Efficacy of ceftriaxone in treatment of serious childhood infections

Volume 103 Number 1

We thank Drs. I. H. Patel and R. E. Weinfeld for high-power liquid chromatographic ceftriaxone determinations; the house officers at Arkansas Children's Hospital for management of patients; and Mrs. Elizabeth Robinson and Mrs. Penni Jacobs for editorial assistance.

REFERENCES 1. Bradsher RW, Ulmer WC: B-Lactam antibiotic susceptibility of bacteria responsible for neonatal meningitis. (In press.) 2. Bradsher RW: Ceftriaxone (RO 13-9904) therapy of serious infection. Antimicrob Agents Chemother 22:36, 1982. 3. Steele RW, Eyre LB, Bradsher RW, Weinfeld RE, Patel IH, Spicehandler J: Pharmacokinetics of ceftriaxone in pediatric patients with meningitis. (In press.) 4. Del Rio M, McCracken GH Jr, Nelson JD, Chrane D, Shelton S: Pharmacokinetics and cerebrospinal fluid bactericidal activity of ceftriaxone in the treatment of pediatric patients with bacterial meningitis. Antimicrob Agents Chemother 22:622, 1982. 5. Gavan TL, Barry AL: Microdilution test procedures. In Lennette EH, Balows A, Hausler WJ Jr, Truant JP, editors: Manual for clinical microbiology. Washington, D.C., 1980, American Society for Microbiology, p 459. 6. Patel IH, Chen S, Parsonnet M, Hackman MR, Brooks MA,

Clinical and laboratory observations

7.

8.

9.

10.

11.

12.

13.

14 1

Konikoff J, Kaplan SA: Pharmacokinetics of ceftriaxone m humans. Antimicrob Agents Chemother 20:634, 1981. Schaad UB, McCracken GH, Loock CA, Thomas ML: Pharmacokinetics and bacteriologic efficacy of moxalactam, cefotaxime, Cefoperazone, and rocephin in experimental bacterial meningitis. J Infect Dis 143:156, 1981. Sande MA: Antibiotic therapy of bacterial meningitis: Lessons we've learned. Am J Med 71:507, 1981. McCracken GH Jr, Mize SG: A controlled study of intrathecal antibiotic therapy in gram-negative enteric meningitis of infancy. Report of the Neonatal Meningitis Cooperative Study Group. J PEDIATR89:66, 1976. Eickhoff TC, Ehret J: Comparative in vitro studies of RO 13-9904, a new cephalosporin derivative. Antimicrob Agents Chemother 19:435, 1981. Gnann JW Jr, Goetter WE, Elliott AM, Cobbs CG: Ceftriaxone: In vitro studies and clinical evaluation. Antimicrob Agents Chemother 22:1, 1982. Shelton S, Nelson JD, McCracken GH Jr: In vitro susceptibility of gram-negative bacilli from pediatric patients to moxalactam, cefotaxime, RO 13-9904, and other cephalosporins. Antimicrob Agents Chemother 13:476, 1980. Kaiser AB, McGee ZA: Aminoglycoside therapy for gramnegative bacillary meningitis. N Engl J Med 293:1215, 1975.

Efficacy of ceftriaxone in treatment of serious childhood infections Ellen Gould Chadwick, M.D., Edward M. Connor, M.D., Stanford T. Shulman, M.D., and Ram Yogev, M.D. Chicago, Ill.

CEFTRIAXONE is a new cephalosporin with a broad spectrum of activity and increased potency against grampositive and gram-negative aerobic and anaerobic bacteria. Pharmacokinetic data indicate that ceftriaxone is unique when compared with other new cephalosporins in respect to its prolonged serum half-life, averaging 4 to 4.4 hours in pediatric patients. 1,2 In contrast, the longest serum half,lives for other new cephalosporins are 2.0 _+ 0.4 hours for cefotaxime in neonates 3 and 2.0 hours for moxalactam in children. 4 Mean cerebrospinal fluid ceftriaxone concentrations were shown to be 5.1% of serum values in children, with individual C S F concentrations exceeding the mean inhibitory concentrations of the infecting organisms by 480 to 5600 times. ~ Furthermore, Del Rio et al? reported that

From Division of Infectious Disease, The Children's Memorial Hospital, Northwestern University Medical School. Reprint requests: Stanford T. Shulman, M.D., Department of Pediatrics, Division of Infectious Diseases, The Children's Memorial Hospital, 2300 Children's Plaza, Chicago, IL 60614.

the modal C S F bactericidal titer was >_1:2048 in four infants with meningitis during treatment with ceftriaxone. The few side effects reported in patients treated with ceftriaxone have been mild and reversible?. 6 The purpose of this study was to evaluate the efficacy and safety of ceftriaxone in children with a variety of serious bacterial infections.

