ANTIMIROBIAL AGENTS AND HEMOTHERAPY, Mar 1982, p 402-406 0066-4804/82/030402-05$0200/0 Vol 21, No 3 Efficacy of eftriaxone in Serious Bacterial Infections JAY S EPSTEIN, SUSAN M HASSELQUIST, AND GARY L SIMON* Division of Infectious Diseases, Department of Medicine, George Washington University Medical enter, Washington, D 20037 Received 8 October 1981/Accepted 21 December 1981 eftriaxone is a new semisynthetic cephalosporin with broad-spectrum in vitro activity and an unusually long serum half-life The clinical efficacy of ceftriaxone was evaluated in 35 infections in 34 patients; 12 of these patients had skin and soft tissue infections, 10 had infections of the urinary tract, 8 had pneumonia, 2 had biliary tract infections, 1 had sinusitis, 1 had diverticulitis, and 1 had a retroperitoneal abscess Of the 35 infections, 9 were bacteremic The bacteria isolated included Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus faecalis, other streptococcal species, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Serratia marcescens, Enterobacter cloacae, Haemophilus influenzae, Pseudomonas aeruginosa, Bacteroides fragilis, other Bacteroides species, and anaerobic cocci Improvement or cure occurred in 32 episodes, for a response rate of 91% There were three treatment failures in patients with soft tissue infections No serious drug toxicities were observed At a dosage regimen of 1 g every 12 h the peak and trough serum antibiotic concentrations were well above the minimal inhibitory concentrations of most pathogens Our findings suggest that ceftriaxone is a safe and effective antibiotic for therapy of serious bacterial infections eftriaxone is a new semisynthetic 3-lactam antibiotic with excellent antimicrobial activity against most gram-positive and gram-negative bacteria, including Pseudomonas aeruginosa (1, 2, 4, 7, 9) The broad in vitro spectrum of ceftriaxone suggests that this agent may provide adequate therapy against most bacterial infections Furthermore, the long serum half-life of 65 to 86 h indicates that this drug can be given less frequently than conventional agents (3, 6, 8; N Wright and R Wise, Program Abstr Int onf hemother 12th, Florence, Italy, abstr no 988, 1981) In this report we describe our experience with ceftriaxone in the treatment of 35 bacterial infections MATERIALS AND METHODS All patients were adults hospitalized at The George Washington University Hospital, Washington, D Patients were entered into the study on the basis of documented or presumed bacterial infections after evaluation by the Division of Infectious Diseases staff Informed consent was obtained before participation in the study The ages of the patients ranged from 23 to 82 years (mean, 56 years) The sex distribution was 22 males and 16 females Before therapy, cultures of blood, urine, and other appropriate sites (eg, sputum, wound, abscess cavity) were obtained ultures were obtained again 48 h after therapy was initiated and 48 h after completion of therapy, when clinically appropriate Ṫhe diagnosis of bacteremia was established by positive blood cultures associated with an appropriate 402 clinical setting A diagnosis of pneumonia was based on roentgenographic evidence of a pulmonary infiltrate and a positive culture and compatible Gram stain of sputum The diagnosis of urinary tract infection was based on pyuria and culture from freshly voided urine of 105 or more organisms per ml The criteria for soft tissue infection included erythema, suppuration, and a positive culture Diagnoses of osteomyelitis, acute sinusitis, and retroperitoneal abscess were established by appropriate roentgenographic studies and cultures of the infected sites Infections of the biliary tract were diagnosed by the characteristic clinical and laboratory findings of right upper quadrant tenderness and elevation of the serum bilirubin and alkaline phosphatase levels In one case there was an associated bacteremia, and in another a stone-laden, pathological gall bladder was observed during surgery eftriaxone (disodium salt) was obtained as a crystalline powder from Hoffmann-LaRoche Inc The dose of drug (1 g every 12 h) was dissolved in 50 ml of 5% glucose and infused intravenously over a period of 20 min No other antimicrobial agents were administered during ceftriaxone therapy Toxicity was monitored by measuring hemoglobin, hematocrit, differential leukocyte count, platelet count, serum creatinine, and liver function enzymes and by urinalysis before therapy, every 4 days during therapy, and after the drug was discontinued The patients were examined daily by a member of the Division of Infectious Diseases staff Toxicity was reported if it occurred in any patient who received ceftriaxone for 3 or more days, regardless of ultimate outcome or status of the infection The clinical response was evaluated for each documented infection in patients who received at least 72 h Downloaded from http://aacasmorg/ on July 7, 2018 by guest
