Explaining the Poor Bacteriologic Eradication Rate of Single-Dose Ceftriaxone in Group A Streptococcal Tonsillopharyngitis: A Reverse Engine
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《小儿科》
Departments of Pediatrics
Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio
Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota
Ordway Research Institute and New York State Department of Health, Albany, New York
ABSTRACT
Objective. To explore pharmacokinetic factors underlying the poor bacteriologic eradication rate with a single 500-mg dose of ceftriaxone for streptococcal tonsillopharyngitis and to identify the minimum ceftriaxone dose required for effective treatment.
Methods. Population modeling techniques were applied to pharmacokinetic data derived from paired plasma and tonsil samples from 153 children to assess the contribution of pharmacokinetic variability to patients' responses to ceftriaxone. In addition, a Monte Carlo simulation was performed to determine (1) the amount of time that free ceftriaxone concentrations must exceed the minimum inhibitory concentration (MIC) of group A Streptococcus to achieve bacteriologic eradication and (2) the ceftriaxone dose required to maintain free drug concentrations above the target MIC for the requisite amount of time. Ceftriaxone MICs for group A Streptococcus were obtained from a previous trial, in which all MICs (n = 115) were 0.064 mg/L; 33.9% were susceptible at 0.016 mg/L, 66.4% were susceptible at 0.032 mg/L, and 1.7% were susceptible at 0.064 mg/L.
Results. Mean population pharmacokinetic parameters and their variances reflected substantial variability of clearance and half-life in the target population. Tonsillar ceftriaxone protein binding was 89.1%. The proportions of 1000 simulated patients with free ceftriaxone concentrations that exceeded MICs of 0.016 mg/L, 0.032 mg/L, and 0.064 mg/L at 24 hours were 71.7%, 65.4%, and 57.2%, respectively, and at 48 hours were 41.8%, 35.8%, and 28.6%, respectively. The amount of time that free ceftriaxone concentrations need to exceed MIC to achieve bacteriologic success was estimated to be 36 hours. Using this time criterion, two 500-mg doses of ceftriaxone separated by 18 hours should achieve a bacteriologic cure rate of 95%.
Conclusions. Pharmacokinetic variability and high ceftriaxone tonsillar protein binding explain the high microbiologic failure rate for a single 500-mg dose of ceftriaxone in group A streptococcal tonsillopharyngitis. Monte Carlo simulation suggests that a second dose administered 18 hours after the first will be required to achieve an acceptable bacteriologic cure rate.
Key Words: tonsillopharyngitis ceftriaxone pharmacokinetics pharmacodynamics pharyngitis
Abbreviations: MIC, minimum inhibitory concentration HPLC, high-performance liquid chromatography NPEM, nonparametric expectation maximization MAP, maximum aposterion probability
Penicillin in a 10-day course has been standard therapy since the 1950s for tonsillopharyngitis attributed to group A -hemolytic Streptococcus.1, 2 Although effective in eradicating group A -hemolytic Streptococcus in 90% of patients through the early 1970s, penicillin therapy for streptococcal tonsillopharyngitis is now associated with a failure rate of 30%.1–5 Poor compliance rates, reported to be as low as 8% by the ninth day of treatment,6 may be one reason for penicillin failure.1 Penicillin failure has also been hypothesized to arise from bacterial co-pathogenicity, whereby penicillin-susceptible Streptococcus is protected by co-localized bacterial strains that do not share the penicillin susceptibility of Streptococcus.7, 8 For example, -lactamase–producing Staphylococcus aureus, Haemophilus influenzae, or Moraxella catarrhalis and -lactamase–positive anaerobes that colonize the pharynx and mouth may neutralize the non–-lactamase–stable penicillin before it can eradicate the group A Streptococcus. Finally, penicillin failure may arise from tolerance, in which Streptococcus that is exposed repeatedly to sublethal concentrations of penicillin becomes increasingly resistant to eradication.9
The persistence of Streptococcus after failed penicillin therapy is of major clinical concern considering the risk for development of rheumatic fever, a well-established sequela of tonsillopharyngitis,10 as well as the possibility of the reemergence of life-threatening systemic diseases, including necrotizing pneumonitis, streptococcal toxic shock, and necrotizing fasciculitis.11, 12 These risks have stimulated attempts at improving antibiotic treatment outcomes in streptococcal tonsillopharyngitis.13, 14
The broad-spectrum cephalosporin ceftriaxone (Rocephin; Hoffman-La Roche, Nutley, NJ) possesses characteristics that may help it to overcome the limitations of oral penicillin therapy. With its long half-life (5.8–8.7 hours in healthy adults),15 ceftriaxone has been demonstrated microbiologically effective with only a single 50-mg/kg intramuscular administration for acute otitis media caused by S pneumoniae, H influenzae, or M catarrhalis16 or a single 125-mg intramuscular administration for gonorrhea caused by Neisseria gonorrhea.17 These single-dose regimens eliminate the compliance challenge associated with courses of oral antibiotic therapy that require several days. Besides effectively eradicating bacteria with a single administration, ceftriaxone is -lactamase stable. Thus, unlike penicillin, the drug is not susceptible to deactivation by -lactamase–producing bacteria that may co-inhabit the pharynges with group A -hemolytic streptococci.
These characteristics of ceftriaxone suggest that its use should be associated with a high bacteriologic cure rate in streptococcal tonsillopharyngitis. Surprisingly, 2 clinical trials that were conducted to evaluate this hypothesis revealed that a single 500-mg dose yielded a bacteriologic eradication rate of only 46%.18 To assess better the apparent discrepancies between predicted versus observed pharmacologic effect, we assessed the pharmacokinetic factors underlying the poor bacteriologic eradication rate associated with this regimen and identified the minimum dose of ceftriaxone required for effective treatment of group A streptococcal tonsillopharyngitis.
METHODS
In this study, population-based modeling techniques were applied to pharmacokinetic data derived from paired plasma and tonsil samples from 153 children to assess the contribution of pharmacokinetic variability to a patient's response to ceftriaxone. In addition, a Monte Carlo simulation was performed to determine in the context of the actual minimum inhibitory concentration (MIC) data derived from a ceftriaxone clinical study18 (1) the amount of time that free ceftriaxone concentrations need to exceed the MIC of group A Streptococcus to achieve microbiologic success and (2) the ceftriaxone dose required to maintain free drug concentrations above the MIC for the requisite amount of time.
Patients
Male or female children who were aged 2 to 12 years and scheduled to undergo elective tonsillectomy were eligible for the study. Children were excluded from the study when they were unavailable for administration of study medication at the specified time before tonsillectomy, were allergic to -lactam antibiotics, or had received any antibiotic therapy within 7 days or corticosteroids within 30 days before study entry. The study was approved by the Institutional Review Board of the University Hospitals of Cleveland, and written, informed consent was obtained from parents and/or guardians before study treatment.