See related articles, pp. 70 and 138. M A T E R I A L S AND M E T H O D S Pediatric patients with signs and symptoms suggesting a bacterial infection were enrolled in the study. Patients were excluded if they had (1) history of a significant penicillin allergy, (2) severe renal or hepatobiliary disease, (3) received other antibiotics that might contribute to eradication of the infection (patients who had received prior antibiotics for an organism resistant to those antibiotics were not excluded), or (4) infection with organisms

14 2

Table

Clinical and laboratory observations

The Journal o f Pediatrics July 1983

I. Infections and pathogens treated with ceftriaxone in 34 patients ]

[

Number o f patients

Ventriculitis

9

Meningitis Pyelonephritis Cellulitis

6 4

Abscess

4*

3

Osteomyetitis

3

Periorbital cellulitis

2*

Organism E. coli H. influenzae type b S. epidermidis K. oxytoca E. cloacae H. influenzae type b E. coli S. aureus S. pyogenes Aeromonas hydrophila S. aureus S. pyogenes S. aureus Salmonella, group D

Non-enterococcal group D streptococcus

Infected seroma

It

Sepsis SBE

1

1

S. pyogenes S. aureus S. aureus H. influenzae, type b S. fecalis Salmonella paratyphi S. viridans

Number o f organisms

Duration o f therapy (days)

3 2 2 1 1 6 4 3

10 to 18 10 to 12 6to 12 16 30 10 to 11 10 5 to6

1 1

5 5

2

5t06

1 1 1 1

5 42 42 17~:

2

5-7

1 1 1 1 1 1

7 6:~

10 26

*One patienthad a mixedinfectioncaused by S. aureus and S. pyogenes. "~AIIisolateswere recovered fromone patient. ~:Seetext for details.

resistant to ceftriaxone (patients with mixed infections were included if the predominant species was susceptible to ceftriaxone). Written informed consent was obtained from parents of all patients. To assess potential side effects of ceftriaxone, pretherapy tests included complete blood count with differential, platelet count, serum glutamic oxalate transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase, total bilirubin, prothrombin time, blood urea nitrogen, creatinine, and urinalysis. These tests were repeated every four to seven days until the conclusion of treatment. Ceftriaxone, the sole antibiotic used, was administered intravenously over 15 to 30 minutes in a dosage of 25 to 37.5 mg/kg/dose every t2 hours, except in patients with CNS infections or osteomyelitis, who received 50 mg/ kg/dose every 12 hours, All patients were treated for at least five days. The clinical response was evaluated daily by one of us. Infection was documented by strict criteria. (1) Two positive blood cultures were needed to identify patients with septicemia. (2) A positive c~lt~ure for pathogenic organism(s) obtained by aspiration from soft tissue was a prerequisite for cellulitis. (3) Two urine cultures with ~105 colonies/ml of a single organism in a clean-catch midstream urine sample accompanied by signs and syrup-

toms of an upper urinary tract infection (e.g., fever and flank pain) were required to identify pyelonephritis. (4) A diagnostic technetium or gallium scan with a positive bone aspiration culture identified osteomyelitis. (5) A positive CSF or ventricular fluid culture was necessary to document meningitis or ventriculitis, respectively, All patients with ventriculitis had ventriculoperitoneal shunts prior to the acute infection. Repeat cultures were obtained two to seven days after start of treatment when feasible. Each organism isolated was screened for ceftriaxone susceptibility by Kirby-Ba~er disk; MICs and MBCs were determined by methods previously reported. 7 In addition, MICs and MBCs of standard antibiotics for the organisms were evaluated, Serum and CSF concentrations of ceftriaxone were measured by either the agar diffusion method 7 using a strain of Escherichia coli, provided by HoffmanLaRoche as the seed organism, or by high-pressure liquid chrbma'tography,~ kindly performed by Dr. I. H. Patel, Hoffman-LaRoche. Outcome was classified as cure, improvement, or failure. Cure was defined as one or more negative cultures of the infected site at the end of treatment (and during follow-up when feasible), with satisfactory clinical response. Improvement was defined as incomplete clinical response to therapy despite negative repeat cultures. Failure was

