Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA
Received 17 February 2005; returned 4 May 2005; revised 3 June 2005; accepted 10 June 2005
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Abstract |
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Methods: The efficacy of single versus multi-dose regimens of azithromycin was compared in mouse pneumonia, acute peritonitis, and neutropenic thigh infection models and in a gerbil model of Haemophilus influenzae acute otitis media. Azithromycin was administered as a single oral dose on the first treatment day, or as two divided doses over 2 treatment days, or as three divided doses over 3 treatment days. The pharmacokinetics of azithromycin was profiled following single and multi-dose regimens with the single dose data fit to an Emax model to characterize the PK-PD of azithromycin.
Results: In the mouse efficacy models, administration of single-dose azithromycin produced superior rates of survival and bacterial clearance compared with the same total dose divided over 2 or 3 days. In the gerbil model, a single dose sterilized the middle ear and more rapidly cleared H. influenzae. The pharmacokinetic evaluation confirmed similar total exposure (AUC) in serum and pulmonary tissue for the three regimens. Correlation of PK-PD parameters and antimicrobial efficacy confirmed a concentration-dependent and dosing-independent relationship for azithromycin.
Conclusions: These data are consistent with data reported from clinical studies and indicate that a single-dose regimen would be at least as effective as the same dose administered over several days.
Keywords: azithromycin , clarithromycin , amoxicillin/clavulanate , single-dose regimen , acute otitis media , Haemophilus influenzae , Streptococcus pneumoniae
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Introduction |
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The antimicrobial efficacy of a drug is determined by the interrelationship between its pharmacokinetic and pharmacodynamic (PK-PD) properties. The development of an effective short-course or single-dose regimen requires a concentration-dependent antimicrobial effect; as drug concentration increases, the rate and extent of killing also increase, making the goal one of dosing to maximize drug concentration.8 For such agents, the PK-PD predictor of efficacy is AUC/MIC or Cmax/MIC. In contrast, drugs such as clarithromycin and ß-lactams display minimal concentration-dependent killing; the extent of killing is dependent on the duration of exposure and these drugs therefore require frequent dosing to maintain the drug concentration above the MIC for much of the dosing interval.8
The pharmacokinetic properties that make azithromycin suitable for single-dose therapy are high tissue penetration, including high concentrations in the middle ear, and an extended elimination half-life of more than 60 h that allows for once daily dosing.8,9 Pharmacodynamic properties of azithromycin include bactericidal activity against key respiratory tract pathogens and a prolonged post-antibiotic or persistent effect.8 In addition, azithromycin is concentrated within phagocytes, which provide targeted delivery to the site of infection, further enhancing local tissue concentrations and improving in vivo efficacy.8,10,11 Furthermore, the PK-PD parameter that most closely correlates with the efficacy of azithromycin is AUC/MIC.12,13
The objective of this study was to evaluate the impact of administering oral azithromycin as a single-dose regimen in several preclinical infection models and thus provide a scientific rationale in support of existing clinical efficacy data. In vivo efficacy studies were conducted with azithromycin administered orally, either as a single large dose or divided over 2 or 3 days in mouse models of acute peritonitis, neutropenic thigh infection, and pneumococcal pneumonia; and in a gerbil model of Haemophilus influenzae AOM. Additionally, serum and pulmonary tissue pharmacokinetics were established for the three dosing intervals and 24 h PK-PD parameters were correlated with efficacy. In this study, we demonstrate that azithromycin administered over a shorter (1 day) dosing period provides superior efficacy when compared with 2 or 3 day regimens. Most significantly, a 1 day regimen results in more rapid eradication of H. influenzae in the gerbil model of otitis media than does a regimen lasting several days.
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Materials and methods |
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Stock solutions of azithromycin (Zithromax; Pfizer), clarithromycin (Abbott Laboratories) and amoxicillin/clavulanate (GlaxoSmithKline) were prepared before each experiment and diluted in a 0.5% methyl cellulose or ethanol/Tween 80/phosphate-buffered saline (5:5:90, by volume) vehicle to the desired concentration.
Bacterial strains
Bacterial strains used in this study were: Streptococcus pneumoniae 02J1016, serotype 3, a penicillin- and macrolide-susceptible strain originally isolated from blood culture (strain P 4241); Streptococcus pyogenes 02C0203, ATCC 12384, group A, type 3, a macrolide-susceptible strain; Enterococcus faecalis 03A1085, a vancomycin-susceptible, clinically derived strain; H. influenzae 54A1100, ATCC 43095, a non-serotype B, penicillin and macrolide-susceptible strain; H. influenzae 54A1218, a non-serotype B, penicillin-resistant and macrolide-susceptible strain (both H. influenzae strains were isolated from otitis media).
