Michael R. Jacobs, MD, PhD FDA Presentation Nov 7, 2001

Michael R. Jacobs, MD, PhD FDA Presentation Nov 7, 2001
Selection of antibiotics for acute otitis media: Application of pharmakokinetic and pharmacodynamic principles Michael R. Jacobs, MD, PhD Professor of Pathology Case Western Reserve University Director of Clinical Microbiology University Hospitals of Cleveland Cleveland, OH Food and Drug Administration Anti-Infective Drugs Advisory Committee Meeting November 7, 2001, to consider the safety and efficacy of a new drug application (NDA) 50–710, Pfizer, Inc., for 1-day and 3-day dosing regimens of azithromycin suspension for the treatment of otitis media In response to notice of the above meeting on pages of the Federal Register, Vol. 66, No. 202, dated Thursday, October 18, 2001, I have requested permission to make an oral presentation during the time allowed for public presentations. I am representing myself as a scientist and physician working on principles related to the treatment of otitis media, and have submitted full disclosures of my work related to this subject [Attachment A], and of all external financial support that I have received related to this subject [Attachment B].

S. pneumoniae Penicillin Susceptibility United States 1979–20001–4
Michael R. Jacobs, MD, PhD FDA Presentation Nov 7, 2001 S. pneumoniae Penicillin Susceptibility United States 1979–20001–4 34 13 16 29 11 25 33 17 3.8 2 3 4 5 6 7 8 10 15 14 20 30 40 50 60 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988–89 1990–91 1992–93 1994–95 1997 1998 1999 2000 Year % Penicillin resistant Resistant MIC > 2.0 g/ml Intermediate MIC = 0.12–1.0 g/ml This figure summarizes the development of penicillin resistance in S pneumoniae in the United States over the last 20 years. During the 1980s, the prevalence of penicillin-resistant S pneumoniae in national surveillance studies was consistently low. In a survey, only 3.8% of isolates demonstrated intermediate to high levels of resistance.1 By 1995, a study of isolates from 30 US centers demonstrated an overall resistance rate of 23.6%, with 1 in 3 strains demonstrating a high level of resistance.1 In 1997, Jacobs et al conducted a surveillance study of isolates from 31 states to determine susceptibilities of S pneumoniae to 10 oral b-lactam, macrolide/azalide, and fluoroquinolone antibiotics.2 Among S pneumoniae isolates, approximately 50% showed some degree of resistance: 17% were penicillin intermediate and 33% were penicillin resistant.2 In a 1998 study by the same investigators, 45% of isolates of S pneumoniae were resistant to penicillin: 16% intermediate and 29% resistant.3 1. Doern GV. Am J Med 1995; 99(suppl 6B):3S–7S. 2. Jacobs MR et al. Antimicrob Agents Chemother 1999; 43:1901–1908. 3. Jacobs MR et al. ICAAC 1999, poster C-61. 4. Jacobs MR. USA Alexander Project data 2000 1. Doern GV. Trends in antimicrobial susceptibility of bacterial pathogens of the respiratory tract. Am J Med. 1995:99(suppl 6B):3S-7S. 2. Jacobs MR, Bajaksouzian S, Zilles A, Lin G, Pankuch GA, Appelbaum PC. Susceptibilities of Streptococcus pneumoniae and Haemophilus influenzae to 10 oral antimicrobial agents based on pharmacodynamic parameters: 1997 U.S. Surveillance Study. Antimicrob Agents Chemother. 1999;43: 3. Jacobs MR, Bajaksouzian S, Lin G, Zilles A, Pankuch GA, Appelbaum PC. Susceptibility of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis to oral agents: results of a 1998 U.S. outpatient surveillance study. Poster presented at 39th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999; San Francisco, Calif. Poster C-61.