Volume 103 Number 1

Clinical and laboratory observations

14 3

Table II. MICs and MBCs of ceftriaxone and other antibiotics for recovered pathogens Mean MIC/MBC (#g/ml)

Number of organisms

Ceftriaxone

H. influenzae type b

9

0.004/0.007

E. coil Salmonella

7 2

0.07/0.07 0.125/0.125

S. pyogenes S. aureus S. epidermidis Other1"

3 8 2 6

0.02/0.02 1.4/2.6 4/8

Alternate drug

Ampicillin* Chloramphenicol Amikacin Ampicillin Chloramphenicol Penicillin Nafcillin Nafcillin

0.30/0.73 1.17/8.75 8.30/16.0 3.6/3.6 4/>32 0.22/0.22 0.3/0.36 0.19/0.19

*One ampicillin-resistantisolatedeleted. tSee text. defined as persistence of the pathogen in cultures after initiation of treatment or emergence of ceftriaxoneresistant organisms. RESULTS Forty-seven patients were included in the study; however, in 13 all cultures were negative, and they were subsequently excluded. The spectrum of diseases of the 34 patients (ages 3 weeks to 14 years, mean 5.3 years) with positive bacterial cultures is summarized in Table I. Thirty-one of 34 patients (91%) were cured, one patient improved, one patient had a treatment failure, and one patient was not evaluable. Fifteen of 34 patients (44%) had CNS infections caused by a variety of gram-positive and gram-negative organisms (Table I); 14 of 15 patients were cured of their infection. One patient with Haemophilus influenzae meningitis could only be classified as improved, despite the fact that the organism was highly sensitive to ceftriaxone (MIC and MBC = 0.004 #g/ml). He had a bacteriologic cure documented by sterile CSF and improving CSF findings on the third and eleventh days of therapy. The CSF ceftriaxone concentration 10 hours after a dose on the eleventh day was 3.2 #g/ml; however, he had an unfavorable clinical response, remaining irritable and febrile. Serial CT scans suggested a focal area of cerebritis. Ceftriaxone therapy was discontinued on day 11, and chloramphenicol (100 m g / k g / d a y PO) was given for seven days. Repeat CT scan on the hospital day 21 showed signs of resolution. The patient in whom treatment was considered a failure had a postoperative epidural seroma infected with H. influenzae, Staphylococcus aureus, and enterococcus. The first two pathogens were sensitive to ceftriaxone, whereas the enterococcus, with an MIC of 128 lzg/ml, was resistant. None of the three organisms could be eradicated with ceftriaxone, which necessitated a change in the antibiotic regimen. Two of three patients with osteomyelitis were cured, but

in one patient with group D non-enterococcal streptococcal osteomyelitis, ceftriaxone was discontinued because of icteric hepatitis, later shown serologically to be caused by acute hepatitis A. This patient was classified as unevaluable, although his clinical progress at the time Ceftriaxone was stopped was satisfactory. The MBC of ceftriaxone averaged 35 and 440 times lower than the MBCs of ampicillin and chloramphenicol, respectively, for isolates of H. influenzae type b (Table II). E. coli as well as Klebsiella oxytoca, Enterobacter cloacae, and Aeromonas hydrophila were substantially more sensitive to ceftriaxone (MBC = 0.0625 to 0.125 #g/ml) than ko amikacin (MBC = 2 to 32 #g/ml). Although S. pyogenes, S. viridans, and non-enterococcal group D streptococcus were highly sensitive to ceftriaxone (MIC = 0.02 to 0.31 tzg/ml), they were equally susceptible to ampicillin or penicillin. In contrast, staphylococcal isolates were seven to 40 times less susceptible to ceftriaxone than to nafcillin, and enterococci were resistant to ceftriaxone (MBC > 128 #g/ml). Serum ceftriaxone concentrations were measured in 15 of 34 patients. Values drawn one hour after injection ranged from 70 to 300 #g/ml (mean = 181.6/~g/ml), and trough values drawn just prior to the next dose varied from 23 to 100 ug/ml (mean = 49.3 izg/ml). Concentrations of ceftriaxone in CSF were measured from one to 12 hours after a dose in five patients with CNS infection; values ranged from 3.2 #g/ml to 13.7 #g/ml. No adverse clinical reactions were noted. Laboratory side effects were observed in 12 of 34 patients, including four patients with leukopenia (<4,500/mm 3) noted between days 7 and 22 of treatment, four patients with eosinophilia (>_500/mm 3) noted on days 6 and 14 of treatment, three patients with elevated liver enzyme values, and one patient with prolonged prothrombin time. All abnormalities returned to normal after the drug had been discontinued. Thrombocytosis occurred in 10 patients.