Procedures
Patients received ceftriaxone, 500 mg, as a single intramuscular dose with 1% lidocaine as diluent immediately before (time 0) or at 0.5, 1, 2, 4, 12, and 24 hours before collection of plasma and tonsillar specimens during tonsillectomy. A target of at least 13 patients were to be randomized to each ceftriaxone dosing time point. Because of unanticipated changes in the surgical schedule, several groups included >13 patients.
Plasma and Tonsil Samples: Specimen Preparation and Analyses
A 5-mL blood sample was drawn from the antecubital vein (1) immediately before ceftriaxone administration and (2) immediately after removal of the tonsils. After separation from whole blood by centrifugation at 5000 rpm at 5°C, plasma was rapidly frozen at –70°C until assay by high-pressure liquid chromatography (HPLC). All samples were analyzed within 2 months of collection.
For preparing plasma for HPLC analysis, a thawed 0.2-mL sample was combined with 0.2 mL of acetonitrile and vortexed for 15 s. After standing for 15 minutes at room temperature, the sample was vortexed again and centrifuged at 15800 x g for 3 minutes at room temperature with a Marathon 26KMR refrigerated centrifuge (Fisher, Pittsburgh, PA). Then, 0.2 mL of the supernatant solution was added to 0.5 mL of the aqueous portion of the mobile phase for injection into the HPLC.
Standards and controls in plasma were prepared between 1 and 400 μg/ml. The within- and between-day precisions were 2.0% and 4.3%, respectively. The within- and between-day accuracies were 2.0% and 3.9%, respectively.
The entire amount of tonsillar tissue obtained during tonsillectomy was collected, patted dry, weighed, and rapidly frozen at –70°C until preparation for extraction and drug determination by HPLC. For preparing the tonsillar tissue for assay, excess blood was washed from thawed samples with 3 exchanges of 50 to 100 mL of water along with intermittent vortex mixing. Tissue was cut into small pieces of 4 mm3, blotted, and weighed. A volume of water equaling 4 times the tissue wet weight was added to create a 5-fold dilution. The entire tonsillar tissue obtained from each patient was homogenized in a Tempest Virtishear homogenizer (Gardiner, NY) with 2 probes, 1 with a 10-mm stator for tissue samples that weighed <1 g and the second with a 60-mm stator for tissue samples that weighed >1 g. Tissue homogenates were subjected to 15 minutes of centrifugation at 300 x g. The supernatant solution was retained for additional analysis as the "total" homogenate. Early experiments demonstrated that neither homogenization times <50 s nor centrifugation at 3000 x g caused a loss of ceftriaxone. Total homogenate was centrifuged further at 26000 x g for 4 minutes at room temperature, a step resulting in loss of <1% of ceftriaxone. Acetonitrile (2.3 mL) was added to 0.7 mL of homogenate solution before vortexing for 20 s and centrifugation at 3000 x g for 3 minutes. The resulting supernatant solution was added to 4.7 mL of methylene chloride. After 15 s of vortex mixing, the tube was centrifuged at 3000 x g for 1 minute to yield a clear upper layer for HPLC.
The same centrifugation and filtration methods were used to obtain a measure of tonsillar protein binding. In this assay, the final supernatant solution was filtered through a Centrifree Micropartition Device (Millipore, Bedford, MA) to obtain a protein-free fraction. Nineteen filtrates were analyzed in tandem with their total homogenate over the concentration range of 1 to 25 μg/g tissue.
Standards and controls in pooled blank tonsil homogenate were prepared between 0.2 and 20 μg/mL. The within- and between-day precisions were 2.2% and 2.2%, respectively. The within- and between-day accuracies were 6.0% and 4.4%, respectively.
HPLC analyses for both plasma and tonsillar samples used a Varian model 9112 HPLC, UV 9050 detector with 9100 Rainin Autosampler (Varian Analytical Instruments; San Fernando, CA) equipped with a Rheodyne 7739 injector valve and a Digital computer/Pentium II processor. Five microliters of sample was injected onto a Zorbax C8 Stablebond Guard column (12.5 x 4.6 mm) followed by an Eclipse XCB-C8 analytical column (150 x 4 mm). Mobile phase that contained 17% acetonitrile and 83% aqueous solution (0.03 M potassium phosphate and 0.01 M n-heptyl amine [pH 6.5]; Sigma, St Louis, MO) at 30°C was pumped at 1 mL/min. The ceftriaxone peak emerging at 6 minutes was detected at 270 nm, and the area (for plasma) or height (for tonsil homogenate) was integrated. Concentrations of unknowns in plasma and tonsillar tissue homogenate were determined by the external standard method. A linear equation was derived from log-transformed data and then applied to unknowns.
Population Pharmacokinetic Modeling
A population pharmacokinetic modeling approach was applied to the systemic and tissue disposition of ceftriaxone.19, 20 All plasma and tonsillar samples were modeled simultaneously with the nonparametric expectation maximization (NPEM) program of Jelliffe et al,21 run on the Blue Horizon supercomputer at the University of California at San Diego Supercomputer Center. Maximum aposterion probability (MAP) Bayesian estimates were determined with the "population of one" utility of NPEM. These estimates were used to generate predicted ceftriaxone concentrations for the plasma and tonsillar samples for each patient. Two- and 3-compartment open models with first-order input into and elimination from the central compartment were evaluated. Models were discriminated on the basis of the Akaike information criterion. Ranges for parameter estimation were set by first computing the iterative Bayesian front end to the NPEM program. For the weighting function, it was assumed that the total observed variance was proportional to the variance identified in the plasma and tonsillar assays. Consequently, estimates of observation variances were generated by fitting polynomial functions to the observed between-day SDs of the drug concentration standard.
Monte Carlo Simulation
To model time and dose criteria for microbiologic success, we performed a 1000-patient Monte Carlo simulation with the simulation module program ADAPT II.22 The mean parameter vector and covariance matrix from the population model were embedded in subroutine PRIOR. The subroutine PRIOR is the subroutine in the ADAPT II package of programs in which the mean parameter vector and covariance matrix from the population PK analysis is coded. This subroutine allows the performance of Monte Carlo simulations by the ADAPT II, among other things. Both normal and log-normal distributions were evaluated by examining the fidelity with which the original means and SDs were recaptured from the previous estimates. A log-normal distribution was found to recapture the data most accurately.
In determining the amount of time that free tonsillar tissue ceftriaxone concentrations need to exceed MICs of group A streptococci to achieve bacteriologic eradication, the frequency of times above the MIC for 24, 48, 72, 96, and 120 hours was evaluated. Ultimately, 36 hours after ceftriaxone dosing was determined to be optimal by calculating an expectation over the MIC distribution. The optimal amount of time to exceed MIC was defined as the postdose period during which the frequency of times above MIC most closely matched the documented microbiologic success rate in the reported clinical trial.18 To accomplish this analysis, we determined MIC data for 115 group A Streptococcus isolates that were submitted to the laboratory of 1 of the authors (E.L.K.).
