ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, July 1982, p. 1-9 Vol. 22, No. 10066-4804/82/070001-09$02.00/0

Ceftriaxone: In Vitro Studies and Clinical EvaluationJOHN W. GNANN, JR.,* WILLIAM E. GOETTER, ANN M. ELLIOTT, AND C. GLENN COBBSDepartment of Medicine, University ofAlabama School of Medicine, Birmingham, Alabama 35294

Received 28 December 1981/Accepted 9 April 1982

The in vitro activity of ceftriaxone against 437 clinical isolates of gram-negativebacilli was determined. Ceftriaxone was found to have high in vitro activityagainst Enterobacteriaceae, with the exception of Enterobacter cloacae. Cef-triaxone was only minimally active against Pseudomonas aeruginosa and Acine-tobacter calcoaceticus. We evaluated the clinical efficacy and toxicity of ceftriax-one in 55 adult patients. Bacterial infection was confirmed by the isolation ofetiological bacteria in 30 patients. Infectious disorders treated included 10pneumonias, 13 urinary tract infections, and 7 soft tissue or bone infections.Pathogens identified were 25 isolates of gram-negative bacilli, 5 isolates ofStaphylococcus aureus, 5 isolates of pneumococci, and 4 isolates of otherstreptococci. The overall efficacy of ceftriaxone was excellent. The clinical curerate was 93%, and the bacteriological cure rate was 93%. A total of 30 adversereactions were noted in 22 of 55 patients receiving ceftriaxone, but only onenecessitated discontinuation of treatment. Adverse effects frequently noted wereelevated hepatic enzymes (16%), thrombocytosis (16%), and eosinophilia (8%).Ceftriaxone is an effective and well-tolerated antimicrobial agent that appearspromising for the treatment of serious gram-negative bacillary infections.

Since introduction of the parent compoundcephalothin in 1962, cephalosporins have beenpopular with physicians because of their rela-tively broad range of antibacterial activity andlack of serious toxicity. Ceftriaxone (Ro 13-9904), a 2-aminothiazolyl methoxyimino cepha-losporin derivative, is one of several "third-generation" cephalosporins developed in recentyears. Included in this group are the currentlymarketed drugs cefotaxime (10) and moxalactam(13), as well as the investigational agents cefo-perazone (16), ceftazidime (20), cefmenoxime*(28), and ceftizoxime (12). All possess excellentactivity against many gram-positive and gram-negative bacteria, including a number of speciesnot susceptible to earlier cephalosporins. Cefsu-lodin (25), a related drug, has activity directedagainst Pseudomonas aeruginosa and Staphylo-coccus aureus.The chemical manipulations that have result-

ed in the extension of antimicrobial activity havegenerally not resulted in substantial changes inpharmacokinetic properties. The serum half-lives of cefotaxime and moxalactam are 1.25 h(14) and 2.73 h (30), respectively, which do notdiffer substantially from the half-life of cefazo-lin, which is 1.8 h (3). In contrast, ceftriaxone,which is structurally somewhat similar to cefo-taxime but has a triazine substituent at the 3position on the nucleus (21), has a serum half-lifeof 6.5 to 8.6 h (22, 26). Thus, ceftriaxone has thelongest half-life of any cephalosporin.

After examination of the in vitro susceptibilityof a large number of clinical isolates of gram-negative bacilli to ceftriaxone, we undertook aclinical trial to evaluate the efficacy of ceftriax-one in the treatment of a variety of bacterialinfections.

MATERIALS AND METHODSIn vitro studies. Sterile standardized ceftriaxone

powder was provided by Hoffmann-La Roche Inc.Minimum inhibitory concentrations (MICs) were de-termined by a standard microdilution technique (2). Atotal of 437 gram-negative aerobic bacillary isolatescollected from clinical sources over the last 2 yearswere tested for susceptibility to ceftriaxone. We alsotested six strains of Listeria monocytogenes and 15strains of group B streptococci. MICs were also deter-mined on all isolates identified in the study population.Species with MICs of s16 ,ug/ml were consideredsusceptible to ceftriaxone (criterion established by themanufacturer).