Temporal Trends in Macrolide Resistance Among Invasive Streptococcus pneumoniae Isolates and Macrolide Use USA Temporal Trends in Macrolide Resistance Among Invasive Streptococcus pneumoniae Isolates and Macrolide Use Susceptibility data are from Active Bacterial Core Surveillance, ; macrolide prescription rates are from the National Ambulatory Medical Care Survey/National Hospital Ambulatory Medical Care Survey, Macrolides are important therapeutic agents. Clinical treatment guidelines for empiric therapy for community-acquired pneumonia in adults have recommended using macrolides as first-line agents.1-3 The increasing frequency of macrolide resistance among pneumococci and increasing MICs among resistant strains suggest that these treatment recommendations may need reevaluation. Alternative antimicrobial agents for macrolide-resistant infections exist or are in development. For young children who are penicillin-allergic, however, the management of respiratory tract infections may become problematic because doxycycline and fluoroquinolones are not available as alternatives for this age group. Hyde, TB, et al. JAMA. 2001; 286: Hyde, TB, et al. JAMA 2001; 286:

S. pneumoniae: susceptibility of middle ear fluid isolates in two time periods* Agent MIC90 (ug/ml) % Susceptible* Amoxicillin Amox-clav Cefuroxime Cefprozil Clarithromycin Azithromycin .03 .5 .12 2 >4 16 >2 100 98 91 92 54 55 63 The recent increase in resistance of the major bacterial respiratory tract pathogens to oral antimicrobial agents has produced a need to reevaluate treatment choices in respiratory tract infections. Otitis media is caused by three key pathogens, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Currently in the USA about half of S. pneumoniae isolates are penicillin-intermediate or -resistant, and more than 40% of H. influenzae isolates and 90% of M. catarrhalis isolates produce b-lactamases. Although regions of the United States differ in prevalence of antibiotic resistance, all regions now have substantial resistance. The interpretation of minimum inhibitory concentrations (MICs) of pathogens needs to be correlated with pharmacokinetic and clinical data. MIC breakpoints should be based on pharmacokinetic and pharmacodynamic characteristics, such as the amount of time an antimicrobials maintain effective concentrations in serum or at the site of infection. Jacobs, MR. Increasing Antibiotic Resistance among Otitis Media Pathogens and their Susceptibility to Oral Agents based on Pharmacodynamic Parameters. Pediatr Infect Dis J 2000; 19:S47-56 *Based on PK/PD breakpoints Jacobs M PIDJ 2000;19:S 47 : N=50; : N=440

H. influenzae: susceptibility of middle ear fluid isolates in two time periods* Agent MIC90 (ug/ml) % Susceptible* Amoxicillin Amox-clav Cefuroxime Cefprozil Clarithomycin Azithromycin >8 .5 1 8 16 2 84 100 94 6 54 97 76 14 While many b-lactams are active against the major otitis media pathogens, macrolides and azalides have limited activity against H. influenzae and 30% of isolates of S. pneumoniae are now macrolide/azalide resistant. In choosing the most appropriate agents for empiric use in otitis media, amoxicillin-clavulanate is the only b-lactam or macrolide/azalide antibiotic that is effective against > 90% of the 3 key respiratory pathogens. Introduction of conjugate pneumococcal vaccines will have a significant impact on otitis media as these vaccines contain the major serotypes associate with antimicrobial resistance. Jacobs, MR. Increasing Antibiotic Resistance among Otitis Media Pathogens and their Susceptibility to Oral Agents based on Pharmacodynamic Parameters. Pediatr Infect Dis J 2000; 19:S47-56 *Based on PK/PD breakpoints Jacobs M PIDJ 2000;19:S 47 : N=50; : N=271

Acute otitis media studies in children
Michael R. Jacobs, MD, PhD FDA Presentation Nov 7, 2001 Acute otitis media studies in children

The role of antibacterials is to eradicate the causative organisms from the site of infection Dagan R. Personal communication