RESULTS
Patients
A total of 153 patients were enrolled into the study. Patients ranged in age from 2 to 12 years (mean ± SD: 6.4 ± 2.5 years) and weighed between 10.0 and 81.4 kg (mean ± SD: 31.3 ± 18.4 kg). Seventy-seven were male. Paired plasma and tonsillar samples were obtained from all 153 patients. The number of patients to whom ceftriaxone was administered 0, 0.5, 1, 2, 4, 12, and 24 hours before plasma and tonsillar sample collection was 17, 21, 23, 26, 18, 23, and 25, respectively.
Population Pharmacokinetics
The mean parameter values for the population pharmacokinetic analysis are shown in Table 1. The absorption rate constant was 3.09 (SD: 5.67) with marked variability observed among patients. The volume of the central compartment (V) was small (2.13 L; SD: 1.79), and the average plasma clearance was 0.56 L/hour (SD: 0.15).
The fit of the population pharmacokinetic model to the observed data was good; Bayesian estimates of predicted ceftriaxone concentrations for the plasma and tonsillar samples for each patient agreed well with the observed concentrations. For the plasma samples, the equation of best-fit line was Observed = 0.95 x Predicted + 2.93 (r2 = 0.958, P < .001; Fig 1A), whereas for tonsillar samples, the equation of best-fit line was Observed = 1.01 x Predicted + 0.488 (r2 = 0.92, P < .001; Fig 1B).
Ceftriaxone Protein Binding in Tonsil or Tissue
The average ceftriaxone protein binding in tonsillar or tissue over the range of 1 to 25 μg/g of tissue was 89.1 ± 4.9%. Protein binding was concentration independent over this range.
Modeled Time and Dose Criteria for Microbiologic Success
Ceftriaxone MICs for the 115 group A Streptococcus isolates ranged from 0.016 mg/L to 0.064 mg/L. The majority (64.3%) of isolates had a ceftriaxone MIC of 0.032 mg/L; 33.9% and 1.7% of isolates had MICs of 0.016 mg/L and 0.064 mg/L, respectively.
At 24 hours after dosing with 500 mg of ceftriaxone, the proportions of simulated patients with free tonsillar ceftriaxone concentrations that exceeded the MICs of 0.016, 0.032, and 0.064 mg/L for group A Streptococcus were 71.1%, 65.4%, and 57.2%, respectively (Fig 2). At 48 hours after dosing with 500 mg of ceftriaxone, the proportions of simulated patients with free tonsillar ceftriaxone concentrations that exceeded the MICs of 0.016, 0.032, and 0.064 mg/L were 41.8%, 35.8%, and 28.6%, respectively (Fig 2). The proportions of simulated patients who achieved MIC targets decreased further as time after dosing increased (at 72, 96, and 120 hours postdose).
Expectation over the MIC distributions and MIC target attainment rates yielded an estimated bacteriologic eradication rate of 67.3% if 24 hours of adequate free drug levels were required to eradicate group A Streptococcus and 37.7% if 48 hours were required. The actual microbiologic success rate of 46% in the reported clinical trial18 lies between these modeled microbiologic success rates at 24 and 48 hours. Therefore, in another assessment, a 36-hour target for the amount of time that free tonsillar ceftriaxone concentrations needed to exceed the MIC range of 0.016 to 0.064 mg/L, a time midway between the 24- and 48-hour targets, was examined. The estimated microbiologic success rate after a single intramuscular 500-mg ceftriaxone dose was 49.9% if 36 hours of time with free tonsillar ceftriaxone concentrations that exceeded the MIC was required to eradicate group A Streptococcus. Because this microbiologic success rate modeled at 36 hours postdose was consistent with that obtained in the clinical trial,18 the target of continuously achieving 36 hours of free ceftriaxone concentrations in tonsillar tissue that exceeded the MIC for group A Streptococcus was chosen as the criterion for defining microbiologic success.
This criterion was used in evaluating the microbiologic performance of a 1000-mg ceftriaxone dose to determine whether it would eradicate more successfully group A Streptococcus than the 500-mg dose. The results of the simulation indicate that a single 1000-mg dose would not achieve the microbiologic success criterion in an acceptable fraction of patients. In fact, a single intramuscular dose of 8 g of ceftriaxone would be required to attain an 81.5% microbiologic success rate. In contrast, 2 doses of 500 mg of ceftriaxone each separated by 18 hours would attain the target free ceftriaxone concentration above the target MIC in tonsillar tissue, resulting in a microbiologic success rate exceeding 95%.
DISCUSSION
This study was conducted to explain the puzzling finding from 2 clinical trials18 that a single 500-mg intramuscular dose of ceftriaxone achieves a microbiologic success rate approximating only 50% in children with group A streptococcal tonsillopharyngitis and to identify a dosing regimen associated with a higher probability of success. In both trials, the efficacy of ceftriaxone was compared with that of penicillin. The penicillin efficacy data have been reported previously.18 Our results suggest that the low microbiologic success rate associated with the single 500-mg dose is not attributed to intrinsic activity of ceftriaxone against group A Streptococcus as nearly all group A Streptococci are highly susceptible to ceftriaxone with MICs <0.1 mg/L.23 Rather, this unexpectedly low clinical efficacy seems to be attributable to the drug's high degree of binding to plasma protein in tonsillar tissue combined with a more rapid-than-expected ceftriaxone clearance in a substantial portion of children. Previous research has shown that protein binding of ceftriaxone in plasma is very high (90%–95%).24 The current study extends this observation by demonstrating that protein binding of ceftriaxone is also high (90%) in the tonsils, the microbiologic target of ceftriaxone in tonsillopharyngitis.
In addition to high plasma and tonsillar protein binding, the variability of ceftriaxone pharmacokinetics in children may account for the low microbiologic success of a single 500-mg dose. Population pharmacokinetic values that were derived by modeling data from plasma and tonsillar samples from 153 children who underwent tonsillectomy reflect substantial pharmacokinetic variability in this target population. For example, the upper limit of the 95% confidence interval for the mean serum clearance for ceftriaxone was a value 50% higher than the mean value of 0.556 L/hour. This finding suggests that some patients clear ceftriaxone very rapidly with a consequential reduction in the half-life of the drug, an effect that would decrease the probability that ceftriaxone drug concentrations would exceed the requisite MIC for the necessary period for bacteriologic eradication. Consistent with our population-based pharmacokinetic data, Monte Carlo simulation revealed a group of patients with high ceftriaxone clearance rates and short half-lives. In these patients, the attainment of free ceftriaxone concentrations in the tonsils for 36 continuous hours above the requisite MICs would be virtually impossible. Thus, pharmacokinetic variability coupled with the need to maintain free tonsillar tissue drug concentrations above the MIC for 36 hours after a single dose may explain the poor performance of a single 500-mg dose of ceftriaxone in eradicating group A Streptococcus.18
The requirement that ceftriaxone free drug concentrations continuously exceed the MIC for 36 hours may explain why a single intramuscular dose effectively eradicates N gonorrhea from the urinary tracts of patients with gonorrhea17 but does not eradicate group A Streptococcus from the pharynx of patients with tonsillopharyngitis.18 In gonorrhea, the mucosal site of bacteriologic eradication is anatomically located distal to ceftriaxone's primary organ for clearance, the kidneys, ensuring prolonged exposure of the urinary tract to very high concentrates of free, active ceftriaxone. Ceftriaxone concentrates within the renal tubules, which may facilitate the prolonged maintenance of free drug concentrations that exceed the MIC. The tonsils, in contrast, which are the mucosal site of bacteriologic eradication in tonsillopharyngitis, possess no such concentrating mechanism.