Clnical trial. The trial was designed as an open,noncomparative study of parenteral ceftriaxone inserious bacterial infections. Patients hospitalized atthe University of Alabama Medical Center and at theVeterans Administration Medical Center, Birming-ham, Ala., were available for treatment. House offi-cers at these institutions identified potential subjectsand notified one of the investigators, who then inter-viewed and examined the patients. If eligibility criteriawere fulfilled, written informed consent was obtained,and the patient was enrolled.Any adult with suspected or proven serious bacteri-

al infection of the blood stream, skin, soft tissue, bone,

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joint, genitourinary tract, gastrointestinal tract, orhepatobiliary tract was eligible for enrollment in thestudy, with the following exceptions: (i) minors under18 years of age; (ii) patients with a history of hypersen-sitivity to beta-lactam antibiotics; (ii) patients withinfections caused by bacteria presumed or provenresistant to ceftriaxone; (iv) patients receiving othereffective antibiotic therapy; (v) patients at risk for life-threatening Pseudomonas infections (e.g., patientswith leukemia or granulocytopenia); (vi) patients withcentral nervous system infections; (vii) patients withsevere renal insufficiency (serum creatinine greaterthan 5.0 mg/dl), and (viii) pregnant or lactating fe-males.For retention in the study, the etiological bacteria

had to be isolated, identified, and proved susceptibleto ceftriaxone by disk diffusion criteria (resistant <12mm, intermediate 13 to 15 mm, sensitive >16 mm).

Ceftriaxone (supplied by Hoffmann-La Roche Inc.,Nutley, N.J.) was administered by intravenous infu-sion (except in one patient, who also received the drugintramuscularly after hospital discharge). The stan-dard dose of ceftriaxone was 1 g diluted in 50 ml ofeither normal saline or 5% dextrose in water andinfused over 20 to 30 min. The dose was repeatedevery 12 h for a minimum of 5 days. No otherantibacterial agents were administered concomitantly.Aerobic and anaerobic blood cultures were obtained

from each patient before initiation of therapy. Inpatients with pneumonia, expectorated sputum or na-sotracheal aspirate was obtained for Gram stain andculture. In patients with urinary tract infections, urinewas collected for microscopic analysis and quantita-tive culture. In patients with soft tissue or boneinfections, inflammatory material was obtained forGram stain and culture by surgical drainage or needleaspiration. Cultures were collected on all patientsbefore therapy, after 48 h of therapy, and after comple-tion of therapy.

All patients were closely monitored to determinebacteriological and clinical outcome. Bacteriologicalcure was defined as follows: for patients with bacter-emia, a sterile blood culture; for patients with pneumo-nia, elimination of the etiological agent from sputum;for patients with soft tissue or bone infections, elimi-nation of the etiological bacteria from wounds ordrainage; for patients with urinary tract infections, asterile urine culture (<1,000 colonies per ml).The following criteria were used to define clinical

cure: for patients with pneumonia, defervescence offever and improvement of cough, dyspnea, and signsof consolidation together with radiographic improve-ment; for patients with soft tissue or bone infections,resolution or improvement of inflammation and heal-ing of wounds (plus radiographic improvement ofosteomyelitis); for patients with urinary tract infec-tions, resolution of fever, costovertebral angle tender-ness, dysuria, frequency, and urgency; for patientswith bacteremia, resolution of signs and symptoms ofsepsis.

Subjects were questioned and examined daily forevidence of drug toxicity. Complete blood counts,hepatic enzymes, clotting studies, renal function tests,and urinalysis were obtained twice weekly duringtherapy.

Ceftriaxone plasma levels were measured in mostpatients on the 1st and 4th days of therapy. Peripheral

venous blood was collected in a heparinized tube 30min and 12 h after infusion of a dose. An agar platebioassay technique was utilized. A 2,000-sg/ml stocksolution of ceftriaxone was prepared in sterile water.Working standards were prepared in pooled humanplasma, ranging in concentration from 2.0 to 200.00Fg/ml. Standards and patients specimens were depro-teinized by adding 2.0 ml of acetonitrile to 0.25 ml ofplasma and 0.75 ml of sterile water. The samples wereblended in a Vortex mixer for 15 s and centrifuged at100 g for 6 min. A bioassay plate was prepared bymixing melted antibiotic medium no. 1 and Escherich-ia coli 1346 in a transparent polystyrene tray (23 by 23cm) with lid and allowing the agar to harden. Wellswere cut into the agar with a 3.0-mm well cutter, andsupernatants from the centrifuged samples were inocu-lated into the wells with microcapillary pipettes. Stan-dards and patient samples were tested in duplicate.The plate was incubated overnight, and the diameterof the zone of inhibition around each was measuredwith calipers. A graph of the zone on inhibition (inmillimeters) versus drug concentration (in microgramsper milliliter) for the standards was plotted on semilog-arithm paper for each plate. The concentration ofceftriaxone in the clinical specimens was then readfrom this curve.Peak and trough plasma specimens from five pa-

tients were assayed by high-pressure liquid chroma-tography (kindly performed by Hoffmann-La RocheInc.). Results were compared with levels determinedby the bioassay technique.