MIC determination
MICs for S. pneumoniae, S. pyogenes, E. faecalis and H. influenzae were determined using the broth microdilution procedure recommended by the NCCLS.14 Test trays were incubated at 35°C without CO2. For testing streptococci, the cation-adjusted MuellerHinton broth was supplemented with 23% lysed horse blood. For testing H. influenzae, freshly prepared Haemophilus Test Medium broth was used. MICs were determined a minimum of five times and modal MIC values were reported.
Animals
Female Swiss CF-1 mice (1820 g) aged 56 weeks were used for pharmacokinetic studies and for S. pneumoniae and S. pyogenes infection; female DBA/2 mice (1820 g) aged 56 weeks were used for E. faecalis and H. influenzae infection; female Mongolian gerbils (4550 g) aged 67 weeks were used for H. influenzae infection. All animals were obtained from Charles River Laboratories, Inc. (Wilmington, MA, USA). All procedures involving animals were approved by, and were in compliance with guidelines established by, the Pfizer Institutional Animal Care and Use Committee.
Pharmacokinetic evaluation
For single dose pharmacokinetic evaluation of azithromycin, CF-1 mice were administered an oral dose of azithromycin at 200, 100, 50, 25 or 12.5 mg/kg. Blood samples were taken starting at 0.25 h post-dose and at pre-determined intervals over a 24 h period (5 mice per time point for a total of 30 mice per dose level). To evaluate the pharmacokinetics of accelerated dosing with azithromycin, CF-1 mice were orally administered azithromycin at 100 mg/kg once daily for 1 day (5 mice per time point for a total of 40 mice), 50 mg/kg once daily for 2 days (5 mice per time point for a total of 65 mice), or 33 mg/kg once daily for 3 days (5 mice per time point for a total of 105 mice). Blood and pulmonary tissue samples were taken starting at 0.5 h post-dose and at pre-determined intervals over a 96 h period. For all pharmacokinetic experiments, serum and lung tissue samples were prepared and maintained at 70°C until further analysis. Serum and pulmonary tissue concentrations of azithromycin were determined by a validated LC/MS assay using Turbo IonSpray mass spectrometry detection.15 The lower and upper limits of quantification for the assay were 50 µg/L and 5 mg/L, respectively, and intra- and inter-assay variability was <7%. Pharmacokinetic parameters were calculated using non-compartmental methods using WinNonlin 2.1 software (Pharsight Corporation, Mountain View, CA, USA). Single dose pharmacokinetic data were subsequently used to estimate 24 h pharmacodynamic parameters of AUC/MIC, Cmax/MIC and time above MIC in order to explore the relationship between PK-PD parameters and antimicrobial effect (corrected for free fraction). Accelerated dosing pharmacokinetic data were used to establish the effect of dosing over 1, 2 or 3 days on serum and pulmonary tissue concentrations of azithromycin.
PK-PD versus efficacy evaluation
To evaluate the relationship between PK-PD parameters and antimicrobial efficacy, pulmonary (10 mice per dose level for a total of 180 mice per model), neutropenic thigh (5 mice per dose level for a total of 90 mice per model), and acute peritonitis infection models (10 mice per dose level for a total of 180 mice per model) were used in a total of five efficacy trials: normal CF-1 mice were challenged with a log phase culture of S. pneumoniae via the intranasal route (105 cfu/mouse in 40 µL); neutropenic CF-1 mice (neutropenia was induced using oral cyclophosphamide; 150 mg/kg 4 days prior and 100 mg/kg 1 day prior to infection) were challenged intramuscularly via the thigh with
105 cfu/mouse of either S. pneumoniae or S. pyogenes in 50 µL of vehicle; and normal CF-1 mice were challenged intraperitoneally with either S. pneumoniae (
103 cfu/mouse in 500 µL) or S. pyogenes (
105 cfu/mouse in 500 µL).