Outpatient clinical studies in respiratory tract infections
Michael R. Jacobs, MD, PhD FDA Presentation Nov 7, 2001 Outpatient clinical studies in respiratory tract infections High rate of spontaneous resolution makes it difficult to show clinical differences between agents Bacteriologic outcome studies are not often performed due to necessity for invasive procedure (ear, sinus or lung tap) to obtain specimen Most studies are therefore designed to show “equivalent” clinical outcome between established and new agents Inadequacies of agents studied are therefore often not apparent Outpatient clinical studies in respiratory tract infections High rate of spontaneous resolution makes it difficult to show clinical differences between agents Bacteriologic outcome studies are not often performed due to necessity for invasive procedure (ear, sinus or lung tap) to obtain specimen Most studies are therefore designed to show “equivalent” clinical outcome between established and new agents Inadequacies of agents studied are therefore often not apparent Marchant C, et al. J Pediatr 1992; 120:72–77 Marchant C. et al. J Pediatr 1992; 120:72–77.

Sample sizes required to detect differences between antibacterial drugs for acute otitis media Comparison of bacteriologic vs clinical outcomes in trials of two drugs (half the patients would be in each arm of a study) In randomized, double-blind trials of antibiotic therapy for acute otitis media that determined both clinical and bacteriologic outcomes on days 4-7 of therapy, clinical success rates were 93% [236 of 253] for patients with bacteriologic success, 62% [25 of 40] for those with bacteriologic failure, and 80% [124 of 155] for those with nonbacterial acute otitis media. These rates were used to calculate the effectiveness of three strategies for assessing drug efficacy: (1) tympanocentesis and culture before and during therapy (bacteriologic efficacy), (2) tympanocentesis before therapy and assessment of clinical efficacy in bacterial acute otitis media, and (3) no tympanocentesis and assessment of clinical efficacy in clinical (total) acute otitis media. For a drug with a bacteriologic efficacy of 100%, calculated clinical efficacy was 93% for bacterial acute otitis media and 89% for clinical acute otitis media. For a drug with bacteriologic efficacy of 27%, a rate consistent with no antibacterial therapy, efficacy was 71% for bacterial acute otitis media and 74% for clinical acute otitis media. If efficacy is measured by symptomatic clinical response, drugs with excellent antibacterial activity will appear less efficacious than they really are and drugs with poor antibacterial activity will appear more efficacious than they really are. This slide shows calculated sample sizes needed to show these differences in clinical studies based on study design and bacteriological efficacy of agents. Marchant, C. D., Carlin, S. A. Johnson, C. E., Shurin, P. A. Measuring the comparative efficacy of antibacterial agents for acute otitis media: the "Pollyanna phenomenon." J Pediatr 1992; 120:72–77. Marchant C. et al. J Pediatr 1992; 120:72–77.

Azithromycin in AOM: clinical outcome at end of therapy studies
Michael R. Jacobs, MD, PhD FDA Presentation Nov 7, 2001 Azithromycin in AOM: clinical outcome at end of therapy studies Four studies using a common comparator were compared1-4 Study designs differed two were clinical diagnosis and outcome1,3 one was bacteriologic diagnosis, clinical outcome2 one was bacteriologic diagnosis and outcome4 Patient ages in these studies differed: the first three were 0.5–15 years old (mean 4–6 years), while the fourth was years (mean 1.3 years) Sample sized required for studies to be powered to show differences between agents were determined based on calculations published by Marchant et al.5 Azithromycin in AOM: clinical outcome at end of therapy studies Four studies using a common comparator were compared1-4 Study designs differed two were clinical diagnosis and outcome1,3 one was bacteriologic diagnosis, clinical outcome2 one was bacteriologic diagnosis and outcome4 Patient ages in these studies differed: the first three were 0.5–15 years old (mean 4–6 years), while the fourth was years (mean 1.3 years) Sample sized required for studies to be powered to show differences between agents were determined based on calculations published by Marchant et al.5 1McLinn S. et al. Pediatr Infect Dis J 1996; 15, supp1: S3–9 2Aronovitz G. et al. Pediatr Infect Dis J 1996; 15, supp1: S15–19 3Khurana C.et al. Pediatr Infect Dis J 1996; 15, supp1: S24–29 4Dagan R. et al. Pediatr Infect Dis J 2000; 19:95–104 5Marchant C. et al. J Pediatr 1992; 120:72–77 1McLinn S. et al. Pediatr Infect Dis J 1996; 15, supp1: S3–9 2Aronovitz G. et al. Pediatr Infect Dis J 1996; 15, supp1: S15–19 3Khurana C.et al. Pediatr Infect Dis J 1996; 15, supp1: S24–29 4Dagan R. et al. Pediatr Infect Dis J 2000; 19:95–104 5Marchant C. et al. J Pediatr 1992; 120:72–77