Otitis media is a closed-space infection. In this circumstance, there is also no clearance organ to interfere with the maintenance of the free drug concentrations in excess of the MIC. Recent pharmacokinetic studies with -lactam agents measured in acute otitis media demonstrate that the time course at the infection site demonstrates a prolonged terminal half-life. This may explain the effectiveness of single-dose ceftriaxone in this infection site. Nevertheless, Leibovitz and colleagues25 described similar compromised bacterial eradication rates for children with acute otitis media caused by penicillin-nonsusceptible strains of S pneumoniae (53% single intramuscular dose vs 97% 3 daily consecutive intramuscular doses).
The results of 1000-patient simulation experiments performed in this study indicate that a single 1000-mg intramuscular dose of ceftriaxone, like the 500-mg dose, would be insufficient to achieve an acceptable bacteriologic success rate. In fact, an intramuscular ceftriaxone dose of 8 g would be required to exceed a modest 80% bacteriologic eradication rate. Obviously, this dose is much too high to be administered to children. However, when our simulation exercises assumed 2 doses rather than a single dose, an optimal regimen of 2 individual 500-mg intramuscular doses of ceftriaxone separated by 18 hours yielded a robust bacteriologic eradication rate that exceeded 95%. Like the single-dose regimen studied previously,18 this 2-dose regimen, compared with currently recommended oral regimens, would be expected to be associated with higher compliance rates and minimal risk for treatment failures arising from co-pathogenicity. Clearly, additional clinical evaluation of this 2-dose regimen is warranted as the pharmacokinetic data suggest that it may be highly effective at eradicating group A Streptococcus in tonsillopharyngitis.
ACKNOWLEDGMENTS
Support for this work was provided in part by an unrestricted educational grant from Roche Laboratories and in part by a Pediatric Pharmacology Research Unit grant from the National Institute of Child Health and Development (HD31323-12).
FOOTNOTES
Accepted Jan 13, 2005.
Conflict of interest: All authors have received grant support and been consultants to Roche.
REFERENCES
Pichichero ME, Casey JR, Mayes T, et al. Penicillin failure in streptococcal tonsillopharyngitis: causes and remedies. Pediatr Infect Dis J. 2000;19 :917 –923
Bisno AL, Gerber MA, Gwaltney JM Jr, et al. Practice guidelines for the diagnosis and management of group A streptococcal pharyngitis. Infectious Diseases Society of America. Clin Infect Dis. 2002;35 :113 –125
Pichichero ME. Group A streptococcal tonsillopharyngitis: cost-effective diagnosis and treatment. Ann Emerg Med. 1995;25 :390 –403
Pichichero ME. Controversies in the treatment of streptococcal pharyngitis. Am Fam Physician. 1990;42 :1567 –1576
Stillerman M. Comparison of oral cephalosporins with penicillin therapy for group A streptococcal pharyngitis. Pediatr Infect Dis. 1986;5 :649 –654
Pichichero ME, Green JL, Francis AB, et al. Recurrent group A streptococcal tonsillopharyngitis. Pediatr Infect Dis J. 1998;17 :809 –815
Brook I. Penicillin failure and copathogenicity in streptococcal pharyngotonsillitis. J Fam Pract. 1994;38 :175 –179
Brook I, Gober AE. Persistence of group A beta-hemolytic streptococci in toothbrushes and removable orthodontic appliances following treatment of pharyngotonsillitis. Arch Otolaryngol Head Neck Surg. 1998;124 :993 –995
Kim KS, Kaplan EL. Association of penicillin tolerance with failure to eradicate group A streptococci from patients with pharyngitis. J Pediatr. 1985;107 :681 –684
Bronze MS, Dale JB. The reemergence of serious group A streptococcal infections and acute rheumatic fever. Am J Med Sci. 1996;311 :41 –54
Stevens DL, Tanner MH, Winship J, et al. Severe group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A. N Engl J Med. 1989;321 :1 –7
Johnson DR, Wotton JT, Shet A, et al. A comparison of group A streptococci from invasive and uncomplicated infections: are virulent clones responsible for serious streptococcal infections J Infect Dis. 2002;185 :1586 –1595
Pichichero ME, Hoeger W, Marsocci SM, et al. Variables influencing penicillin treatment outcome in streptococcal tonsillopharyngitis. Arch Pediatr Adolesc Med. 1999;153 :565 –570
el-Daher NT, Hijazi SS, Rawashdeh NM, et al. Immediate vs. delayed treatment of group A beta-hemolytic streptococcal pharyngitis with penicillin V. Pediatr Infect Dis J. 1991;10 :126 –130
Cohen R, Navel M, Grunberg J, et al. One dose ceftriaxone vs. ten days of amoxicillin/clavulanate therapy for acute otitis media: clinical efficacy and change in nasopharyngeal flora. Pediatr Infect Dis J. 1999;18 :403 –409
Handsfield HH, Hook EW 3rd. Ceftriaxone for treatment of uncomplicated gonorrhea: routine use of a single 125-mg dose in a sexually transmitted disease clinic. Sex Transm Dis 1987;14 :227 –230
Kaplan EL, Johnson DR. Unexplained reduced microbiological efficacy of intramuscular benzathine penicillin G and of oral penicillin V in eradication of group a streptococci from children with acute pharyngitis. Pediatrics. 2001;108 :1180 –1186
Sheiner LB, Beal S, Rosenberg B, et al. Forecasting individual pharmacokinetics. Clin Pharmacol Ther. 1979;26 :294 –305
Sheiner LB, Beal SL. Bayesian individualization of pharmacokinetics: simple implementation and comparison with non-Bayesian methods. J Pharm Sci. 1982;71 :1344 –1348
Jelliffe R, Bayard D, Milman M, et al. Achieving target goals most precisely using nonparametric compartmental models and "multiple model" design of dosage regimens. Ther Drug Monit. 2000;22 :346 –353
D'Argenio DZ, Schumitzky A. A program package for simulation and parameter estimation in pharmacokinetic systems. Comput Programs Biomed. 1979;9 :115 –134
Cellesi C, Chigiotti S, Zanchi A, et al. Susceptibility of macrolide and beta-lactam antibiotics of Streptococcus pyogenes strains isolated over a four-year period in central Italy. J Chemother. 1996;8 :188 –192
Yuk JH, Nightingale CH, Quintiliani R. Clinical pharmacokinetics of ceftriaxone. Clin Pharmacokinet. 1989;17 :223 –235
Leibovitz E, Piglansky L, Raiz S, Press J, Leiberman A, Dagan R. Bacteriologic and clinical efficacy of one day vs three day intramuscular ceftriaxone for treatment of nonresponsive acute otitis media in children. Pediatr Infect Dis J. 2000;19 :1040 –1045(Jeffrey L. Blumer, PhD, M)
Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio
Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota
Ordway Research Institute and New York State Department of Health, Albany, New York
ABSTRACT
Objective. To explore pharmacokinetic factors underlying the poor bacteriologic eradication rate with a single 500-mg dose of ceftriaxone for streptococcal tonsillopharyngitis and to identify the minimum ceftriaxone dose required for effective treatment.