RESULTSIn vitro studies. The activity of ceftriaxone

against 437 gram-negative bacdillary isolates isshown in Table 1. The drug was extremelyactive against E. coli, Proteus mirabilis, andindole-positive Proteus sp. Activity was verygood against Klebsiella sp., Enterobacter aero-genes, Serratia marcescens, and Providenciasp. Several strains of Enterobacter cloacae andCitrobacter sp. were relatively resistant to cef-triaxone. The MIC90 for P. aeruginosa was 25.0,ug/ml; 15% of the P. aeruginosa strains testedwere clearly resistant to ceftriaxone (MIC >16p,g/ml). Acinetobacter calcoaceticus (biotypesnot identified) also demonstrated significantresistance to ceftriaxone.

In a previous report from this laboratory,these gram-negative bacilli were tested for sus-ceptibility to moxalactam, cefotaxime, cefaman-dole, cefoxitin, cefazolin, carbenicillin, ticarcil-lin, gentamicin, tobramycin, and amikacin (7).The activity of ceftriaxone was quite similar tothat of cefotaxime and moxalactam. Ceftriaxonewas less active against E. cloacae, slightly moreactive against P. aeruginosa and A. calcoaceti-cus, and substantially more active against Citro-bacter sp. than cefotaxime or moxalactam.

Ceftriaxone was only moderately activeagainst the six Listeria isolates (MIC90 12.5 ,ug/ml), but showed very good activity against thegroup B streptococci (MICgo 0.78 p1g/ml). Moxa-

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CLINICAL EVALUATION OF CEFTRIAXONE 3

TABLE 1. In vitro activity of ceftriaxone against aerobic gram-negative bacilli

Species Notof isolates Range of MIC (pLg/ml) MIC50 (Lg/ml) MIC90 (,ug/ml)

E. coli 50 '0.10-0.78 <0.10 '0.10Klebsiella spp. 50 '0.10->100 0.20 0.78E. aerogenes 25 <0.10-6.25 0.39 1.56E. cloacae 22 0.20-50.0 0.39 12.5P. mirabilis 50 '0.10-.20 '0.10 sO.10Proteus spp. 30 '0.10-0.39 <0.10 '0.10

(indole-positive)P. aeruginosa 75 3.13->100 12.5 25.0S. marcescens 50 '0.10-12.5 0.39 1.56A. calcoaceticus 50 1.56-50.0 12.5 25.0Providencia spp. 16 '0.10-1.56 <0.10 0.39Citrobacter spp. 16 s0.10-50.0 <0.10 6.25

TABLE 2. Patients with pneumonia treated with ceftriaxonea

Patient Age Underlying disease Species isolated Days of Outcomeno. (yr) therapy Bacteriological Clinical

13 76 DM, hepatic K. pneumoniae (S) 10 Cure Cureencephalopathy

19 72 DM, IHD Group A streptococcus (S) 7 Cure Cure20 33 Phenobarbital overdose H. influenzae (S) 7 Cure Cure23 53 Alcoholism S. pneumoniae (S) 6 Cure Cure25 51 Chronic anemia S. pneumoniae (S, B) 10 Cure Cure29 21 Quadriplegia Group C streptococcus (S) 9 Cure Failure34 84 COPD, IHD S. aureus (S) 20 Cure Cure46 79 COPD, lung cancer S. pneumoniae (S) 5 Cure Cure52 53 Kyphoscoliosis S. pneumoniae (S) 6 Cure Cure53 34 Quadriplegia S. pneumoniae (S) 6 Final culture Cure

not collecteda Abbreviations: S, sputum; B, blood; DM, diabetes mellitus; IHD, ischemic heart disease; COPD, chronic

obstructive pulmonary disease.

lactam, tested simultaneously against the same15 group B streptococcal isolates, was signifi-cantly less active (MIC90 12.5 ,ug/ml).

Clinical trial. Between January and May 1981,55 patients were treated with ceftriaxone. Therewere 30 males and 25 females with a mean age of57 years (range 18 to 90 years). Duration oftherapy ranged from 2 to 57 days, with a mean of10 days. Of these 55 subjects, 30 had definitebacterial pathogens isolated and were followedfor bacteriological and clinical outcome. Of theremaining group of 25 patients, 15 had no patho-gen isolated, 7 subsequently received additionalantibiotics (though none of these seven patientsreceived additional antibiotics because of sus-pected ceftriaxone failure), and 3 were proven tohave nonbacterial diseases. These 25 patientswere evaluated only for drug tolerance andpharmacokinetics.Table 2 summarizes the outcome of 10 pa-

tients with pneumonia treated with ceftriaxone.Five patients had pneumococcal pneumonia (in-cluding one with bacteremia), and two had pneu-monia due to other streptococci. Haemophilus

influenzae, Klebsiella pneumoniae, and S. aure-us were cultured from one patient each. Nine ofthe ten patients were cured bacteriologically andclinically. Patient 29, a young man with group Cstreptococcal pneumonia requiring ventilatorysupport, was improving with ceftriaxone thera-py. The streptococcus had been cleared from hissputum, but he developed pulmonary superin-fection with a resistant strain of A. calcoaceti-cus, requiring the addition of tobramycin.