Azithromycin in AOM: clinical outcome at end of treatment Comparator Azithro Mean age (range) years ? (1-15) 4.0 (2-15) 5.7 (0.5-12) 1.3 (0.5-4) N evaluable at EOT 553 (82%) 92 (54%) 444 (84%) 143 (60%) P value for clin. outcome No. of patients needed to show: 60% vs 90% bact. efficacy clin/100 bact 30% vs 90% bact. efficacy clin/30 bact Azithromycin in AOM: clinical outcome at end of therapy studies Three studies do not show any statistically significant differences in clinical outcome between agents studied1-3 Patients in these studies were years old; mean 4–6 years Based on numbers of patients enrolled, very large differences in bacteriologic eradication, e.g. 90% vs 30-40%, could be present4 In the fourth study of younger children (mean age 1.3 y), clinical success in bacterially proven AOM was significantly better for comparator (86% vs 70%, p = 0.023), as was bacteriologic success (83% vs 49%, p = 0.001)5 The major differences between these studies are Age range of patients studied Study design – 2 clinical only, 1 bacteriologic diagnosis with clinical outcome, 1 bacteriologic diagnosis and outcome Three of the studies were not powered to show statistically significant differences in clinical outcome between agents studied, even the activity of one agent was very poor as too few patients were enrolled 1McLinn S. et al. Pediatr Infect Dis J 1996; 15, supp1: S3–9 2Aronovitz G. et al. Pediatr Infect Dis J 1996; 15, supp1: S15–19 3Khurana C.et al. Pediatr Infect Dis J 1996; 15, supp1: S24–29 4Marchant C. et al. J Pediatr 1992; 120:72–77 5Dagan R. et al. Pediatr Infect Dis J 2000; 19:95–104

Using pharmacokinetics and pharmacodynamics to predict bacterial efficacy

Evaluating antibacterial efficacy using pharmacokinetics and pharmacodynamics Pharmacokinetics (PK) serum concentration profile penetration to site of infection Pharmacodynamics (PD) susceptibility – MIC (potency) concentration- vs time-dependent killing persistent (post-antibiotic) effects (PAE) Pharmacokinetic (PK) and pharmacodynamic (PD) parameters are key to predicting the efficacy of antibiotics MIC values provide us with a static picture of how a pathogen is affected by fixed concentrations of antibiotic in vitro In the body, the antibiotic concentration is constantly changing – pharmacokinetic measurements can be used to estimate the dynamic situation within the body, at the site of infection Different antibiotics kill pathogens in different ways – a knowledge of pharmacodynamic properties (concentration vs time-dependant killing; persistent effects) together with the MIC enable us to interpret the dynamic picture and predict more closely what will happen during a clinical infection