Methods. Population modeling techniques were applied to pharmacokinetic data derived from paired plasma and tonsil samples from 153 children to assess the contribution of pharmacokinetic variability to patients' responses to ceftriaxone. In addition, a Monte Carlo simulation was performed to determine (1) the amount of time that free ceftriaxone concentrations must exceed the minimum inhibitory concentration (MIC) of group A Streptococcus to achieve bacteriologic eradication and (2) the ceftriaxone dose required to maintain free drug concentrations above the target MIC for the requisite amount of time. Ceftriaxone MICs for group A Streptococcus were obtained from a previous trial, in which all MICs (n = 115) were 0.064 mg/L; 33.9% were susceptible at 0.016 mg/L, 66.4% were susceptible at 0.032 mg/L, and 1.7% were susceptible at 0.064 mg/L.
Results. Mean population pharmacokinetic parameters and their variances reflected substantial variability of clearance and half-life in the target population. Tonsillar ceftriaxone protein binding was 89.1%. The proportions of 1000 simulated patients with free ceftriaxone concentrations that exceeded MICs of 0.016 mg/L, 0.032 mg/L, and 0.064 mg/L at 24 hours were 71.7%, 65.4%, and 57.2%, respectively, and at 48 hours were 41.8%, 35.8%, and 28.6%, respectively. The amount of time that free ceftriaxone concentrations need to exceed MIC to achieve bacteriologic success was estimated to be 36 hours. Using this time criterion, two 500-mg doses of ceftriaxone separated by 18 hours should achieve a bacteriologic cure rate of 95%.
Conclusions. Pharmacokinetic variability and high ceftriaxone tonsillar protein binding explain the high microbiologic failure rate for a single 500-mg dose of ceftriaxone in group A streptococcal tonsillopharyngitis. Monte Carlo simulation suggests that a second dose administered 18 hours after the first will be required to achieve an acceptable bacteriologic cure rate.
Key Words: tonsillopharyngitis ceftriaxone pharmacokinetics pharmacodynamics pharyngitis
Abbreviations: MIC, minimum inhibitory concentration HPLC, high-performance liquid chromatography NPEM, nonparametric expectation maximization MAP, maximum aposterion probability
Penicillin in a 10-day course has been standard therapy since the 1950s for tonsillopharyngitis attributed to group A -hemolytic Streptococcus.1, 2 Although effective in eradicating group A -hemolytic Streptococcus in 90% of patients through the early 1970s, penicillin therapy for streptococcal tonsillopharyngitis is now associated with a failure rate of 30%.1–5 Poor compliance rates, reported to be as low as 8% by the ninth day of treatment,6 may be one reason for penicillin failure.1 Penicillin failure has also been hypothesized to arise from bacterial co-pathogenicity, whereby penicillin-susceptible Streptococcus is protected by co-localized bacterial strains that do not share the penicillin susceptibility of Streptococcus.7, 8 For example, -lactamase–producing Staphylococcus aureus, Haemophilus influenzae, or Moraxella catarrhalis and -lactamase–positive anaerobes that colonize the pharynx and mouth may neutralize the non–-lactamase–stable penicillin before it can eradicate the group A Streptococcus. Finally, penicillin failure may arise from tolerance, in which Streptococcus that is exposed repeatedly to sublethal concentrations of penicillin becomes increasingly resistant to eradication.9
The persistence of Streptococcus after failed penicillin therapy is of major clinical concern considering the risk for development of rheumatic fever, a well-established sequela of tonsillopharyngitis,10 as well as the possibility of the reemergence of life-threatening systemic diseases, including necrotizing pneumonitis, streptococcal toxic shock, and necrotizing fasciculitis.11, 12 These risks have stimulated attempts at improving antibiotic treatment outcomes in streptococcal tonsillopharyngitis.13, 14
The broad-spectrum cephalosporin ceftriaxone (Rocephin; Hoffman-La Roche, Nutley, NJ) possesses characteristics that may help it to overcome the limitations of oral penicillin therapy. With its long half-life (5.8–8.7 hours in healthy adults),15 ceftriaxone has been demonstrated microbiologically effective with only a single 50-mg/kg intramuscular administration for acute otitis media caused by S pneumoniae, H influenzae, or M catarrhalis16 or a single 125-mg intramuscular administration for gonorrhea caused by Neisseria gonorrhea.17 These single-dose regimens eliminate the compliance challenge associated with courses of oral antibiotic therapy that require several days. Besides effectively eradicating bacteria with a single administration, ceftriaxone is -lactamase stable. Thus, unlike penicillin, the drug is not susceptible to deactivation by -lactamase–producing bacteria that may co-inhabit the pharynges with group A -hemolytic streptococci.
These characteristics of ceftriaxone suggest that its use should be associated with a high bacteriologic cure rate in streptococcal tonsillopharyngitis. Surprisingly, 2 clinical trials that were conducted to evaluate this hypothesis revealed that a single 500-mg dose yielded a bacteriologic eradication rate of only 46%.18 To assess better the apparent discrepancies between predicted versus observed pharmacologic effect, we assessed the pharmacokinetic factors underlying the poor bacteriologic eradication rate associated with this regimen and identified the minimum dose of ceftriaxone required for effective treatment of group A streptococcal tonsillopharyngitis.
METHODS
In this study, population-based modeling techniques were applied to pharmacokinetic data derived from paired plasma and tonsil samples from 153 children to assess the contribution of pharmacokinetic variability to a patient's response to ceftriaxone. In addition, a Monte Carlo simulation was performed to determine in the context of the actual minimum inhibitory concentration (MIC) data derived from a ceftriaxone clinical study18 (1) the amount of time that free ceftriaxone concentrations need to exceed the MIC of group A Streptococcus to achieve microbiologic success and (2) the ceftriaxone dose required to maintain free drug concentrations above the MIC for the requisite amount of time.
Patients
Male or female children who were aged 2 to 12 years and scheduled to undergo elective tonsillectomy were eligible for the study. Children were excluded from the study when they were unavailable for administration of study medication at the specified time before tonsillectomy, were allergic to -lactam antibiotics, or had received any antibiotic therapy within 7 days or corticosteroids within 30 days before study entry. The study was approved by the Institutional Review Board of the University Hospitals of Cleveland, and written, informed consent was obtained from parents and/or guardians before study treatment.
Procedures
Patients received ceftriaxone, 500 mg, as a single intramuscular dose with 1% lidocaine as diluent immediately before (time 0) or at 0.5, 1, 2, 4, 12, and 24 hours before collection of plasma and tonsillar specimens during tonsillectomy. A target of at least 13 patients were to be randomized to each ceftriaxone dosing time point. Because of unanticipated changes in the surgical schedule, several groups included >13 patients.