Thirteen patients were treated for urinarytract infections, including three with bacteremicillness (Table 3). Eleven patients had clinicalsigns and symptoms consistent with pyelone-phritis (fever, costovertebral angle tenderness,and leukocytosis in addition to dysuria, frequen-cy, and urgency). E. coli was isolated from theurine of nine patients, including all three patientswith bacteremia. Two patients had urinary tractinfections due to multiply resistant gram-nega-tive bacilli (patient 22, S. marcescens; patient36, Providencia stuartii) that were susceptibleonly to third-generation cephalosporins. Patient40 had E. coli and enterococci isolated from her

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TABLE 3. Patients with urinary tract infections treated with ceftriaxone

Patient Age Infectiona Underlying disease' Species isolated' Dayof Outcomeno. (yr) '''" therapy Bacteriological" Clinical

1 77 Cystitis DM, CHF, CRF E. coli (U) 11 Cure Cure9 72 Pyelonephritis CVA P. aeruginosa (U) 2 Failure Failure

P. stuartii (U)17 21 Pyelonephritis None E. coli (U) 7 Cure Cure21 70 Pyelonephritis COPD, HTN E. aerogenes (U) 8 Cure Cure22 82 Cystitis DM, dementia, atrial S. marcescens (U)' 7 Cure Cure

fibrillation24 59 Pyelonephritis DM, HTN E. coli (U, B) 14 Cure Cure

Bacteremia28 26 Pyelonephritis Ureterolithiasis E. coli (U) 6 Cure Cure30 24 Pyelonephritis SLE E. coli (U, B) 14 Cure Cure

Bacteremia33 68 Pyelonephritis DM, CRF E. coli (U, B) 14 Cure Cure

Bacteremia35 90 Pyelonephritis CHF, CVA, seizures E. coli (U), 5 Cure Cure

P. mirabilis (U)36 18 Pyelonephritis Rhabdomyosarcoma P. stuartii (U)' 10 Cure Cure37 19 Pyelonephritis Sickle trait E. coli (U) 5 Cure Cure40 88 Pyelonephritis IHD, PTE, dementia E. coli (U), 7 Cure Cure

Enterococcus (U)a Clinical impression of site of urinary tract infection.b Abbreviations: DM, diabetes mellitus; CHF, congestive heart failure; CRF, chronic renal failure; CVA,

cerebrovascular accident; COPD, chronic obstructive pulmonary disease; HTN, hypertension; SLE, systemiclupus erythematosus; IHD, ischemic heart disease; PTE, pulmonary thromboembolus.

I U, Urine; B, blood.dMultiply resistant species.' Follow-up cultures taken 1 day after completion of therapy.

urine (obtained by catheterization). Follow-upurine cultures were sterile, despite in vitroresistance of the enterococcus to ceftriaxone.Patient 9 had pyelonephritis due to P. stuartii(susceptible) and P. aeruginosa (resistant).Urine cultures remained positive for P. aerugin-osa after 2 days of ceftriaxone therapy. sogentamicin was substituted. In all, 12 of the 13patients were considered cured clinically andbacteriologically (on the basis of urine culturesobtained 1 day after completion of therapy).Only 3 of 13 patients returned for follow-upurine cultures at 1 week after completion oftherapy, and only 2 patients returned at 1 monthpost-therapy; all follow-up cultures obtainedwere sterile.The outcome of 7 patients with soft tissue and

bone infections is summarized in Table 4. Threepatients with cellulitis of the lower extremitydue to gram-positive bacteria were cured clini-cally and bacteriologically. Patient 2, an intrave-nous drug abuser, presented with gram-negativecellulitis of her left forearm and was begun onceftriaxone. She improved clinically, and fol-low-up cultures were negative, but she left thehospital against medical advice after 8 days oftherapy. Patient 12 presented with a 2-yearhistory of recurrent osteomyelitis of the leftfemur after a motor vehicle accident. Bone

cultures taken at surgery revealed S. marces-cens and P. mirabilis. He received 2 weeks ofintravenous ceftriaxone followed by 6 weeks ofceftriaxone given intramuscularly, resulting inan apparent clinical cure. However, 2 monthsafter completion of therapy, he presented with arelapse of osteomyelitis. S. marcescens wasagain isolated and again was susceptible in vitroto ceftriaxone. Patient 32, with chronic maxil-lary sinusitis (characterized by fever, tender-ness, and nasal drainage) due to S. aureus and P.aeruginosa, was responding well but developeda rash requiring that the drug be stopped.

In summary, among 30 evaluable patients, abacteriological cure rate of 93% and a clinicalcure rate of 93% were achieved (Table 5). Thesusceptibility of the clinical isolates to ceftriax-one is shown in Table 6.

