Twice daily ceftriaxone therapy for serious bacterial infections in children

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1 Journal of Antimicrobial Chemotherapy (1984) 13, Twice daily ceftriaxone therapy for serious bacterial infections in children Tasnee Chonmaitree*, Blaise L. Congenif, Jose Munoz+, Tamara A. Rakusan*, Keith R. Powell^ and Quellin T. Box* Department of Pediatrics, University of Texas Medical Branch, Galveston*, Department of Pediatrics, Northeastern Ohio Universities College of Medicine at Children's Hospital Medical Center ofakron\, and Department ofpediatrics, University of Rochester, Rochester, N. Y.% U.S.A. The clinical efficacy and safety of ceftriaxone, a long half-life cephalosporin were evaluated in 48 children with a variety of serious bacterial infections. Clinical cure was achieved in 92% (44 of 48) of patients. Peak serum bactericidal titres for Haemophilus influenzae type b, Streptococcus pneumoniae, Str. pyogenes and Escherichia coli were > 1 :1024. Mean peak and trough ceftriaxone levels were 173 and 42 mg/1, respectively. Mild and transient diarrhoea was observed in 10% of patients. Laboratory side effects encountered were eosinophilia, thrombocytosis and neutropenia in another 8%. Ceftriaxone is a useful antibiotic for common childhood infections. Its prolonged half-life allows twice daily administration which reduces problems related to intravenous therapy as well as the cost and personnel time. Introduction Newly developed cephalosporins are being considered as alternatives to the current therapy for serious bacterial infections in children because of their broad spectrum of activity, their relative safety compared with other types of antibiotics and their superior penetration into cerebrospinal fluid (CSF) compared with the older cephalosporins (Schaad et al, 1981). Ceftriaxone is a newly developed cephalosporin with excellent in-vitro activity against common bacteria causing serious childhood infections such as Haemophilus influenzae type b, Streptococcus pneumoniae and Neisseria meningitidis. A potential advantage over other recently developed cephalosporins is its long half-life. Ceftriaxone has a serum half-life of 4 8 h compared with 1-3 h for latamoxef (moxalactam), cefotaxime, cefoperazone and other investigative third-generation cephalosporins; therefore, administration intervals can be extended to every 12 h or longer (Chadwick et al., 1983a; Del Rio et al., 1982; O'Callaghan, 1979; Schaad, et al., 1981). The efficacy of twice daily ceftriaxone therapy in adults (Bradsher, 1982; Epstein, Hasselquist & Simon, 1982; Gnann et al., 1982; Maslow et al., 1982) as well as the pharmacokinetics of ceftriaxone in infants and children have been described (Chadwick et al., 1983a; Del Rio et al., 1982; Latif & Dajani, 1983; Schaad & Stoeckel, 1982). We studied the clinical efficacy and safety of twice daily ceftriaxone therapy for serious bacterial infections in infants and children /84/ $02.00/ The British Society for Antimicrobial Chemotherapy

2 512 T. Chonmaitree et al. Table I. Diagnosis and outcome of patients treated with ceftriaxone No of patients with satisfactory outcome*/no. treated Duration of therapy (days) Cellulitis 10/ Meningitis 7/ Urinary tract infection 7/7 5-8 Pneumonia 4/ Epiglottitis 4/4 5-7 Septicaemia 3/4 2-7 Septic arthritis Osteomyelitis 3/3 3/ Mastoiditis V-P shunt infection 2/3 0/ Wound infection 1/1 5 Total 44/48 Satisfactory clinical response with subsequent negative cultures of the infected site when available. Materials and methods Hospitalized infants and children with a variety of bacterial infections were enrolled in the study. Written informed consent was obtained from the parents in all cases. Cultures of blood and other infected body sites were obtained prior to antibiotic therapy and during or at the end of therapy when available. Patients with negative pretreatment cultures were excluded from the study except for three patients with positive latex agglutination