Plasma and Tonsil Samples: Specimen Preparation and Analyses
A 5-mL blood sample was drawn from the antecubital vein (1) immediately before ceftriaxone administration and (2) immediately after removal of the tonsils. After separation from whole blood by centrifugation at 5000 rpm at 5°C, plasma was rapidly frozen at –70°C until assay by high-pressure liquid chromatography (HPLC). All samples were analyzed within 2 months of collection.
For preparing plasma for HPLC analysis, a thawed 0.2-mL sample was combined with 0.2 mL of acetonitrile and vortexed for 15 s. After standing for 15 minutes at room temperature, the sample was vortexed again and centrifuged at 15800 x g for 3 minutes at room temperature with a Marathon 26KMR refrigerated centrifuge (Fisher, Pittsburgh, PA). Then, 0.2 mL of the supernatant solution was added to 0.5 mL of the aqueous portion of the mobile phase for injection into the HPLC.
Standards and controls in plasma were prepared between 1 and 400 μg/ml. The within- and between-day precisions were 2.0% and 4.3%, respectively. The within- and between-day accuracies were 2.0% and 3.9%, respectively.
The entire amount of tonsillar tissue obtained during tonsillectomy was collected, patted dry, weighed, and rapidly frozen at –70°C until preparation for extraction and drug determination by HPLC. For preparing the tonsillar tissue for assay, excess blood was washed from thawed samples with 3 exchanges of 50 to 100 mL of water along with intermittent vortex mixing. Tissue was cut into small pieces of 4 mm3, blotted, and weighed. A volume of water equaling 4 times the tissue wet weight was added to create a 5-fold dilution. The entire tonsillar tissue obtained from each patient was homogenized in a Tempest Virtishear homogenizer (Gardiner, NY) with 2 probes, 1 with a 10-mm stator for tissue samples that weighed <1 g and the second with a 60-mm stator for tissue samples that weighed >1 g. Tissue homogenates were subjected to 15 minutes of centrifugation at 300 x g. The supernatant solution was retained for additional analysis as the "total" homogenate. Early experiments demonstrated that neither homogenization times <50 s nor centrifugation at 3000 x g caused a loss of ceftriaxone. Total homogenate was centrifuged further at 26000 x g for 4 minutes at room temperature, a step resulting in loss of <1% of ceftriaxone. Acetonitrile (2.3 mL) was added to 0.7 mL of homogenate solution before vortexing for 20 s and centrifugation at 3000 x g for 3 minutes. The resulting supernatant solution was added to 4.7 mL of methylene chloride. After 15 s of vortex mixing, the tube was centrifuged at 3000 x g for 1 minute to yield a clear upper layer for HPLC.
The same centrifugation and filtration methods were used to obtain a measure of tonsillar protein binding. In this assay, the final supernatant solution was filtered through a Centrifree Micropartition Device (Millipore, Bedford, MA) to obtain a protein-free fraction. Nineteen filtrates were analyzed in tandem with their total homogenate over the concentration range of 1 to 25 μg/g tissue.
Standards and controls in pooled blank tonsil homogenate were prepared between 0.2 and 20 μg/mL. The within- and between-day precisions were 2.2% and 2.2%, respectively. The within- and between-day accuracies were 6.0% and 4.4%, respectively.
HPLC analyses for both plasma and tonsillar samples used a Varian model 9112 HPLC, UV 9050 detector with 9100 Rainin Autosampler (Varian Analytical Instruments; San Fernando, CA) equipped with a Rheodyne 7739 injector valve and a Digital computer/Pentium II processor. Five microliters of sample was injected onto a Zorbax C8 Stablebond Guard column (12.5 x 4.6 mm) followed by an Eclipse XCB-C8 analytical column (150 x 4 mm). Mobile phase that contained 17% acetonitrile and 83% aqueous solution (0.03 M potassium phosphate and 0.01 M n-heptyl amine [pH 6.5]; Sigma, St Louis, MO) at 30°C was pumped at 1 mL/min. The ceftriaxone peak emerging at 6 minutes was detected at 270 nm, and the area (for plasma) or height (for tonsil homogenate) was integrated. Concentrations of unknowns in plasma and tonsillar tissue homogenate were determined by the external standard method. A linear equation was derived from log-transformed data and then applied to unknowns.
Population Pharmacokinetic Modeling
A population pharmacokinetic modeling approach was applied to the systemic and tissue disposition of ceftriaxone.19, 20 All plasma and tonsillar samples were modeled simultaneously with the nonparametric expectation maximization (NPEM) program of Jelliffe et al,21 run on the Blue Horizon supercomputer at the University of California at San Diego Supercomputer Center. Maximum aposterion probability (MAP) Bayesian estimates were determined with the "population of one" utility of NPEM. These estimates were used to generate predicted ceftriaxone concentrations for the plasma and tonsillar samples for each patient. Two- and 3-compartment open models with first-order input into and elimination from the central compartment were evaluated. Models were discriminated on the basis of the Akaike information criterion. Ranges for parameter estimation were set by first computing the iterative Bayesian front end to the NPEM program. For the weighting function, it was assumed that the total observed variance was proportional to the variance identified in the plasma and tonsillar assays. Consequently, estimates of observation variances were generated by fitting polynomial functions to the observed between-day SDs of the drug concentration standard.
Monte Carlo Simulation
To model time and dose criteria for microbiologic success, we performed a 1000-patient Monte Carlo simulation with the simulation module program ADAPT II.22 The mean parameter vector and covariance matrix from the population model were embedded in subroutine PRIOR. The subroutine PRIOR is the subroutine in the ADAPT II package of programs in which the mean parameter vector and covariance matrix from the population PK analysis is coded. This subroutine allows the performance of Monte Carlo simulations by the ADAPT II, among other things. Both normal and log-normal distributions were evaluated by examining the fidelity with which the original means and SDs were recaptured from the previous estimates. A log-normal distribution was found to recapture the data most accurately.
In determining the amount of time that free tonsillar tissue ceftriaxone concentrations need to exceed MICs of group A streptococci to achieve bacteriologic eradication, the frequency of times above the MIC for 24, 48, 72, 96, and 120 hours was evaluated. Ultimately, 36 hours after ceftriaxone dosing was determined to be optimal by calculating an expectation over the MIC distribution. The optimal amount of time to exceed MIC was defined as the postdose period during which the frequency of times above MIC most closely matched the documented microbiologic success rate in the reported clinical trial.18 To accomplish this analysis, we determined MIC data for 115 group A Streptococcus isolates that were submitted to the laboratory of 1 of the authors (E.L.K.).
RESULTS
Patients
A total of 153 patients were enrolled into the study. Patients ranged in age from 2 to 12 years (mean ± SD: 6.4 ± 2.5 years) and weighed between 10.0 and 81.4 kg (mean ± SD: 31.3 ± 18.4 kg). Seventy-seven were male. Paired plasma and tonsillar samples were obtained from all 153 patients. The number of patients to whom ceftriaxone was administered 0, 0.5, 1, 2, 4, 12, and 24 hours before plasma and tonsillar sample collection was 17, 21, 23, 26, 18, 23, and 25, respectively.