Adverse reactions to ceftriaxone. Seven pa-tients developed apparent hypersensitivity re-sponses while receiving ceftriaxone (Table 7). Infive patients this was manifested by asympto-matic eosinophilia with a mean eosinophil countof 8% (range 6 to 9%o). Patient 11 maintained alow-grade fever (about 38°C) during the lastweek of her course of therapy which resolved 2days after the ceftriaxone was discontinued.Patient 32, previously mentioned, developed adiffuse, pruritic maculopapular rash on the 5th

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CLINICAL EVALUATION OF CEFTRIAXONE 5

TABLE 4. Patients with miscellaneous soft tissue and bone infections treated with ceftriaxone

Patient Age Infection Underlying Species isolated Days of Outcomeno. (yr) diseasea therapy Bacteriological Clinical

2 35 Cellulitis IV drug abuse A. calcoaceticus 8 Cure Course not(arm) S. marcescens completed

10 72 Cellulitis COPD, CHF S. aureus 10 Cure Cure(leg)

11 61 Cellulitis COPD, chest S. aureus 10 Cure Cure(leg) trauma

12 29 Osteomyelitis Trauma S. marcescens 57 Failure FailureP. mirabilis

15 74 Periurethral BPH, COPD, E. coli 9 Cure Cureabscess AF

32 78 Chronic IHD, HTN S. aureus 7 Drug dis- Drug dis-sinusitis P. aeruginosa continued continued

51 58 Cellulitis COPD, Group A streptococcus, 12 Cure Cure(leg) alcoholism S. aureus

a Abbreviations: COPD, chronic obstructive pulmonary disease; CHF, congestive heart failure; BPH, benignprostatic hypertrophy; AF, atrial fibrillation; IHD, ischemic heart disease; HTN, hypertension; IV, intravenous.

TABLE 5. Outcome of bacterial infections in 30 patients treated with ceftriaxone

Diagnosis No. of Bacteriological result (no.) Clinical result (no.)patients Cure Failure Unevaluable Cure Failure Unevaluable

PneumoniaWith bacteremia 1 1 1Without bacteremia 9 8 1 8 1

Urinary tract infectionsWith bacteremia 3 3 3Without bacteremia 10 9 1 9 1

Miscellaneous soft tissue 7 5 1 1 4 1 2and bone infections

day of therapy. This was the only instance inwhich ceftriaxone had to be discontinued be-cause of an adverse reaction.

Elevated hepatic enzymes were noted in 9 of55 patients (16%), all of whom had normal liverfunctions when therapy was initiated. The meanpeak transaminase in these patients was 144 IU/liter (range 54 to 360 IU/liter); the mean peakalkaline phosphate was 285 IU/liter (range 151 to400 IU/liter). Follow-up testing, available in onlythree cases, revealed the enzyme abnormalitiesreturning toward normal within 2 days afterceftriaxone was discontinued.

Hematological abnormalities developed in 13patients. Patient 13 had a leukocyte count of7,800/mm3 at the start of therapy which fell to3,100/mm3 by the completion of therapy 9 dayslater; no follow-up leukocyte count was avail-able. Two patients (patients 12 and 26) hadminor (2 s) prolongations of their prothrombintimes, which reverted to normal despite continu-ation of ceftriaxone. Nine patients (16%) devel-oped thrombocytosis with a mean peak plateletcount of 546,000/mm3 (range 406,000 to 824,000/mm3). All of these patients had platelet counts of

less than 350,000/mm3 at the start of therapy,and none had a primary hematological disease.Unfortunately, post-therapy platelet countswere not available for most of these patients. Anadditional patient (patient 39, pneumonia andsickle cell anemia) had a platelet count of495,000/mm3 on the 4th day of therapy whichrose to 1,300,000/mm3 on day 8 and to 1,500,000/mm3 on day 12. During the same interval, herhematocrit remained stable at 22% and her leu-kocyte count fell from 16,600/mm3 to 12,500/mm . No clotting or bleeding abnormalities werenoted in our patients with thrombocytosis.

Patient 7 (who had chronic obstructive pulmo-nary disease and pneumonia) experienced 1 dayof diarrhea while receiving ceftriaxone. No renalfunction abnormalities were documented in anyof the 55 patients. No phlebitis or pain withinfusion was noted. Patient 12 took 6 weeks ofintramuscular ceftriaxone (reconstituted in 1%lidocaine) and reported no excess pain withinjections.