Oral azithromycin therapy was initiated 18 h after intranasal challenge, or 1.0 h after intraperitoneal or intramuscular challenge using a once per 24 h, once per 12 h, once per 6 h, or once per 3 h dosing interval that covered a 64-fold dose range for each infection model (0.39200 mg/kg per day) and continued for a total of 24 h. Streptococcal clearance (efficacy) was determined in the pulmonary infection model by quantifying the bacterial population (cfu/mouse) at 18 h and 42 h post-challenge following aseptic excision of infected lungs, or at 1.0 h and 25 h post-challenge in the neutropenic infection models following aseptic excision of infected thigh muscle. The bacterial burden for untreated infected controls at 18 h and 1 h for the pulmonary and thigh infection models, respectively, served as baseline controls. Standard plate counting methods were used to enumerate bacteria grown on blood agar plates; the limit of detection was 100 cfu/mouse. Efficacy outcome was determined as the change in log10 cfu between 18 h and 42 h (pulmonary) or 1 h and 25 h (thigh) post-challenge for each dosing interval. The change in bacterial burden for the untreated infected controls from 18 h to 42 h served as a measure for Emin (log10 cfu/mouse). Emax was defined as the eradication or the greatest differential in bacterial burden observed. In order for efficacy of bacterial burden reduction and survival to be pooled, responses were calculated for each dose as the ratio of the difference of EdoseEmin/EmaxEmin with responses ranging from 0 to 1.
For the acute peritonitis and pulmonary infection models, survival was scored daily and moribund animals were euthanized and scored as non-survivors. Efficacy outcome was determined from the survival data at Day 6 (peritonitis) or Day 10 (pulmonary) post-challenge. For each dose, a response was determined from the ratio of survivors to the total number of animals in the group with responses ranging from 0 (no survivors) to 1 (maximum survivors). Data for the five efficacy trials were pooled and efficacy response was correlated with PK-PD parameters.
Evaluation of single- versus multi-dose azithromycin regimens
The influence of a shorter antimicrobial dosing regimen was investigated using acute peritonitis and pulmonary infection models in mice, and a gerbil AOM model. For the acute peritonitis model, normal CF-1 and DBA/2 mice were challenged intraperitoneally with a 10 LD100 inoculum of a log-phase culture of one of S. pneumoniae (103 cfu/mouse), or S. pyogenes (105 cfu/mouse), and overnight OD adjusted plate scrapings were used for E. faecalis (107 cfu/mouse) and H. influenzae (107 cfu/mouse). With enterococcal and Haemophilus strains, the inoculum was fortified with 3% Brewer's yeast as a bacterial enhancing adjuvant while for streptococcal strains, the suspending vehicle was brain heart infusion (BHI) broth. Oral therapy with azithromycin or clarithromycin was initiated 0.5 h after bacterial challenge and administered once daily, either as a single dose on the first treatment day, or as two divided doses over 2 treatment days, or as three divided doses over 3 treatment days (10 mice per dose level for a total of 140 mice per model, all infection models were repeated in triplicate). For all models, a 64-fold dose range was used using a fourfold titration scheme. For the E. faecalis and H. influenzae models, the 64-fold dose range covered 3.12 to 200 mg/kg. The S. pneumoniae model covered 1.56 to 100 mg/kg, and the S. pyogenes model covered 0.78 to 50 mg/kg. Control groups included non-infected BHI or 3% Brewer's yeast-treated animals as well as inocula of 1 LD100 and 100 LD100. Survival was scored over 6 days at which time the effective dose 50 (ED50) was determined using non-linear regression techniques with GraphPad Prism v4.0 (GraphPad Software Inc., San Diego, CA, USA).
For the pulmonary infection model, CF-1 mice were infected intranasally with an LD100 inoculum of a log phase pneumococcal culture (105 cfu/mouse). Oral therapy with azithromycin (3.1200 mg/kg) or clarithromycin (6.2400 mg/kg) was initiated 18 h after bacterial challenge and administered once daily for 1, 2 or 3 days as before (10 mice per dose level for a total of 140 mice per model, repeated in triplicate). Therapy was withheld for 18 h in order to establish a bacteraemia (104 cfu/mL of blood) prior to antibiotic treatment (unpublished data and Duong et al.16). Survival was recorded over 10 days at which time the ED50 was determined using non-linear regression techniques with GraphPad Prism v4.0.
For the AOM model, gerbils were infected with 1034 cfu of H. influenzae via intra-bulla instillation. Oral therapy with azithromycin, clarithromycin, or amoxicillin/clavulanate (3.1200, 6.2400 and 3.1200 mg/kg, respectively) was initiated 18 h after challenge and administered once daily for 1, 2 or 3 days as before (5 gerbils per dose level, total of 50 gerbils per study and done in triplicate). Bullae were tapped 72 h after initiation of therapy, washed with 100 µL of saline and recoverable H. influenzae were enumerated to a detection limit of 100 cfu. ED50 values were calculated from the percentage of animals that cleared the H. influenzae infection over the evaluated dose range at 72 h. For some experiments, oral therapy was initiated 24 h after intra-bulla challenge of gerbils and consisted of a total therapeutic dose of 200 mg/kg azithromycin administered once daily over 1, 2, or 3 days (15 gerbils per dosing regimen, 65 gerbils per study and repeated in triplicate). Bullae were tapped at 24, 48, 72 and 96 h following challenge, washed with 100 µL of saline and recoverable H. influenzae were enumerated to a detection limit of 100 cfu.