Patterns of antibacterial activity
Michael R. Jacobs, MD, PhD FDA Presentation Nov 7, 2001 Patterns of antibacterial activity Pattern Pharmacodynamic correlate Time-dependent killing Time above MIC and minimal to moderate (T > MIC) persistent effects Time-dependent killing AUC/MIC ratio and prolonged persistent effects Concentration-dependent AUC/MIC ratio killing and prolonged or persistent effects Peak/MIC ratio In the immunocompetent host, for a pathogen to be susceptible to a specific dosing regimen of a specific antibiotic (i.e. likely to be eradicated in vivo by the antibiotic), the minimum inhibitory concentration (MIC) of the drug against the pathogen, an in vitro determination, must meet or exceed specific pharmacokinetic and pharmacodynamic (PK/PD) parameters of the dosing regimen used. These parameters differ depending on whether the in vivo activity of the antibiotic in question is time-dependent, as in the case of beta lactams and macrolides, or concentration-dependent, as in the case of azalides and fluoroquinolones. For antibiotics exhibiting time-dependent activity, the PK/PD parameter that should be met or exceeded is the serum concentration of unbound antibiotic that is present for 40-50% of the dosing interval. For antibiotics exhibiting concentration-dependent killing, the PK/PD parameter that should be met or exceeded is the unbound serum area-under-the-curve (AUC) time-concentration value over 24 hours divided by The highest MIC of an agent that meets the appropriate PK/PD parameter is defined as the susceptible PK/PK limit or breakpoint for the specified dosing regimen of that agent. Such breakpoints can be used to predict whether a particular pathogen will be susceptible to the specified antibiotic using the specified dosing regimen. If the MIC of the antibiotic against the pathogen is lower than the breakpoint, the pathogen is likely to be susceptible; if the MIC is higher than the breakpoint, the pathogen is likely not to be susceptible. To assure high probability of achieving a successful outcome in the empiric treatment of a specific infectious disease, such as acute otitis media, the respective MIC90s of an antimicrobial against the major pathogens associated with the disease should be at or below the PK/PD breakpoint of that antimicrobial at the dosage regimen used.

Relationship between time above MIC and efficacy in animal infection models infected with S. pneumoniae 100 Penicillins 80 Cephalosporins 60 Mortality after 4 days of therapy (%) 40 20 In animal models of pneumococcal infection, penicillins provide complete protection against mortality after 4 days of treatment when serum drug concentrations are above the MIC of the agent against an organism for =>40% of the dosing interval. This occurs at =>50% of the dosing interval for cephalosporins. 20 40 60 80 100 Time serum conc. is above MIC (%) Craig W. Diagn Microbiol Infect Dis 1996; 25:213–217.

Relationship between time above MIC and bacterial eradication with -lactams in otitis media Time serum conc. is above MIC (% of dosing interval) Bacterial eradication day 4-6 of therapy (%) 20 40 60 80 100 PSSP PISP-PRSP H. influenzae Spontaneous resolution of H. influenzae* S. pneumoniae* Similarly, in acute otitis media studies in humans, >80% bacterial eradication on day 4-6 of therapy occurs when serum concentration of the beta-lactam is =>40% of the dosing interval. This applies to all major otitis media pathogens, and is only affected by antimicrobial resistance to the extent that this affects time above MIC. It should be noted that placebo studies have have shown that spontaneous resolution of S. pneumoniae in acute otitis media occurs in 16% of patients, and of H. influenzae in 48% of patients.[Howie, V. Clin Pediatr 1972, 11: ]. Craig W., Andes D. Pediatr Infect Dis J 1996; 15:255–259. Dagan R. et al. studies *Howie, V. Clin Pediatr 1972, 11: ].