Overall, 30 possible adverse reactions werenoted in 22 of 55 patients. Ninety percent of theadverse reactions consisted of abnormal labora-

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TABLE 6. Susceptibility of clinical isolates toceftriaxone in 30 patients

Species No. of MIC (,ug/ml)isolates Median Range

S. aureus 5 6.25 1.56-12.5S. pneumoniae 5 0.1 _aStreptococcus group A 2 0.1Streptococcus group C 1 0.2Enterococcus 1 100.0E. coli 11 0.1 0.1-0.39S. marcescens 3 0.78 0.78-3.13A. calcoaceticus 2 18.75 12.5-25.0P. mirabilis 2 6.3 0.2-12.5P. stuartii 2 6.3 0.2-12.5P. aeruginosa 2 53.1 6.25-100E. aerogenes 1 50.0H. influenzae 1 0.2K. pneumoniae 1 0.1

a None.

tory test results without associated symptoms orsigns. Many of these patients were seriously illand receiving multiple medications; some ofthese adverse reactions were probably notcaused by the ceftriaxone, but all were tempo-rally related to ceftriaxone administration. Cef-triaxone had to be discontinued because of anadverse reaction in only one case (patient 32,rash).

Ceftriaxone plasma levels. Plasma ceftriaxonelevels were determined by bioassay in 50 pa-tients on the 1st and 4th days of therapy (Table8). Five sets of peak and trough levels wereanalyzed both by bioassay and high-pressureliquid chromatography (HPLC). The mean peaklevel was 93.8 ± 30.5 ,ug/ml by HPLC and 63.6± 16.6 ,u.g/ml by bioassay. The mean troughlevel was 32.4 ± 10.1 ,g/ml by HPLC and 29.4

4.4 ,ug/ml by bioassay.

DISCUSSIONCeftriaxone is an investigational cephalospo-

rin characterized by a uniquely long half-life anda broad spectrum of activity against gram-posi-tive and gram-negative bacterial pathogens. Toassess the potential clinical value of ceftriaxone,its properties must be compared with those ofother third-generation cephalosporins, particu-larly the two agents already available for clinicaluse. All third-generation cephalosporins (exceptcefsulodin) have high in vitro activity againstEnterobacteriaceae. E. aerogenes, E. coli, K.pneumoniae, Proteus species, S. marcescens,and Providencia species are usually quite sus-ceptible to ceftriaxone, moxalactam, and cefo-taxime (1, 7, 9, 17, 18, 23, 31). In several reports,including this one, E. cloacae has shown ahighly variable degree of susceptibility to third-generation cephalosporins, with a number of

TABLE 7. Adverse reactions possibly attributableto ceftriaxone in 55 patients

Reaction' No. ofreactions'

HypersensitivityEosinophilia (>5%) 5Fever 1Rash ic

HepaticElevated SGOT (>40 IU/liter) 5Elevated alkaline phosphatase 2(>115 IU/liter)

Elevated SGOT and alkaline 2phosphatase

HematologicalLeukopenia 1(WBC <4,000/mm3)

Prolonged PT (>2 s) 2Thrombocytosis 10(>400,000/mm3)

GastrointestinalDiarrhea 1a Abbreviations: SGOT, serum glutamic oxalacetic

transaminase; WBC, leukocyte count; PT, pulmonarythrombocytosis.

b A total of 22 patients had 30 reactions.c Drug discontinued.

resistant strains reported (11, 23). Ceftriaxone,cefotaxime, and moxalactam are only minimallyactive against P. aeruginosa, other Pseudomo-nas species, and Acinetobacter species (1, 8, 18,23, 29). Although ceftriaxone may prove usefulfor treating infections due to Pseudomonas sp.or Acinetobacter sp. after in vitro testing hasdemonstrated susceptibility, the incidence ofresistant strains is too high to permit ceftriaxoneto be used alone for initial therapy of infectiousdisorders caused by these bacteria. Cefopera-zone (16), ceftazidime (20), and cefsulodin (25)may prove to be more effective antipseudomonalcephalosporins.

Ceftriaxone, moxalactam, and cefotaximehave all proved to be extremely active againstSalmonella species (6, 8), Shigella species (1,18), Neisseria meningititis (18), Neisseria gon-orrheae (including penicillin-resistant strains)(24, 32), and Haemophilus influenzae (includingampicillin-resistant strains) (19, 24).Although the third-generation cephalosporins

have enhanced activity against gram-negativebacilli, their activity against gram-positive cocciis inferior to that of first-generation cephalospo-rins. The MIC90 of ceftriaxone and cefotaximefor S. aureus (penicillin G susceptible or resist-ant) are in the range of 3.1 to 6.3 ,ug/ml, whereasmoxalactam is slightly less active (1, 8, 11, 18,23). All three of the drugs have been clinicallyeffective in treating S. aureus infections, butnone is as active against this bacterium as are

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CLINICAL EVALUATION OF CEFTRIAXONE 7

TABLE 8. Plasma levels of ceftriaxone in 50patients

Mean and SD of drug level in plasmaDay (14/ml)

Peaka Troughb

1 103 ± 32 39 ± 164 119 ± 38 53 ± 20a At 30 mh after infusion.b At 12 h after infusion.

the penicillinase-resistant semisynthetic penicil-lins or the first-generation cephalosporins (8).All cephalosporins, including these neweragents, are inactive against methicillin-resistantS. aureus (29). The susceptibility of Staphylo-coccus epidermidis to ceftriaxone is variable,but the overall activity is poor (18). Ceftriaxoneand cefotaxime are both very active againstStreptococcus pneumoniae, Streptococcus pyo-genes, Streptococcus agalactiae, and viridansgroup streptococci (1, 8, 11, 18, 23, 29). Moxa-lactam, however, is significantly less activeagainst streptococcal species, especially pneu-mococci and group B streptococci (8, 18). Allcephalosporins are inactive against Streptococ-cus faecalis (8, 18).