VOL 21, 1982 of ceftriaxone therapy ure was defined as resolution of systemic and local signs of infection, accompanied by elimination of the pathogen from cultures of the original site of infection Improvement was defined as the occurrence of two of the following: (i) resolution of fever, (ii) elimination of the pathogen from the infected site, or (iii) disappearance of local signs of infection Patients in whom urinary tract infections were eradicated while they were receiving ceftriaxone but who were placed on subsequent antibiotic suppression were categorized as improved rather than cured Patients in whom soft tissue infections responded to ceftriaxone but who required amputation for underlying chronic osteomyelitis or vascular insufficiency were also classified as improved rather than cured The osteomyelitis in these cases was not evaluated for efficacy of the drug Four patients could not be evaluated for clinical efficacy Two of these patients had pulmonary infiltrates but were not infected One of these two had recurrent pulmonary emboli, and the other had pulmonary hemorrhage Two other patients could not be assessed because they died within 36 h of initiation of therapy One, who had metastatic bronchogenic carcinoma and P aeruginosa pneumonia and bacteremia, initially defervesced and appeared to improve clinically during ceftriaxone therapy, but then rapidly deteriorated and died; the other, who had Staphylococcus aureus bacteremia, died of preexisting gastrointestinal bleeding from a duodenal ulcer The susceptibilities of bacterial isolates to ceftriaxone were determined initially by standardized disk diffusion methods The minimal inhibitory concentrations (MI) for most isolates were determined by a microtiter dilution technique, using Trypticase soy broth and an inoculum of 005 ml of an overnight broth culture containing 105 colony-forming units per ml Sera for measurements of concentrations of ceftriaxone were obtained immediately before and 10 min after antibiotic infusion on day 4 of therapy The antibiotic concentration was determined by the agar well diffusion method, using Escherichia coil as the test organism RESULTS A total of 35 infections in 34 patients were evaluated for clinical response to ceftriaxone (Table 1) These included 12 skin and soft tissue infections, 10 urinary tract infections, 8 pneumonia infections, 2 biliary infections, 1 diverticulitis, 1 sinusitis, and 1 retroperitoneal abscess The overall response rate was 91%, with a total of 19 infections cured and 13 improved Three patients with soft tissue infections did not respond to ceftriaxone therapy There were 10 urinary tract infections which were improved or cured by ceftriaxone therapy Five episodes were associated with bacteremia The bacteria isolated included E coli (seven cases), Serratia marcescens (two cases), and Proteus mirabilis (one case) In one patient with a urinary tract infection and bacteremia due to LINIAL TRIAL OF EFTRIAXONE 403 S marcescens (MI, 78 p,g/ml), the isolate was resistant to all of the antibiotics currently available in the hospital, including amikacin There were 12 patients with skin and soft tissue infections who received ceftriaxone Seven of these patients had adult onset diabetes mellitus, two were intravenous drug abusers, and one developed an infected hematoma while receiving heparin for iliac vein thrombophlebitis A single pathogen was isolated from four patients, including S aureus from two patients, Staphylococcus epidermidis from one patient, and a streptococcal species from one patient The remaining eight patients had polymicrobial infections Nine patients were cured or improved, and three failed In two diabetic patients there was underlying chronic osteomyelitis, which was surgically excised after improvement of cellulitis due to ceftriaxone treatment In one patient who failed after 9 days of therapy, there was persistent erythema and purulence at the site of infection, and S epidermidis (MI, 25 pg/ml) was isolated (patient 9) This patient responded to a specific anti-staphylococcal antibiotic In the other two patients who failed, fever persisted despite surgical debridement, and both of these patients required amputation to control the infection In one patient (patient 10) all of the organisms isolated were susceptible to ceftriaxone, whereas in the other (patient 8) only the enterococcus was resistant (MI, >256 pg/mi) Eight patients with pneumonia were cured by ceftriaxone therapy Five of these patients were infected with Streptococcus pneumoniae, one was infected with Haemophilus influenzae, and two were infected with both S aureus and a streptococcal species Two patients with biliary infections responded to ceftriaxone therapy In one patient blood cultures were positive for Klebsiella pneumoniae The other patient had a fever of 393 and clinical and laboratory evidence of biliary obstruction, but negative blood cultures This patient underwent a cholecystectomy after 1 week of therapy with ceftriaxone, at which time gall bladder cultures were sterile There was a single episode of sinusitis, which improved with resolution of fever and purulent drainage A culture of the sinus revealed a mixed flora, including P aeruginosa and S marcescens A case of diverticulitis with polymicrobial bacteremia also improved with ceftriaxone therapy, with resolution of fever, leukocytosis, and abdominal tenderness Several weeks after discharge, the symptoms recurred, and a sigmoid resection confirmed the presence of a diverticular abscess An intravenous drug abuser with a retroperitoneal abscess improved with ceftriaxone therapy and percutaneous drainage despite Downloaded from http://aacasmorg/ on July 7, 2018 by guest
