Explaining the Poor Bacteriologic Eradication Rate of Single-Dose
Ceftriaxone in Group A Streptococcal Tonsillopharyngitis: A Reverse
Engineering Solution Using Pharmacodynamic Modeling
Jeffrey L. Blumer, PhD, MD*‡; Michael D. Reed, PharmD*‡; Edward L. Kaplan, MD§; and George L. Drusano, MD㛳
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 ceftri-axone dose required for effective treatment.
Methods. Population modeling techniques were ap-plied 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 sim-ulation was performed to determine (1) the amount of time that free ceftriaxone concentrations must exceed the minimum inhibitory concentration (MIC) of group A Streptococcusto achieve bacteriologic eradication and (2) the ceftriaxone dose required to maintain free drug con-centrations above the target MIC for the requisite amount of time. Ceftriaxone MICs for group A Strepto-coccuswere obtained from a previous trial, in which all MICs (nⴝ115) were<0.064 mg/L; 33.9% were
suscepti-ble 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 parame-ters and their variances reflected substantial variability of clearance and half-life in the target population. Ton-sillar ceftriaxone protein binding was 89.1%. The propor-tions 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 sep-arated 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
ad-ministered 18 hours after the first will be required to achieve an acceptable bacteriologic cure rate. Pediatrics 2005;116:927–932; tonsillopharyngitis, ceftriaxone, phar-macokinetics, pharmacodynamics, pharyngitis.
ABBREVIATIONS. MIC, minimum inhibitory concentration; HPLC, high-performance liquid chromatography; NPEM, non-parametric expectation maximization; MAP, maximum aposterion probability.
P
enicillin in a 10-day course has been standard therapy since the 1950s for tonsillopharyngitis attributed to group A -hemolytic Streptococ-cus.1,2 Although effective in eradicating group A-hemolytic Streptococcus in ⬃90% of patients through the early 1970s, penicillin therapy for strep-tococcal tonsillopharyngitis is now associated with a failure rate of ⬃30%.1–5 Poor compliance rates, re-ported to be as low as 8% by the ninth day of treat-ment,6may be one reason for penicillin failure.1 Pen-icillin failure has also been hypothesized to arise from bacterial co-pathogenicity, whereby penicillin-susceptibleStreptococcusis protected by co-localized bacterial strains that do not share the penicillin sus-ceptibility of Streptococcus.7,8 For example,  -lacta-mase–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 Strep-tococcus. Finally, penicillin failure may arise from tolerance, in which Streptococcus that is exposed re-peatedly to sublethal concentrations of penicillin be-comes increasingly resistant to eradication.9
The persistence ofStreptococcusafter failed penicil-lin therapy is of major cpenicil-linical 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-threaten-ing systemic diseases, includlife-threaten-ing necrotizlife-threaten-ing pneu-monitis, streptococcal toxic shock, and necrotizing fasciculitis.11,12These risks have stimulated attempts at improving antibiotic treatment outcomes in strep-tococcal tonsillopharyngitis.13,14
The broad-spectrum cephalosporin ceftriaxone (Rocephin; Hoffman-La Roche, Nutley, NJ) possesses characteristics that may help it to overcome the lim-itations of oral penicillin therapy. With its long half-life (5.8 – 8.7 hours in healthy adults),15 ceftriaxone From the Departments of *Pediatrics and ‡Pharmacology, Case Western
Reserve University School of Medicine, Cleveland, Ohio; §Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota; and㛳Ordway Research Institute and New York State Department of Health, Albany, New York.
Accepted for publication Jan 13, 2005. doi:10.1542/peds.2004-2294
Conflict of interest: All authors have received grant support and been consultants to Roche.
Reprint requests to (J.L.B.) Department of Pediatrics, Tulane University School of Medicine, 1430 Tulane Ave, SL-37, New Orleans, LA 70112. E-mail: [email protected]
has been demonstrated microbiologically effective with only a single 50-mg/kg intramuscular admin-istration for acute otitis media caused by S pneu-moniae, 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 associ-ated with courses of oral antibiotic therapy that re-quire 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 pharyn-ges 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. Sur-prisingly, 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%.18To assess better the apparent discrep-ancies between predicted versus observed pharma-cologic effect, we assessed the pharmacokinetic fac-tors 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 tonsillopharyngi-tis.