Ceftriaxone and cefotaxime are frequently in-active against Bacteroides fragilis, the anaerobegenerally considered most resistant to beta-lac-tam antibiotics (1, 8, 18, 23). Moxalactam,slightly more active against anaerobes than theother two drugs, has about the same level ofactivity against B. fragilis as cefoxitin (8, 18).To summarize, ceftriaxone, cefotaxime, and

moxalactam are all very active against the Enter-obacteriaceae, Neisseria species, and H. in-fluenzae. Ceftriaxone and cefotaxime are moreactive than moxalactam against gram-positivepathogens, whereas moxalactam has slightlybetter antianaerobic activity. None of thesethree drugs is dependably active against P. aeru-ginosa, A. calcoaceticus, or enterococci.

Ceftriaxone's principal advantage over theother third-generation cephalosporins may be itsprolonged serum half-life. In this study, peakplasma ceftriaxone levels on the 4th day oftherapy averaged 119 ,ug/ml, as determined by abioassay. Trough levels, drawn 12 h after thepreceding dose, averaged 53 p,g/ml, emphasizingceftriaxone's prolonged duration of action.When compared with HPLC, the bioassay tech-nique may underestimate ceftriaxone plasmalevels, particularly at the higher levels. Ceftriax-one is highly bound to human plasma proteins,requiring deproteinization of the samples withacetonitrile before analysis. Inadequate depro-teinization could account for some of the lowlevels measured.

Ceftriaxone was very well tolerated in ourstudy group of 55 patients. The adverse reac-tions most frequently noted (thrombocytosis,16%; elevated hepatic enzymes, 16%; eosino-philia, 8%) were all asymptomatic laboratoryabnormalities. Eosinophilia, elevated liver func-tion tests, and thrombocytosis have been previ-ously associated with the administration ofthird-generation cephalosporins. Eosinophiliahas been reported in 4 to 11% of patients receiv-ing moxalactam (13, 27) and in 8 to 10% ofpatients receiving cefotaxime (W. Greene, P.Inannini, M. Kunkel, A. Harmon, and V. T.Andriole, Program Abstr. Intersci. Conf. Anti-microb. Agents Chemother. 21st, Chicago, Ill.1981, abstr. no. 134; C. J. Schleupner, J. Engle,21st ICAAC, abstr. no. 136). Transient liverfunction abnormalities have also been noted in14 to 22% of patients receiving moxalactam (13,27). Though thrombocytosis can be associatedwith the stress of infection, a clear temporalrelationship between the onset of thrombocyto-sis and the initiation of ceftriaxone therapy wasapparent in these cases. Thrombocytosis hasalso been reported in 7 of 36 patients (19%)receiving moxalactam (27).

In the clinical study reported here, ceftriaxonewas effective as a single agent in treating 30patients with pneumonia, urinary tract infec-tions, and soft tissue infections caused by avariety of bacterial pathogens. The four patientsin this series with bacteremic illnesses respond-ed well to ceftriaxone. We did not have theopportunity to treat any patients with intraab-dominal or pelvic infections. The bacteriologicaland clinical cure rates of 93% achieved in thisclinical trial are impressive, particularly sincemany of the patients treated had complex under-lying medical problems. Although ceftriaxonewould certainly not be considered the drug ofchoice for some of the infections treated in thisseries (e.g., pneumococcal pneumonia or E. coliurinary tract infection), we felt that it was impor-tant to establish the safety and efficacy of thedrug in treating a wide variety of infectiousdisorders.

Investigators from six other medical centersrecently presented results of studies of the clini-cal efficacy of ceftriaxone (T. R. Beam, T. A.Raab, and J. M. Mylotte, 21st ICAAC, abstr.no. 814; R. W. Bradsher, 21st ICAAC, abstr.no. 813; J. S. Epstein and G. L. Simon, 21stICAAC, abstr. no. 815; L. Eron, R. Goldenberg,and D. Poretz, 21st ICAAC, abstr. no. 810; H.Giamarellou, J. Tsagarakis, G. Petrikkos, K.Mavroudis, and G. K. Daikos, 21st ICAAC,abstr. no. 808; R. C. Trincher and J. P. Rissing,21st ICAAC, abstr. no. 811). Ceftriaxone wasevaluated in a total of 161 patients with seriousbacterial infections, including 46 patients with

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urinary tract infections, 40 with lower respira-tory infections, 41 with soft tissue infections, 12with bone infections, and 22 with miscellaneousinfections. The overall clinical cure rate was

91%. Adverse reactions reported included phle-bitis, elevated liver function tests, diarrhea, andrash, though the drug was generally well tolerat-ed.