Microbiologic outcome of middle ear fluid in experimental acute otitis media in chinchillas due to non-typeable Hemophilus influenzae F E Babl, S I Pelton, Z Li. Experimental Acute Otitis Media Due to Non-typable Haemophilus Influenzae: Comparison of High and Low Dose Azithromycin with Placebo. Presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Toronto, Canada, August 2000 and submitted for publication Azithromycin therapy † ‡ † † 34/34 35/38 76/79 30/30 28/30 40/75†‡ 19/30 10/28† 17/75† Studies of azithromycin in children with acute otitis media show clinical success but tympanocentesis in children with acute otitis media performed at entry and 4-6 days after initiating therapy suggest that non-typable Haemophilus influenzae persists in the middle ear. This study determined if higher doses of azithromycin could achieve more rapid sterilization of Haemophilus influenzae middle ear infection utilizing an experimental acute otitis media model in chinchillas. Animals treated with placebo were compared to animals receiving 30 mg/kg/day [which produced pharmacokinetics similar to current dosing used in humans] or 120 mg/kg/day [equivalent to 4X current human dose] of azithromycin for 5 days each as single daily doses. In this model azithromycin at high dose (120 mg/kg/d) achieved significantly more rapid sterilization of middle ears compared to low dose (30 mg/kg/d) on day 5, and significantly more rapid sterilization compared to low dose (30 mg/kg/d) and placebo on day F E Babl, S I Pelton, Z Li. Experimental Acute Otitis Media Due to Non-typable Haemophilus Influenzae: Comparison of High and Low Dose Azithromycin with Placebo. Presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Toronto, Canada, August 2000 and submitted for publication. * Number of ears; denominator changes due to  in # of animals † p<0.05 Rx vs. placebo ‡ p< vs. 120 mg/kg

Median CFU by treatment group in middle ear fluid in experimental acute otitis media in chinchillas due to non-typeable Hemophilus influenzae F E Babl, S I Pelton, Z Li. Experimental Acute Otitis Media Due to Non-typable Haemophilus Influenzae: Comparison of High and Low Dose Azithromycin with Placebo. Presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Toronto, Canada, August 2000 and submitted for publication Michael R. Jacobs, MD, PhD FDA Presentation Nov 7, 2001 † p<0.05 Rx vs. placebo ‡ p< vs. 120 mg/kg † †‡ † Azithromycin at high dose (120 mg/kg/d) also achieved significantly more complete sterilization of middle ears in the chinchilla model as compared to low dose (30 mg/kg/d) and placebo on days 5, 9 and 11. High dose also achieved significantly more complete sterilization of middle ears compared to low doses (30 mg/kg/d) on day 5. F E Babl, S I Pelton, Z Li. Experimental Acute Otitis Media Due to Non-typable Haemophilus Influenzae: Comparison of High and Low Dose Azithromycin with Placebo. Presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Toronto, Canada, August 2000 and submitted for publication. † Azithromycin therapy

Azithromycin concentrations in plasma and lung after single and multiple 50 mg/kg oral dosing in rats. These levels are about twice those achieved in humans 4 8 12 16 20 24 Hours after dose 0.001 0.01 0.1 1 10 100 Concentration (g/mL or g/g) Plasma: 50 mg/kg Single dose Lung: 50 mg/kg Single dose Plasma: 50 mg/kg Multiple dose Lung: 50 mg/kg Multiple dose H. Influenzae MIC90 2 g/mL The pharmacokinetic values achieved with 50-mg/kg dose of azithromycin are approximately twofold higher than the reported in humans. The 50-mg/kg dose of azithromycin will generally produce a 2-log10 reduction in lung Haemophilus burden in rats. M. J. Mitten, J. Meulbroek, M. Nukkala, L. Paige, K. Jarvis, A. Oleksijew, A. Tovcimak, L. Hernandez, J. D. Alder,† P. Ewing, Y. S. Or, Z. Ma, A. M. Nilius, K. Mollison, And R. K. Flamm. Efficacies Of ABT773, A New Ketolide, Against Experimental Bacterial Infections. AAC 45:2585–2593, 2001 Adapted from Mitten M. et al. Antimicrob Agents Chemother 2001; 45: 2585–2593.