METHODS
In this study, population-based modeling techniques were ap-plied 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 deter-mine in the context of the actual minimum inhibitory concentra-tion (MIC) data derived from a ceftriaxone clinical study18(1) the
amount of time that free ceftriaxone concentrations need to exceed the MIC of group AStreptococcusto achieve microbiologic success and (2) the ceftriaxone dose required to maintain free drug con-centrations 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 corticoste-roids 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 par-ents 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) immedi-ately 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 chromatogra-phy (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 15 800⫻gfor 3 minutes at room temperature with a Marathon 26KMR refriger-ated centrifuge (Fisher, Pittsburgh, PA). Then, 0.2 mL of the su-pernatant 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 400g/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 tonsillec-tomy 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⫻g. The super-natant solution was retained for additional analysis as the “total” homogenate. Early experiments demonstrated that neither ho-mogenization times⬍50 s nor centrifugation at 3000⫻gcaused a loss of ceftriaxone. Total homogenate was centrifuged further at 26 000⫻gfor 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 centrif-ugation at 3000 ⫻ 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⫻gfor 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 Mi-cropartition 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
g/g tissue.
Standards and controls in pooled blank tonsil homogenate were prepared between 0.2 and 20g/mL. The within- and be-tween-day precisions were 2.2% and 2.2%, respectively. The with-in- 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⫻4.6 mm) followed by an Eclipse XCB-C8 analytical column (150⫻4 mm). Mobile phase that contained 17% acetonitrile and 83% aque-ous 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 de-tected 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
estimates were used to generate predicted ceftriaxone concentra-tions for the plasma and tonsillar samples for each patient. Two-and 3-compartment open models with first-order input into Two-and elimination from the central compartment were evaluated. Models were discriminated on the basis of the Akaike information crite-rion. 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 vari-ance was proportional to the varivari-ance 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 simu-lation module program ADAPT II.22The 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 strep-tococci 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.18To accomplish this analysis, we
determined MIC data for 115 group AStreptococcusisolates 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). Sev-enty-seven were male. Paired plasma and tonsillar samples were obtained from all 153 patients. The number of patients to whom ceftriaxone was admin-istered 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⫻Predicted⫹2.93 (r2⫽0.958, P⬍.001; Fig 1A), whereas for tonsillar samples, the equation of best-fit line was Observed⫽1.01⫻Predicted⫹0.488 (r2⫽ 0.92,P⬍ .001; Fig 1B).
Ceftriaxone Protein Binding in Tonsil or Tissue
The average ceftriaxone protein binding in tonsil-lar or tissue over the range of 1 to 25g/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 AStreptococcus 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 ceftriax-one, 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%, respec-tively (Fig 2). At 48 hours after dosing with 500 mg of ceftriaxone, the proportions of simulated patients with free tonsillar ceftriaxone concentrations that ex-ceeded 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 bacteri-ologic eradication rate of 67.3% if 24 hours of ade-quate 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 trial18lies 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 ceftri-axone concentrations needed to exceed the MIC range of 0.016 to 0.064 mg/L, a time midway be-tween the 24- and 48-hour targets, was examined. The estimated microbiologic success rate after a sin-gle intramuscular 500-mg ceftriaxone dose was 49.9% if 36 hours of time with free tonsillar ceftriax-one concentrations that exceeded the MIC was re-quired 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
tonsil-TABLE 1. Ceftriaxone Population Pharmacokinetic Mean (SD) Parameters
Parameter Mean (SD) Volume of distribution L 2.13 (1.79) Plasma clearance, L/h 0.556 (0.150) Elimination rate constants, h⫺1
K12 3.12 (2.44)
K21 5.78 (2.17)
K13 4.72 (3.26)
K31 6.13 (3.75)
Absorption rate constant, h⫺1 3.09 (5.67)
lar tissue that exceeded the MIC for group A Strep-tococcuswas chosen as the criterion for defining mi-crobiologic success.
This criterion was used in evaluating the microbi-ologic performance of a 1000-mg ceftriaxone dose to determine whether it would eradicate more success-fully 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 ceftri-axone would be required to attain an 81.5% micro-biologic 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 microbi-ologic 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 micro-biologic success rate approximating only 50% in chil-dren with group A streptococcal tonsillopharyngitis and to identify a dosing regimen associated with a higher probability of success. In both trials, the effi-cacy of ceftriaxone was compared with that of peni-cillin. The penicillin efficacy data have been reported previously.18Our results suggest that the low micro-biologic 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.23Rather, this un-expectedly low clinical efficacy seems to be
attribut-Fig 1. Ceftriaxone population pharmacokinetic analysis with NPEM. (A) Plasma. The best-fit line is described by the equation Observed ⫽0.95⫻Predicted⫹2.93 (r2⫽ ⫺0.958,P⬍.001). (B) Tonsil. The best-fit line is described by the equation Observed⫽1.01⫻Predicted
⫹0.488 (r2⫽0.92,P⬍.001).