Additipnal studies will have to be undertakento precisely define the clinical indications forceftriaxone (and the other third-generationagents). In the treatment of pulmonary infec-tions, ceftriaxone may have a role in treatinggram-negative bacillary pneumonias and may bea reasonable substitute for the combination of afirst-generation cephalosporin plus an aminogly-coside. Ceftriaxone may be an effective alterna-tive to chloramphenicol for treating ampicillin-resistant H. influenza pulmonary infections.

In the treatment of urinary tract infections,ceftriaxone should be reserved for those situa-tions where a multiply resistant gram-negativebacillus is suspected or isolated. No relapseswere noted in our patients with urinary tractinfections, though we were able to obtain urinecultures at 1 and 6 weeks after completion oftherapy in only 23% of the patients due to failureto return for follow-up cultures. Patients withpolymicrobial soft tissue infections (cellulitis,wound infections, decubitus ulcers) may be can-didates for ceftriaxone therapy. With its poten-tial for once-a-day administration, ceftriaxonecould prove to be a valuable drug for the outpa-tient therapy of chronic osteomyelitis.The high incidence of resistance of B. fragilis

to ceftriaxone raises concerns about using thisdrug alone to treat intraabdominal or pelvicinfections. Whether a third-generation cephalo-sporin alone will be as effective as such regimensas gentamicin plus clindamycin or gentamicinplus chloramphenicol has not yet been adequate-ly studied.An interesting potential use for ceftriaxone is

in the treatment of gonorrhea infections. A sin-gle injection of ceftriaxone (in doses as low as125 mg) eradicated uncomplicated urethral, an-

orectal, and pharyngeal gonorrhea in a series of46 males (H. H. Handsfield, V. L. Murphy, andK. K. Holmes, 21st ICAAC, abstr. no. 812). Asmall dose of ceftriaxone, if proven effective,would clearly be better tolerated by the patientand possibly less expensive than the currentlyrecommended regimen of 4.8 x 106 U of pro-caine penicillin plus 1 g of probenecid.Because of its marginal activity against P.

aeruginosa, ceftriaxone alone cannot be recom-mended as initial therapy in any patient in whomthe risk of P. aeruginosa infection is great, suchas the patient with granulocytopenia. Althoughthe combination of a third-generation cephalo-

sporin and an aminoglycoside may be effectivein some patients with pseudomonal disease (R.Cleeland, W. Delorenzo, L. Gulow, and P.Russo, 21st ICAAC, abstr. no. 804), until moreclinical data are available we recommend thecombination of an aminoglycoside plus an anti-pseudomonal penicillin, such as carbenicillin orticarcillin, for serious pseudomonal infections.Although patients with central nervous sys-

tem infections were excluded from this study,ceftriaxone may prove to be a valuable drug inbacterial meningitis. In therapy of murine men-ingitis due to S. pneumoniae or K. pneumoniae,ceftriaxone was superior to ampicillin or cefo-taxime (4). Other investigators have confirmedthe efficacy of ceftriaxone in the dog meningitismodel (15) and documented effective levels ofthe drug in the cerebrospinal fluid of patientswith meningitis (5). Though rigorous clinicalassessment will be necessary, ceftriaxone ap-pears to be a potentially effective agent forbacterial meningitis, particularly that due togram-negative bacilli or ampicillin-resistant H.influenzae.

Insufficient data are currently available toindicate how effective ceftriaxone will be inpatients with serious intravascular infections.We recommend that ceftriaxone not be routinelyused to treat bacterial endocarditis, particularlyendocarditis due to gram-positive species, untilits efficacy has been documented.

Ceftriaxone has an in vitro spectrum of activi-ty similar to the spectra of the currently avail-able third-generation cephalosporins. However,with its substantially longer half-life, ceftriaxoneappears to have a potentially significant thera-peutic advantage over cefotaxime and moxalac-tam. The high degree of efficacy and low inci-dence of significant toxicity demonstrated in thisstudy should encourage further clinical evalua-tion.

ACKNOWLEDGMENTSThis investigation was supported in part by funds from

Hoffmann-La Roche Inc., Nutley, N.J.We thank W. B. Hotalen and Diana Wilson of Hoffmann-La

Roche Inc. for their assistance. We also thank Madeline Webbfor secretarial assistance during preparation of the manu-script.

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