Population Pharmacokinetics
The mean parameter values for the population pharmacokinetic analysis are shown in Table 1. The absorption rate constant was 3.09 (SD: 5.67) with marked variability observed among patients. The volume of the central compartment (V) was small (2.13 L; SD: 1.79), and the average plasma clearance was 0.56 L/hour (SD: 0.15).
The fit of the population pharmacokinetic model to the observed data was good; Bayesian estimates of predicted ceftriaxone concentrations for the plasma and tonsillar samples for each patient agreed well with the observed concentrations. For the plasma samples, the equation of best-fit line was Observed = 0.95 x Predicted + 2.93 (r2 = 0.958, P < .001; Fig 1A), whereas for tonsillar samples, the equation of best-fit line was Observed = 1.01 x Predicted + 0.488 (r2 = 0.92, P < .001; Fig 1B).
Ceftriaxone Protein Binding in Tonsil or Tissue
The average ceftriaxone protein binding in tonsillar or tissue over the range of 1 to 25 μg/g of tissue was 89.1 ± 4.9%. Protein binding was concentration independent over this range.
Modeled Time and Dose Criteria for Microbiologic Success
Ceftriaxone MICs for the 115 group A Streptococcus isolates ranged from 0.016 mg/L to 0.064 mg/L. The majority (64.3%) of isolates had a ceftriaxone MIC of 0.032 mg/L; 33.9% and 1.7% of isolates had MICs of 0.016 mg/L and 0.064 mg/L, respectively.
At 24 hours after dosing with 500 mg of ceftriaxone, the proportions of simulated patients with free tonsillar ceftriaxone concentrations that exceeded the MICs of 0.016, 0.032, and 0.064 mg/L for group A Streptococcus were 71.1%, 65.4%, and 57.2%, respectively (Fig 2). At 48 hours after dosing with 500 mg of ceftriaxone, the proportions of simulated patients with free tonsillar ceftriaxone concentrations that exceeded the MICs of 0.016, 0.032, and 0.064 mg/L were 41.8%, 35.8%, and 28.6%, respectively (Fig 2). The proportions of simulated patients who achieved MIC targets decreased further as time after dosing increased (at 72, 96, and 120 hours postdose).
Expectation over the MIC distributions and MIC target attainment rates yielded an estimated bacteriologic eradication rate of 67.3% if 24 hours of adequate free drug levels were required to eradicate group A Streptococcus and 37.7% if 48 hours were required. The actual microbiologic success rate of 46% in the reported clinical trial18 lies between these modeled microbiologic success rates at 24 and 48 hours. Therefore, in another assessment, a 36-hour target for the amount of time that free tonsillar ceftriaxone concentrations needed to exceed the MIC range of 0.016 to 0.064 mg/L, a time midway between the 24- and 48-hour targets, was examined. The estimated microbiologic success rate after a single intramuscular 500-mg ceftriaxone dose was 49.9% if 36 hours of time with free tonsillar ceftriaxone concentrations that exceeded the MIC was required to eradicate group A Streptococcus. Because this microbiologic success rate modeled at 36 hours postdose was consistent with that obtained in the clinical trial,18 the target of continuously achieving 36 hours of free ceftriaxone concentrations in tonsillar tissue that exceeded the MIC for group A Streptococcus was chosen as the criterion for defining microbiologic success.
This criterion was used in evaluating the microbiologic performance of a 1000-mg ceftriaxone dose to determine whether it would eradicate more successfully group A Streptococcus than the 500-mg dose. The results of the simulation indicate that a single 1000-mg dose would not achieve the microbiologic success criterion in an acceptable fraction of patients. In fact, a single intramuscular dose of 8 g of ceftriaxone would be required to attain an 81.5% microbiologic success rate. In contrast, 2 doses of 500 mg of ceftriaxone each separated by 18 hours would attain the target free ceftriaxone concentration above the target MIC in tonsillar tissue, resulting in a microbiologic success rate exceeding 95%.
DISCUSSION
This study was conducted to explain the puzzling finding from 2 clinical trials18 that a single 500-mg intramuscular dose of ceftriaxone achieves a microbiologic success rate approximating only 50% in children with group A streptococcal tonsillopharyngitis and to identify a dosing regimen associated with a higher probability of success. In both trials, the efficacy of ceftriaxone was compared with that of penicillin. The penicillin efficacy data have been reported previously.18 Our results suggest that the low microbiologic success rate associated with the single 500-mg dose is not attributed to intrinsic activity of ceftriaxone against group A Streptococcus as nearly all group A Streptococci are highly susceptible to ceftriaxone with MICs <0.1 mg/L.23 Rather, this unexpectedly low clinical efficacy seems to be attributable to the drug's high degree of binding to plasma protein in tonsillar tissue combined with a more rapid-than-expected ceftriaxone clearance in a substantial portion of children. Previous research has shown that protein binding of ceftriaxone in plasma is very high (90%–95%).24 The current study extends this observation by demonstrating that protein binding of ceftriaxone is also high (90%) in the tonsils, the microbiologic target of ceftriaxone in tonsillopharyngitis.
In addition to high plasma and tonsillar protein binding, the variability of ceftriaxone pharmacokinetics in children may account for the low microbiologic success of a single 500-mg dose. Population pharmacokinetic values that were derived by modeling data from plasma and tonsillar samples from 153 children who underwent tonsillectomy reflect substantial pharmacokinetic variability in this target population. For example, the upper limit of the 95% confidence interval for the mean serum clearance for ceftriaxone was a value 50% higher than the mean value of 0.556 L/hour. This finding suggests that some patients clear ceftriaxone very rapidly with a consequential reduction in the half-life of the drug, an effect that would decrease the probability that ceftriaxone drug concentrations would exceed the requisite MIC for the necessary period for bacteriologic eradication. Consistent with our population-based pharmacokinetic data, Monte Carlo simulation revealed a group of patients with high ceftriaxone clearance rates and short half-lives. In these patients, the attainment of free ceftriaxone concentrations in the tonsils for 36 continuous hours above the requisite MICs would be virtually impossible. Thus, pharmacokinetic variability coupled with the need to maintain free tonsillar tissue drug concentrations above the MIC for 36 hours after a single dose may explain the poor performance of a single 500-mg dose of ceftriaxone in eradicating group A Streptococcus.18
The requirement that ceftriaxone free drug concentrations continuously exceed the MIC for 36 hours may explain why a single intramuscular dose effectively eradicates N gonorrhea from the urinary tracts of patients with gonorrhea17 but does not eradicate group A Streptococcus from the pharynx of patients with tonsillopharyngitis.18 In gonorrhea, the mucosal site of bacteriologic eradication is anatomically located distal to ceftriaxone's primary organ for clearance, the kidneys, ensuring prolonged exposure of the urinary tract to very high concentrates of free, active ceftriaxone. Ceftriaxone concentrates within the renal tubules, which may facilitate the prolonged maintenance of free drug concentrations that exceed the MIC. The tonsils, in contrast, which are the mucosal site of bacteriologic eradication in tonsillopharyngitis, possess no such concentrating mechanism.
