemother. 44:597-601. 8. Simon, J. J., and R. C. Miller. 1966. Ampicillin in the treatment of chronic typhoid carriers. N. Engl. J. Med. 274:807-815.

Antimicrobial activity of cefamandole against Salmonella typhi.

ANTicrtoBiAL AGzNTs AND CHmOTHERAPY, Feb. 1977, p. 369-371 Copyright © 1977 American Society for Microbiology Vol. 11, No. 2 Printed in U.S.A. Antim...
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