tests for H. influenzae type b. Cultured specimens were processed in the usual way by the clinical microbiology laboratories. Susceptibilities of bacterial isolates to ceftriaxone were determined initially by standardized disc diffusion methods. The minimum inhibitory concentrations (MIC) were determined by the tube dilution technique, with Mueller-Hinton broth and an inoculum of I0 5 colony-forming units. Ceftriaxone levels were determined during the first three days of intravenous therapy by high pressure liquid chromatography carried out by Hoffman-LaRoche, Nutley, New Jersey. Peak levels were obtained immediately after the completion of infusion, and trough levels were taken immediately preceding the dose. Ceftriaxone was administered twice daily by the intravenous route (10-15 min infusion) at least for the first five days of therapy. The drug was continued intravenously or intramuscularly thereafter. For patients with meningitis 100 mg/kg/day of ceftriaxone was given; doses of mg/kg/day were used in patients with other infections. Pretreatment laboratory studies included complete blood count, urinalysis, BUN, creatinine and liver function studies (SGOT, SGPT, alkaline phosphatase and prothrombin time). These tests were repeated every four days during therapy and at the end of therapy. Results Forty-eight patients (24 male and 24 female) were included in the study. Their ages ranged from 1 month to 17 years with a mean age of 3-9 years and a median age of 1 year. The diagnoses and duration of therapy are shown in Table I. The diagnosis

3 Efficacy of ceftriaxone in childhood infections 513 Table II. Clinical diagnosis and bacterial pathogens from 48 patients treated with ceftriaxone Bacteria No. of isolates Clinical diagnosis H. influenzae type b E. coli Str. pyogenes Staph. aureus Str. pneumoniae Sir. agalactiae Fus. nucleatum Str.faecalis Staph. epidermis Staph. saprophyticus Klebsiella pneumoniae Ser. marcescens Ps. aeruginosa Totalt 17* 'Including three diagnosed by latex particle agglutination only. fa patient with cellulitis grew both Staph. aureus and Sir. pyogenes meningitis (5), pneumonia (4), epiglottitis (4), cellulitis (3), septic arthritis (1) UTI (6), septicaemia (1), V-P shunt infection (1) cellulitis septic arthritis (2), cellulitis (1), wound infection (1) meningitis (2), sepsis (1), mastoiditis (1) septicaemia (1), osteomyelitis (1) cellulitis (1), mastoiditis (1) septicaemia V-P shunt infection UTI osteomyelitis osteomyelitis mastoiditis of septicaemia was made when a blood culture was positive for a pathogenic organism in the presence of associated signs and symptoms. Three patients (one each with epiglottis, pneumonia and septic arthritis) had no organism isolated, but had a positive latex agglutination test for//, influenzae type b from serum or joint fluid. Fortyfour patients (92%) responded satisfactorily to the treatment, and repeat cultures when available were sterile. One patient with enterococcal septicaemia and pyelonephritis had no apparent clinical response to ceftriaxone although the disc sensitivity indicated that the organism was sensitive to the drug. Ceftriaxone was discontinued after 24 h and ampicillin was started. A three year old female who had previously been treated for otitis media developed mastoiditis which clinically responded to ceftriaxone. However, fluid from the middle ear grew Pseudomonas aeruginosa resistant to ceftriaxone pre and post therapy; gentamicin was then added. One patient with a ventriculo-peritoneal shunt and Staphylococcus epidermidis meningitis was treated with ceftriaxone without removal of the shunt. Although the disc sensitivity indicated that the organism was sensitive to ceftriaxone and the CSF bactericidal level at 1 h after dose was 1:8, sterility of the ventricular fluid was not achieved at two and four days after beginning therapy. Another 3 month old patient with a complicated course of Escherichia coli meningitis was treated with latamoxef (moxalactam) and trimethoprim-sulphamethoxazole and discharged with a ventriculoperitoneal shunt. He returned with an E. coli shunt infection and died 20 h after admission and initiation of ceftriaxone therapy. The organism was sensitive to ceftriaxone by disc testing. The clinical diagnoses and bacterial pathogens in the 48 patients treated with ceftriaxone are shown in Table II. All bacterial isolates except Ps. aeruginosa from a middle ear fluid were sensitive to ceftriaxone by Kirby-Bauer sensitivity. MICs of ceftriaxone were available for 12 isolates; for H. influenzae type b (five isolates), they