Data analysis
A sigmoidal Emax doseresponse model derived from the Hill equation (four-parameter logistic equation with variable slope using GraphPad Prism v4.0) was used to determine the relationships between individual PK-PD parameters and antimicrobial efficacy outcomes of bacterial clearance and survival; Y = D + (A D)/(1 + 10(log CX)*b). For the four-parameter logistic equation, Y is the observed effect, D is the bottom, A is the top, C is the EC50 or 50% of the observed maximum effect, X is the log of the concentration and b is the Hill slope.
From these relationships, the coefficient of determination (R2) value was calculated using non-linear least-squares multivariate regression analysis and subsequently used to estimate the goodness of fit for each PK-PD parameter. Non-linear regression analysis was also used to estimate ED50 values from 6 and 10 day survival data. Significance between dosing regimen outcomes for bacterial burden was determined using ANOVA (one-way) and when the F statistic reached significance (P < 0.05) then post-hoc comparison was made using Tukey's multiple comparison test.
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Results |
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The systemic exposure of azithromycin increased in an approximately dose-proportional manner (Figure 1). Serum Cmax values ranged from 0.6 to 15 mg/L and AUC024 values ranged from 3 to 44 mg·h/L. Time to Cmax (Tmax) ranged from 1 to 2 h. Cmax was highest when azithromycin was administered as a single dose of 100 mg/kg on 1 treatment day (100 mg/kg per day), rather than as a divided dose over 2 (50 mg/kg per day), or 3 treatment days (33.3 mg/kg per day) (Figure 2). Whereas Cmax was reached 2 h after administration of the single dose regimen, Cmax was delayed until 26 h when azithromycin was given as either two or three divided doses over a longer treatment period. Azithromycin displayed similar pharmacokinetic behaviour in pulmonary tissue, with Cmax again favouring early delivery of the entire azithromycin dose (Table 1).
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Composite data were obtained from five efficacy trials that measured bacterial burden and survival in mice infected with S. pneumoniae or S. pyogenes and subsequently treated for 24 h with azithromycin. The relationship between efficacy [bacterial clearance and mouse survival expressed as efficacy (response)] and PK-PD parameters of AUC/MIC, Cmax/MIC and time above MIC is shown in Figure 3. For each of the PK-PD parameters, there was a sigmoidal relationship with efficacy. The global PD parameter that best correlated with efficacy outcome was AUC/MIC with an R2 value of 0.70, followed by Cmax/MIC with an R2 value of 0.52. A poor correlation was observed with time above MIC (R2 = 0.29).
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In the murine acute peritonitis infection model, a 1 day dosing regimen of oral azithromycin had a 50% protective effect on mouse 6 day survival at a significantly lower dose than a 2 and/or 3 day dosing regimen when S. pneumoniae, S. pyogenes, E. faecalis, or H. influenzae were used as the challenge organism (Table 2). In contrast, clarithromycin was much less active than azithromycin against S. pneumoniae, S. pyogenes and H. influenzae irrespective of which dosing regimen was used. Clarithromycin did show superior ED50 activity against E. faecalis compared with azithromycin and was effective against this organism when administered as a 1 day dosing regimen. However, in general there was no clear relationship between clarithromycin activity and dosing regimen, since the 2 and 3 day regimens were optimal versus S. pyogenes while the 1 day regimen was superior for E. faecalis.
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Discussion |
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There is existing clinical support for single-dose azithromycin in the treatment of community-acquired infections, coming from clinical trials of AOM and also pharmacokinetic data from healthy adult volunteers showing equivalent serum and white blood cell exposures whether a total dose of 1.5 g of azithromycin was given as a 1 day or 3 day regimen.47,21 PK-PD data have also contributed to the growing evidence base for the selection of a more rational therapeutic regimen.12,13 The purpose of this study was to provide further experimental support for a single-dose azithromycin regimen by leveraging the unique properties of this drug in a variety of animal models of infection.