14 4

Clinical and laboratory observations

No patients, including those with pyelonephritis, who were followed for up to three months after treatment, had a clinical or bacteriologic relapse. Emergence of bacterial resistance to ceftriaxone was not evident, nor were secondary infections caused by resistant agents observed. DISCUSSION The overall clinical cure rate of 91% (31 of 34 patients) and bacteriologic cure rate of 94% (32 of 34) in our study are similar to rates reported in adults by Gnann et al? The 100% bacteriologic cure rate for pediatric CNS infections (15 patients) is comparable to those reported in abstract form by others. 6'9 Although it has been reported that ceftriaxone reaches the CSF less effectively than moxalactam (3% to 5% of serum levels for ceftriaxone 1,2 compared with 18.5% to 37% for moxalactam,4,7 the CSF concentration of ceftriaxone measured in five patients in our study exceeded the MIC of the patient's own organism by 1.25 to 2250 times. CSF ceftriaxone concentrations were reported to surpass the MICs of H. influenzae, N. meningitidis, and S. pneumoniae by 282 to 4200 times, 2 and MICs of group B streptococcus by 20 to 110 times. ~Delaplane et al. 1~were able to cure 100% of 45 infant rats with group B streptococcal meningitis by treatment with low doses (2 mg/kg) of ceftriaxone. Thus, ceftriaxone may be a very useful drug for pediatric CNS infections, with the exception of those caused by Listeria monocytogenes, which is resistant to ceftriaxone." Continued evaluation of ceftriaxone in the treatment of CNS infections will be necessary before definitive recommendations for use can be made. All patients in our study tolerated ceftriaxone well. Diarrhea, reported as a side effect in some series,6'9was not observed in our population nor in those of Gnann et at? or of Maslow et al. ~2 Prolonged prothrombin time was reported in patients receiving moxalactam TM ~4;however, only one patient in our study had an abnormal prothrombin time, which returned to normal while the patient continued to receive medication. Other investigators did not observe clotting abnormalities in a total of 92 patients treated with ceftriaxone.8.Jz. ~5 Thrombocytosis was seen in 12 of our patients and has been reported in other series?. ~5However, elevated platelet counts appear to be a common nonspecific indicator of resolving infection~6and may be unrelated to the use of a specific agent. Shelton et al. 17 demonstrated ceftriaxone to be highly active in vitro against gram-negative organisms isolated from pediatric patients. In addition, comparison of MICs of ceftriaxone and other antibiotics ffor isolates from our patients indicates that H. influenzae and Enterobacteriaceae are more sensitive to ceftriaxone than to standard antibiotics. Because in vitro data suggest that some strains of E. cloacae and Bacteroides fragilis are resistant to

The Journal of Pediatrics July 1983 ceftriaxone, 18 we are reluctant to recommend ceftriaxone as sole antibiotic treatment of E. cloacae or B. fragilis infections until susceptibility has been determined. The MICs of ceftriaxone for gram-positive cocci are greater or equal to those of the penicillins. Although all patients with gram-positive bacterial infections in our study were cured, including one patient with chronic S. aureus osteomyelitis, the new cephalosporins should not be considered drugs of choice for these infections. The prolonged half-life of ceftriaxone has enabled daily outpatient administration of this drug; this may prove to be a cost-effective therapeutic regimen for osteomyelitis or other infections requiring long-term parenteral antibiotic therapy. Eron et al., ~9 treating 29 patients with long bone and soft tissue infections caused by a variety of gram-positive and gramnegative organisms with once daily ceftriaxone therapy, reported a 93% satisfactory clinical response. The high cure rate reported in our group of patients, especially in those with CNS infections, coupled with the minimal side effects observed, suggest that ceftriaxone is a safe and effective therapeutic agent in the treatment of many serious bacterial infections of childhood. The newer cepbalosporins such as ceftriaxone seem particularly promising for CNS infections caused by H. influenzae and Enterobacteriaceae. We thank the Pediatric Housestaff of The Children's Memorial Hospitali Mr. Walter Glogowski and Mr. Gregory Snyder for technical assistance; Ms. Jody A. Kowalski and Ms. Constance Stevens for secretarial assistance. REFERENCES 1. Chadwick EG, Yogev R, Shulman ST, Weinfeld RE, Patel IH: Single-dose ceftriaxone pharmacokinetics in pediatric patients with central nervous system infections. J PEDIATR 102:134, 1983. 2. Del Rio M, McCracken GH, Nelson JD, Chrane D, Shelton S: Pharmaco~i~etics and cerebrospinal fluid bactericidal activity of ceftriaxone in the treatment of pediatric patients with bacterial meningitis. Antimicrob Agents Chemother 22:622, 1982. 3. Kafetzis DA, Brater DC, Kapiki AN, Papas CV, Dellagrammaticas H, Papadatos CJ: Treatment of severe neonatal infections with cefotaxime: Efficacy and pharmacokinetics. J PEDIATR100:483, 1982. 4. Kaplan SL, Mason EO, Garcia H, Kvernland SJ, Loiselle 'l~M,'AndersonDC, Mintz AA, Feigin RD: Pharmacokinetics and cerebrospinal fluid penetration of moxalactam in children with bacterial meningitis. J PEDIATR98:152, 1981. 5. EpsteinJS, Hasselquist SM, Simon GL: Efficacy of ceftriaxone in serious bacterial infections. Antimicrob Agents Chemother 21:402, 1982. 6. Del Rio MA, Chrane DF, Shelton S, McCracken GH, Nelson JD: Ceftriaxone versus standard therapy for acute bacterial meningitis in infants and children. Presented at 22nd ICAAC