4 514 T. Chonmaitree et al. ranged from ^ to 0-25 mg/1; for Streptococcus pyogenes (three isolates) ^ mg/1; for E. coli (2) mg/1; for Str. pneumoniae (1) 0006 mg/1; Staph. aureus (1) 1-6 mg/1 and for Fusobacterium nucleatum (1) 001 mg/1. Peak serum bactericidal titres were measured in 11 cases. The values were ^ 1 : 1024 for H. influenzae type b, Str. pneumoniae, Sir. pyogenes and E. coli, 1 : 128 for Serratia marcescens and 1 : 64 for Staph. aureus. The CSF bactericidal titres obtained within the first 72 h of therapy for H. influenzae type b infections (four patients) ranged from 1 :512 to 5*1 : 1024 and in one patient with Str. pneumoniae infection it was 1 :256. Serum ceftriaxone concentrations were measured in 55 samples. Peak levels (29 samples) ranged from 66 to 271 mg/1 (mean = mg/1) and trough levels (26 samples) ranged from 11 to 44 (mean = 42-1 mg/1). Adverse clinical reactions were observed in five patients (10%). All developed mild diarrhoea with spontaneous resolution and did not require discontinuation of the drug. Abnormalities in laboratory findings occurred in four patients (8%). Two patients developed neutropenia (absolute neutrophil count = 616 and 390 mm 3 ) at day 5 and 14 of therapy respectively. Although neither had any clinical complication, ceftriaxone was discontinued and neutrophil counts became normal within two to seven days. Thrombocytosis and eosinophilia each occurred in one patient and neither required discontinuation of the drug. Discussion The results of our study indicate that ceftriaxone is effective when used as a single drug in the therapy of a variety of serious infections in children. The overall clinical cure rate of 92% (44 of 48) in our study is similar to data reported in adults (Bradsher, 1982; Epstein et al., 1982; Gnann et al., 1982; Maslow et al., 1982) and recently reported in children (Chadwick et al., 19836). Ceftriaxone was effective in treatment of all seven cases of meningitis in our series (five H. influenzae type b and two pneumococcal meningitis). The duration of therapy for patients with meningitis ranged from 10 to 14 days except in one patient with H. influenzae type b meningitis who responded well to therapy and had sterile CSF in 24 h. This patient developed neutropenia and ceftriaxone was discontinued on day 5. The CSF bactericidal titres for sensitive organisms were extremely high (^ 1 :256), the data were consistent with those reported by Del Rio et al. (1983). Two patients with ventriculoperitoneal shunt infection did not respond to ceftriaxone therapy; neither had removal of the shunt and one died before evaluation of ceftriaxone efficacy could be made. Mean peak and trough serum triaxone levels were high and comparable with the levels reported in children by Chadwick et al. (19836). Serum bactericidal concentrations were extremely high for H. influenzae type b, Str. pneumoniae, Str. Pyogenes and E. coli (> 1 : 1024) and moderately high for Ser. marcescens (1 : 128) and Staph. aureus (1 : 64). All patients tolerated ceftriaxone well; the only clinical side effect observed was mild and transient diarrhoea. Laboratory side effects observed in our patients included eosinophilia in one, thrombocytosis in one and neutropenia in two. Therapy was discontinued in only the latter two patients, and their neutrophil counts became normal shortly thereafter. Abnormalities of liver function were not observed in our series.