Otitis media is a closed-space infection. In this circumstance, there is also no clearance organ to interfere with the maintenance of the free drug concentrations in excess of the MIC. Recent pharmacokinetic studies with -lactam agents measured in acute otitis media demonstrate that the time course at the infection site demonstrates a prolonged terminal half-life. This may explain the effectiveness of single-dose ceftriaxone in this infection site. Nevertheless, Leibovitz and colleagues25 described similar compromised bacterial eradication rates for children with acute otitis media caused by penicillin-nonsusceptible strains of S pneumoniae (53% single intramuscular dose vs 97% 3 daily consecutive intramuscular doses).
The results of 1000-patient simulation experiments performed in this study indicate that a single 1000-mg intramuscular dose of ceftriaxone, like the 500-mg dose, would be insufficient to achieve an acceptable bacteriologic success rate. In fact, an intramuscular ceftriaxone dose of 8 g would be required to exceed a modest 80% bacteriologic eradication rate. Obviously, this dose is much too high to be administered to children. However, when our simulation exercises assumed 2 doses rather than a single dose, an optimal regimen of 2 individual 500-mg intramuscular doses of ceftriaxone separated by 18 hours yielded a robust bacteriologic eradication rate that exceeded 95%. Like the single-dose regimen studied previously,18 this 2-dose regimen, compared with currently recommended oral regimens, would be expected to be associated with higher compliance rates and minimal risk for treatment failures arising from co-pathogenicity. Clearly, additional clinical evaluation of this 2-dose regimen is warranted as the pharmacokinetic data suggest that it may be highly effective at eradicating group A Streptococcus in tonsillopharyngitis.
ACKNOWLEDGMENTS
Support for this work was provided in part by an unrestricted educational grant from Roche Laboratories and in part by a Pediatric Pharmacology Research Unit grant from the National Institute of Child Health and Development (HD31323-12).
FOOTNOTES
Accepted Jan 13, 2005.
Conflict of interest: All authors have received grant support and been consultants to Roche.
REFERENCES
Pichichero ME, Casey JR, Mayes T, et al. Penicillin failure in streptococcal tonsillopharyngitis: causes and remedies. Pediatr Infect Dis J. 2000;19 :917 –923
Bisno AL, Gerber MA, Gwaltney JM Jr, et al. Practice guidelines for the diagnosis and management of group A streptococcal pharyngitis. Infectious Diseases Society of America. Clin Infect Dis. 2002;35 :113 –125
Pichichero ME. Group A streptococcal tonsillopharyngitis: cost-effective diagnosis and treatment. Ann Emerg Med. 1995;25 :390 –403
Pichichero ME. Controversies in the treatment of streptococcal pharyngitis. Am Fam Physician. 1990;42 :1567 –1576
Stillerman M. Comparison of oral cephalosporins with penicillin therapy for group A streptococcal pharyngitis. Pediatr Infect Dis. 1986;5 :649 –654
Pichichero ME, Green JL, Francis AB, et al. Recurrent group A streptococcal tonsillopharyngitis. Pediatr Infect Dis J. 1998;17 :809 –815
Brook I. Penicillin failure and copathogenicity in streptococcal pharyngotonsillitis. J Fam Pract. 1994;38 :175 –179
Brook I, Gober AE. Persistence of group A beta-hemolytic streptococci in toothbrushes and removable orthodontic appliances following treatment of pharyngotonsillitis. Arch Otolaryngol Head Neck Surg. 1998;124 :993 –995
Kim KS, Kaplan EL. Association of penicillin tolerance with failure to eradicate group A streptococci from patients with pharyngitis. J Pediatr. 1985;107 :681 –684
Bronze MS, Dale JB. The reemergence of serious group A streptococcal infections and acute rheumatic fever. Am J Med Sci. 1996;311 :41 –54
Stevens DL, Tanner MH, Winship J, et al. Severe group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A. N Engl J Med. 1989;321 :1 –7
Johnson DR, Wotton JT, Shet A, et al. A comparison of group A streptococci from invasive and uncomplicated infections: are virulent clones responsible for serious streptococcal infections J Infect Dis. 2002;185 :1586 –1595
Pichichero ME, Hoeger W, Marsocci SM, et al. Variables influencing penicillin treatment outcome in streptococcal tonsillopharyngitis. Arch Pediatr Adolesc Med. 1999;153 :565 –570
el-Daher NT, Hijazi SS, Rawashdeh NM, et al. Immediate vs. delayed treatment of group A beta-hemolytic streptococcal pharyngitis with penicillin V. Pediatr Infect Dis J. 1991;10 :126 –130
Cohen R, Navel M, Grunberg J, et al. One dose ceftriaxone vs. ten days of amoxicillin/clavulanate therapy for acute otitis media: clinical efficacy and change in nasopharyngeal flora. Pediatr Infect Dis J. 1999;18 :403 –409
Handsfield HH, Hook EW 3rd. Ceftriaxone for treatment of uncomplicated gonorrhea: routine use of a single 125-mg dose in a sexually transmitted disease clinic. Sex Transm Dis 1987;14 :227 –230
Kaplan EL, Johnson DR. Unexplained reduced microbiological efficacy of intramuscular benzathine penicillin G and of oral penicillin V in eradication of group a streptococci from children with acute pharyngitis. Pediatrics. 2001;108 :1180 –1186
Sheiner LB, Beal S, Rosenberg B, et al. Forecasting individual pharmacokinetics. Clin Pharmacol Ther. 1979;26 :294 –305
Sheiner LB, Beal SL. Bayesian individualization of pharmacokinetics: simple implementation and comparison with non-Bayesian methods. J Pharm Sci. 1982;71 :1344 –1348
Jelliffe R, Bayard D, Milman M, et al. Achieving target goals most precisely using nonparametric compartmental models and "multiple model" design of dosage regimens. Ther Drug Monit. 2000;22 :346 –353
D'Argenio DZ, Schumitzky A. A program package for simulation and parameter estimation in pharmacokinetic systems. Comput Programs Biomed. 1979;9 :115 –134
Cellesi C, Chigiotti S, Zanchi A, et al. Susceptibility of macrolide and beta-lactam antibiotics of Streptococcus pyogenes strains isolated over a four-year period in central Italy. J Chemother. 1996;8 :188 –192
Yuk JH, Nightingale CH, Quintiliani R. Clinical pharmacokinetics of ceftriaxone. Clin Pharmacokinet. 1989;17 :223 –235
Leibovitz E, Piglansky L, Raiz S, Press J, Leiberman A, Dagan R. Bacteriologic and clinical efficacy of one day vs three day intramuscular ceftriaxone for treatment of nonresponsive acute otitis media in children. Pediatr Infect Dis J. 2000;19 :1040 –1045(Jeffrey L. Blumer, PhD, M)