Fig 2. Ceftriaxone target attainment for main-taining free drug⬎MIC. The figure depicts the ceftriaxone time ⬎MIC in tonsils with target attainment at 24 hours (), 48 hours (Œ), 72
able 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 sub-stantial portion of children. Previous research has shown that protein binding of ceftriaxone in plasma is very high (90%–95%).24The current study extends this observation by demonstrating that protein bind-ing of ceftriaxone is also high (⬃90%) in the tonsils, the microbiologic target of ceftriaxone in tonsillo-pharyngitis.
In addition to high plasma and tonsillar protein binding, the variability of ceftriaxone pharmacoki-netics in children may account for the low microbi-ologic success of a single 500-mg dose. Population pharmacokinetic values that were derived by mod-eling 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 bacterio-logic 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 requi-site MICs would be virtually impossible. Thus, phar-macokinetic 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 Streptococ-cus.18
The requirement that ceftriaxone free drug concen-trations continuously exceed the MIC for 36 hours may explain why a single intramuscular dose effec-tively eradicates N gonorrheafrom the urinary tracts of patients with gonorrhea17 but does not eradicate group A Streptococcus from the pharynx of patients with tonsillopharyngitis.18In gonorrhea, the mucosal site of bacteriologic eradication is anatomically lo-cated distal to ceftriaxone’s primary organ for clear-ance, 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 mu-cosal site of bacteriologic eradication in tonsillophar-yngitis, 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 con-centrations in excess of the MIC. Recent pharmaco-kinetic studies with -lactam agents measured in acute otitis media demonstrate that the time course at the infection site demonstrates a prolonged
termi-nal half-life. This may explain the effectiveness of single-dose ceftriaxone in this infection site. Never-theless, Leibovitz and colleagues25described similar compromised bacterial eradication rates for children with acute otitis media caused by penicillin-nonsus-ceptible strains ofS pneumoniae(53% single intramus-cular dose vs 97% 3 daily consecutive intramusintramus-cular 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 in-tramuscular ceftriaxone dose of 8 g would be re-quired to exceed a modest 80% bacteriologic eradi-cation 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 eradica-tion rate that exceeded 95%. Like the single-dose regimen studied previously,18 this 2-dose regimen, compared with currently recommended oral regi-mens, would be expected to be associated with higher compliance rates and minimal risk for treat-ment 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 Pedi-atric Pharmacology Research Unit grant from the National Insti-tute of Child Health and Development (HD31323-12).
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DENTISTS PREPARE TO BE ON FRONT LINE OF CIVIL DEFENSE
“Past the five-foot-tall tanks of nitrogen gas, through a narrow, snaking hallway, behind double doors, just past the safety shower, they convene on the 10th floor of a building in Manhattan.
They await an outbreak of smallpox or botulism, or nerve gas in the subway, perhaps a dirty bomb going off in Midtown. They are a creative bunch: well-educated, high-ranking Americans. They are also dentists.
Their leader, the former military contract agent Dianne Rekow. . . . Dr. Rekow’s plan is ambitious, national in scope and revolutionary in concept: she wants to draw dentists into the squadron of so-called ‘first responders’—the police officers, firefighters and emergency medical technicians dispatched for disaster relief and crisis management.
Dentists, she argues, are a rich but overlooked source of help. . . . Dentists have basic knowledge of infectious diseases, minor surgery skills and an infrastructure of medical assistants and equipment. Dr. Rekow, who was recently elected presi-dent of the American Association for Dental Research, is bent on informing the larger medical profession and a post–Sept. 11 society that dentists can offer more in a crisis than free toothbrushes.”
Morgan R.New York Times. August 2, 2005
DOI: 10.1542/peds.2004-2294
2005;116;927
Pediatrics
Jeffrey L. Blumer, Michael D. Reed, Edward L. Kaplan and George L. Drusano
Using Pharmacodynamic Modeling
Group A Streptococcal Tonsillopharyngitis: A Reverse Engineering Solution
Explaining the Poor Bacteriologic Eradication Rate of Single-Dose Ceftriaxone in
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DOI: 10.1542/peds.2004-2294
2005;116;927
Pediatrics
Jeffrey L. Blumer, Michael D. Reed, Edward L. Kaplan and George L. Drusano
Using Pharmacodynamic Modeling
Group A Streptococcal Tonsillopharyngitis: A Reverse Engineering Solution
Explaining the Poor Bacteriologic Eradication Rate of Single-Dose Ceftriaxone in
http://pediatrics.aappublications.org/content/116/4/927
located on the World Wide Web at:
The online version of this article, along with updated information and services, is
by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.