404 EPSTEIN, HASSELQUIST, AND SIMON ANTIMIROB AGENTS HEMOTHER 00 10-0-0 ~ - 2 --2- - 4) Nt4 4)4 10 -ug 0 000 0 o44r)4~4 ) 4 ~~~~~~~~~~~~~~~~~~~~~~o '0~~~~~~~~~~~~~~~~~~~~~~~o 4) Downloaded from http://aacasmorg/ 0~~~~~~~~~~~r '4 '~~~~~~~~~~~ 0 ~ o 0 0 E 41' ') I-4 4) 00~~~~~~~~ 4) 0 u 0uu 0U '4 ~~~~~~~~~~ '4 on July 7, 2018 by guest
VOL 21, 1982 LINIAL TRIAL OF EFTRIAXONE 405 as 00 E E E 40 4 4;: cq s S: o cq m _ a,h X0E 4,E L *w ) Y r "0 4 _O O v 0 00 4)- O 0 m 4-0- )o W0 Q _ a>4 4) *_ d o r ' 0 0 '_ 0 o O _ ) O~ t 3 4-= D the initial isolation of a resistant Bacteroides thetaiotaomicron strain (MI, 125 pg/ml) In 30 patients serum antibiotic concentrations were determined on day 4 of therapy At 10 min after infusion ended, the serum antibiotic concentrations ranged from 66 to 250,ug/ml (mean + standard error of the mean, 1294 ± 84,ug/ml) The serum concentrations of antibiotic immediately before infusion varied from 135 to 145 jig/ ml (mean ± standard error, 421 ± 54,ug/ml) Adverse reactions to ceftriaxone were encountered in eight patients None of these reactions was serious enough to discontinue therapy Five patients developed phlebitis at the intravenous site, and two patients had persistent fevers of 380 to 385 for more than 1 week of therapy In both of these patients the temperature returned to normal within 36 h after the drug treatment was discontinued One, patient complained of dizziness regularly during drug infusion DISUSSION The clinical response rate to ceftriaxone therapy in this study was 91% for 35 bacterial infections which represented a wide spectrum of diseases and pathogens This compares favorably with the results reported by other investigators (5; H Giamarellou, B Poulopoulos, et al, Program Abstr Int onf hemother 12th, Florence, Italy, abstr no 995, 1981; H Pichler, W Valasek, et al, 12th I, abstr no 990; W Graninger, T P Egger, et al, 12th I, abstr no 628; J D Baumgartner, J P Bernard, and M P Glauser, 12th I, abstr no 626) There were three patients who failed to respond to ceftriaxone therapy In two of these patients a staphylococcal species was isolated from the site of infection Like other new 1- lactam antibiotics, ceftriaxone has reduced in vitro activity against staphylococci compared with older agents, such as cephalothin and cefamandole (1, 2, 7) On the other hand, the achievable serum concentration of ceftriaxone far exceeds the MI for most staphylococcal species Whether reduced in vitro activity against staphylococci is a real deficit in the clinical use of this drug remains unresolved, and further studies will be needed to evaluate this issue The serum levels obtained in this small study suggest that adequate antibiotic levels can be achieved with a twice-per-day regimen The mean trough serum concentration of 421,ug/ml exceeds the MI for most pathogens We observed no serious reactions to ceftriaxone in 38 evaluable courses of therapy Transient neutropenia and thrombocytopenia have been reported previously (3) The results of this study indicate that ceftriaxone is an effective agent in the treatment of Downloaded from http://aacasmorg/ on July 7, 2018 by guest
406 EPSTEIN, HASSELQUIST, AND SIMON serious bacterial infections This efficacy, together with favorable pharmacokinetics, indicates a need for a broad comparison of ceftriaxone with currently available antibiotics AKNOWLEDGMENTS We thank Heather Miller for technical assistance and Pamela Wheeler and Patricia Rupinski for secretarial assistance LITERATURE ITED 1 Angehrn, P, P J Probst, R Reiner, and R L Then 1980 Ro 13-9904, a long-acting broad-spectrum cephalosporin: in vitro and in vivo studies Antimicrob Agents hemother 18:913-921 2 Eickhoff, T, and J Ehret 1981 omparative in vitro studies of Ro 13-9904, a new cephalosporin derivative Antimicrob Agents hemother 19:435-442 3 Fernex, M, and L Havas 1981 Introduction and review hemotherapy (Basel) 27(Suppl 1):1-8 ANTIMIROB AGENTS HEMOTHER 4 Hinkle, A M, and G P Bodey 1980 In vitro evaluation of Ro 13-9904 Antimicrob Agents hemother 18:574-578 5 Keller, R, and L Humaur 1981 Treatment of severe respiratory tract infections with ceftriaxone (Ro 13-9904) A pilot study hemotherapy (Basel) 27(Suppl 1):93-99 6 Patel, I H, K Miller, R Weinfeld, and J Spicehandler 1981 Multiple intravenous dose pharmacokinetics of ceftriaxone in man hemotherapy (Basel) 27(Suppl 1):47-56 7 Shannon, K, A King, Warren, and I PhIHips 1980 In vitro antibacterial activity and susceptibility of the cephalosporin Ro 13-9904 to beta-lactamases Antimicrob Agents hemother 18:292-298 8 Stoeckel, K 1981 Pharmacokinetics of Rocephin, a highly active new cephalosporin with an exceptionally long biological half-life hemotherapy (Basel) 27(Suppl 1):42-46 9 Verblst, L, and J Verhaegen 1981 In vitro activity of Ro 13-9904, a new,b-lactamase-stable cephalosporin Antimicrob Agents hemother 19:222-225 Downloaded from http://aacasmorg/ on July 7, 2018 by guest