The finding in this study that composite efficacy data following single-dose administration of azithromycin were most closely correlated with 24 h AUC/MIC confirmed the importance of dose and not dosing interval in determining bacterial clearance and survival rates following streptococcal challenge in mice. The pharmacokinetic relationship between azithromycin and dosing interval was further explored following administration of a total dose of 100 mg/kg azithromycin, given either as a single dose or as a divided dose over 2 or 3 days. Total serum and pulmonary exposures were similar for the three regimens over the 3 day sampling interval, but Cmax was dependent on the initial dose, with the single-dose regimen producing the highest Cmax. These data are consistent with data previously reported by Craig,13 who demonstrated that a 24 h AUC/MIC ratio could be used to predict both bacteriological and clinical efficacy of azithromycin in AOM. Arguably for these azithromycin data as well as for Craig's, the dose and Cmax of azithromycin required for efficacy in murine models are considerably greater than those required in man due to the higher rate of azithromycin clearance in mice. Humanization of azithromycin pharmacokinetics in the mouse has been experimentally impractical but recently a new approach described by Forrest et al.22 in gerbils resulted in minimizing the large peak-to-trough plasma concentrations for a target plasma AUC and would be useful in further probing the impact of peak on efficacy of azithromycin.
In addition to investigating PK-PD relationships using S. pneumoniae and S. pyogenes as challenge organisms, we also wanted to provide robust analysis of antimicrobial efficacy outcomes against a range of pathogens in different animal models. In the acute peritonitis model, bacterial strains were chosen for their ability to produce a more chronic infection amenable to the evaluation of short-course versus single-dose therapy. In the murine peritonitis model, a single-dose regimen of azithromycin was consistently superior to a 2 or 3 day regimen following challenge with S. pneumoniae, S. pyogenes, E. faecalis or H. influenzae, suggesting that dosing azithromycin less frequently is more effective than dosing more often when giving the same total dose. (The in vivo activity of azithromycin against E. faecalis was assessed to provide an example of an efficacious outcome against a non-susceptible organism despite free plasma concentrations below the pathogen's MIC, as has also been shown with H. influenzae.23) In contrast, clarithromycin, a time-dependent antibiotic, was generally less active than azithromycin irrespective of the dosing regimen and would probably benefit from a longer course of therapy. This finding probably relates to the different pharmacokinetics of the two drugs. Whereas azithromycin is rapidly absorbed into tissue and maintains high concentrations for relatively long periods, clarithromycin achieves high serum concentrations, but is rapidly eliminated. Therefore, to maximize efficacy, clarithromycin requires multiple daily dosing.
In the mouse pneumococcal pneumonia model, single-dose azithromycin again demonstrated superior efficacy to a 3 day regimen. However, in the gerbil AOM model, the ED50 for the 1 day regimen was not statistically significantly different from the 2 and 3 day regimens. This may be due to the mechanism of phagocytic delivery of azithromycin.10,24 Since azithromycin concentrations at infection loci are partially driven by phagocytic infiltration and drug deposition during inflammation, the fact that therapy was initiated prior to maximal inflammation in the gerbil model, may have favoured the 2 and 3 day regimens. Even so, all three azithromycin regimens were effective. Since the gerbil does not metabolize clarithromycin to 14-hydroxyclarithromycin and clarithromycin dosing was not optimized, clarithromycin failed in this model. For amoxicillin/clavulanate, the dosing of which was also not optimized to its PK/PD characteristics, the ED50 value was non-significantly lower for a 3 day regimen.
A further set of experiments using the gerbil AOM model investigated the in vivo bacterial clearance kinetics for azithromycin 200 mg/kg delivered as a single dose or as a 2 or 3 day regimen against a penicillin-resistant H. influenzae strain. All three regimens eradicated H. influenzae from the bulla, but sterilization was more rapid using the single-dose azithromycin regimen.
These data provide support for existing clinical data demonstrating that single-dose azithromycin is at least as effective as regimens of a longer duration.46,21 In addition, the marked decrease in ED50 values in murine models and the finding that H. influenzae were cleared more rapidly in the gerbil otitis media model when a single-dose regimen was administered suggests that azithromycin may perform better when administered this way. Increasing the dose of azithromycin early in the infectious process may facilitate earlier clinical cure, even in infections caused by marginally susceptible pathogens.2 Furthermore, such a strategy may negate the potential for selection of resistance and its associated complications.
In conclusion, this study compared the relative efficacy of single-dose versus 2 or 3 day dosing regimens of azithromycin in four different preclinical infection models using clinically relevant bacterial pathogens. These efficacy data indicate that a single-dose azithromycin regimen is better than a longer course of therapy. Additionally, the in vivo bacterial clearance kinetics of azithromycin against H. influenzae suggest that bacterial clearance is more rapid with a single-dose regimen, which could have benefits in minimizing the emergence of resistance. These preclinical data correspond to what has been observed in clinical studies and highlight the advantages of 1 day azithromycin dosing over a more prolonged course of therapy.
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Acknowledgements |
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