5 Efficacy of ceftriaxone in childhood infections 515 An advantage of ceftriaxone over other third generation cephalosporins is its long serum half-life which allows the drug to be given every 12 h or less (O'Callaghan, 1979; Schaad & Stoeckel, 1982). This has reduced some difficulties with intravenous administration in our patients as well as the expense in preparation and personnel time. An advantage of ceftriaxone over latamoxef (moxalactam) is the efficacy of this drug against group B streptococci and Str. pneumoniae (Del Rio et al., 1982; Delaplane, Yoger & Shulman, 1983; Jacobs, Kelly & Speck, 1982). We have successfully treated two patients with group B streptococcal infection and one with pneumonococcal meningitis. Available data do not support the use of latamoxef in the treatment of such conditions (Jacob et al., 1982; McCracken, Nelson & Grimm, 1982; Polk, 1982). Our experience suggests that ceftriaxone is a safe and effective antibiotic for use in common serious bacterial infections in children, especially those caused by H. injluenzae type b and Enterobacteriaceae. The effects of long term use of the drug as well as the efficacy of less than twice daily administration require further study. Acknowledgements We thank the participating paediatric house staff for their cooperation and Joan Latimer and Howard Williams for technical assistance. This work was supported in part by grants from Hoffman-LaRoche Laboratories. References Bradsher, R. W. (1982). Ceftriaxone (Ro ) therapy of serious infection. Antimicrobial Agents and Chemotherapy 22, Chadwick, E. G., Yogev, R., Shulman, S. T., Weinfeld, R. E. & Patel, I. H. (1983a). Singledose ceftriaxone pharmacokinetics in pediatric patients with central nervous system infections. Journal of Pediatrics 102, Chadwick, E. G., Conner, E. M., Schulman, S. T. & Yogev, R. (19836). Efficacy of ceftriaxone in treatment of serious childhood infections. Journal of Pediatrics 103, Del Rio, M., McCracken, Jr., G. H., Nelson, J. D., Chrane, D. & Shelton, S. (1982). Pharmacokinetics and cerebrospinal fluid bactericidal activity of ceftriaxone in the treatment of pediatric patients with bacterial meningitis. Antimicrobial Agents and Chemotherapy 22, Del Rio, M. A., Chrane, D., Shelton, S., McCracken, Jr., G. H. & Nelson, J. D. (1983). Ceftriaxone versus ampicillin and chloramphenicol for treatment of bacterial meningitis in children. Lancet i, Delaplane, D., Yogev, R. & Shulman, S. T. (1983). Ceftriaxone therapy of group B streptococcal bacteraemia and meningitis in infant rats. Journal of Antimicrobial Chemotherapy 11, Epstein, J. S., Hasselquist, S. M. & Simon, G. L. (1982). Efficacy of ceftriaxone in serious bacterial infections. Antimicrobial Agents and Chemotherapy 21, Gnann, J. W., Goetter, W. E., Elliott, A. M. & Cobbs, C. G. (1982). Ceftriaxone: In Vitro studies and clinical evaluation. Antimicrobial Agents and Chemotherapy 22, 1-9. Jacobs, M. R., Kelly, R. & Speck, W. T. (1982). Susceptibility of group B streptococci to 16 P-lactam antibiotics, including new penicillin and cephalosporin derivatives. Antimicrobial Agents and Chemotherapy 22, Latif, R. & Dajani, A. S. (1983). Ceftriaxone diffusion into cerebrospinal fluid of children with meningitis. Antimicrobial Agents and Chemotherapy 23, Maslow, M. J., Levine, J. F., Pollock, A. A., Simberkoff, M. S. & Rahal, Jr., J. J. (1982). Efficacy of a twelve-hourly ceftriaxone regimen in the treatment of serious bacterial infections. Antimicrobial Agents and Chemotherapy 22,

6 516 T. Chonmaitree et al. McCracken, G. H., Nelson, J. D. & Grimm, L. (1982). Pharmacokinetics and bacteriological efficacy of cefoperazone, cefuroxime, ceftriaxone, and moxalactam in experimental Streptococcus pneumoniae and Haemophilus influenzae meningitis. Antimicrobial Agents and Chemotherapy 21, O'Callaghan, C. H. (1979). Description and classification of the newer cephalosporins and their relationships with the established compounds. Journal of Antimicrobial Chemotherapy 5, Polk, R. E. (1982). Moxalactam. Drug Intelligence and Clinical Pharmacy 16, Schaad, U. B., McCracken, Jr., G. H., Loock, C. A. & Thomas, M. L. (1981). Pharmacokinetics and bacteriologic efficacy of moxalactam, cefotaxime cefoperazone and rochephin in experimental bacterial meningitis. Journal of Infectious Diseases 143, Schaad, U. B. & Stoeckel, K. (1982). Single-dose pharmacokinetics of ceftriaxone in infants and young children. Antimicrobial Agents and Chemotherapy 21, (Manuscript accepted I December 198J)