Volume 103 Number 1

7.

8.

9.

10.

1l.

12.

13.

Meeting, American Society of Microbiology, Miami Beach, Fla., 1982. Yogev R, Schreiber M, Gardner S, Shulman ST: Moxalactam in the treatment of pediatric infections. Am J Dis Child 136:836, 1982. Gnann JW, Goetter WE, Elliott AM, Cobbs CG: Ceftriaxone in vitro: Studies and clinical evaluation. Antimicrob Agents Chemother 22:1, 1982. Congeni B: A comparison of ceftriaxone (RO) and traditional therapy in bacterial meningitis. Presented at 22nd ICAAC Meeting, American Society of Microbiology, Miami Beach, Fla., 1982. Delaplane D, Yogev R, Shulman ST: Ceftriaxone therapy of group B streptococcal bacteremia and meningitis in infant rats. J Antimicrob Chemother 11:69, 1983. Neu HC, Meropol N J, Fu KP: Antibacterial activity of ceftriaxone (RO 13-9904) a /3-Jactamase-stable cephalosporin. Antimicrob Agents Chemother 19:414, 1981. Maslow M J, Levine JF, Pollock AA, Simberkoff MS, Rahal J J: Efficacy of a twelve-hourly ceftriaxone regimen in the treatment of serious bacterial infections. Antimicrob Agents Chemother 22:103, 1982. Mathisen GE, Meyer RD, Thompson JM, Finegold SM: Clinical evaluation of moxalactam. Antimicrob Agents Chemother 21:780, 1982.

Clinical and laboratory observations

14 5

14. Pickard W, Durack D, Gallis H: A randomized trial of moxalactam versus tobramyein plus ticarcillin (T + T) in 50 febrile neutropenic patients. Presented at 22nd ICAAC Meeting, American Society of Microbiology, Miami Beach, Fla., 1982. 15. Bradsher RW: Ceftriaxone (RO 13-9904) therapy of serious infections. Antimicrob Agents Chemother 22:36, 1982. 16. Petty BG, Smith CR, Wade JC, Conrad GL, Lipsky J J, EIlner J J, Leitman PS: Double-blind comparison of cefamandole and penicillin in pneumococcal pneumonia. Antimicrob Agents Chemother 14:13, 1978. 17. Shelton S, Nelson JD, McCracken GH: In vitro susceptibility of gram-negative bacilli from pediatric patients to moxalaetam, cefotaxime, RO 13-9904, and other cephalosporins. Antimicrob Agents Chemother 18:476, 1980. 18. Beskid G, Christenson JG, Cleeland R, DeLorenzo W, Trown PW: In vivo activity of ceftriaxone (RO 13-9904),. a new broad-spectrum semisynthetic cephalosporin. Antimicrob Agents Chemother 20:159, 1981. 19. Eron L, Park CH, Goldenberg R, Poretz D: Once daily ceftriaxone therapy of bone and soft tissue infections. Presented at 22nd ICAAC Meeting, American Society of Microbiology, Miami Beach, Fla., 1982.