Clarithromycin concentrations in plasma and lung after single and multiple 50 mg/kg oral dosing in rats. These levels are about twice those achieved in humans 4 8 12 16 20 24 0.001 0.01 0.1 100 Plasma: 50 mg/kg Single dose Lung: 50 mg/kg Single dose Plasma: 50 mg/kg bid Multiple dose Lung: 50 mg/kg bid Multiple dose Hours after dose Concentration (g/mL or g/g) 1 10 H. Influenzae MIC90 16 g/mL The clarithromycin concentrations in plasma following a 50-mg/kg single dose in rats are also approximately twofold higher than the combined concentrations in plasma of clarithromycin and its bioactive metabolite (14-hydroxyclarithromycin is not found in rodents). Using a lethal systemic infection model caused by S. pneumoniae in mice, clarithromycin had an ED50 of 16.5 mg/kg against a macrolide susceptible strain, but the range in ED50 s increased to to >200 mg/kg against ermB or mefE strains (clarithromycin MIC > 4 ug/ml). M. J. Mitten, J. Meulbroek, M. Nukkala, L. Paige, K. Jarvis, A. Oleksijew, A. Tovcimak, L. Hernandez, J. D. Alder,† P. Ewing, Y. S. Or, Z. Ma, A. M. Nilius, K. Mollison, And R. K. Flamm. Efficacies Of ABT773, A New Ketolide, Against Experimental Bacterial Infections. AAC 45:2585–2593, 2001 Adapted from Mitten M. et al. Antimicrob Agents Chemother 2001; 45: 2585–2593.

S. pneumoniae and H. influenzae pneumonia in rats: ED50 based on 3 log10 reduction in cfu/lung AZI, CLARI approved human dosing provides PK similar to approx. 25 mg/kg/d in this model The efficacy of ABT-773 [ED mg/kg/d for =>3log10 kill rate] was consistently better than those of the comparative macrolide antibiotics against S. pneumoniae-induced infections in rodents caused by macrolide resistant strains – mefE strain required 69.7 mg/kg/d for clarithromycin and 78.7 mg/kg/d for azithromycin; ermB strain required >100 mg/kg/d. M. J. Mitten, J. Meulbroek, M. Nukkala, L. Paige, K. Jarvis, A. Oleksijew, A. Tovcimak, L. Hernandez, J. D. Alder,† P. Ewing, Y. S. Or, Z. Ma, A. M. Nilius, K. Mollison, And R. K. Flamm. Efficacies Of ABT773, A New Ketolide, Against Experimental Bacterial Infections. AAC 45:2585–2593, 2001 Similar results were found in two mouse pneumonia studies using telithromycin and azithromycin [100 mg/kg four times daily for 2 days and twice daily for 3 days]. Telithromycin and azithromycin reduced colony counts in lungs by 3log10 cfu/lung at these high dosing regimens. Lower dosing regimens were not tested. K. E. Piper, M. S. Rouse, J. M. Steckelberg, W. R. Wilson, R. Patel. Ketolide Treatment of Haemophilus influenzae Experimental Pneumonia. AAC 1999, 43: H Okamoto, S Miyazaki, K Tateda, Y Ishii, K Yamaguchi. In Vivo Efficacy of Telithromycin (HMR3647) against Streptococcus pneumoniae and Haemophilus influenzae.AAC 2001, 45: 3250–3252. MIC (g/ml) Adapted from Mitten et al. Antimicrob Agents Chemother 2001; 45: 2585–2593

S. pneumoniae and H. influenzae pneumonia in rats: ED50 based on 3 log10 reduction in cfu/lung H. influenzae Macrolide resistant S. pneumoniae (efflux) Macrolide susceptible S. pneumoniae ED50 of macrolide resistant (ribosomal methylase) S. pneumoniae: >100 mg/kg/d See previous slide for text M. J. Mitten, J. Meulbroek, M. Nukkala, L. Paige, K. Jarvis, A. Oleksijew, A. Tovcimak, L. Hernandez, J. D. Alder,† P. Ewing, Y. S. Or, Z. Ma, A. M. Nilius, K. Mollison, And R. K. Flamm. Efficacies Of ABT773, A New Ketolide, Against Experimental Bacterial Infections. AAC 45:2585–2593, 2001 MIC (g/ml) Adapted from Mitten et al. Antimicrob Agents Chemother 2001; 45: 2585–2593

S. pneumoniae and H. influenzae pneumonia in rats: ED50 based on  3 log10 reduction in cfu/lung At dosing comparable to dosing in humans: Azithromycin and clarithromycin were able to reduce inoculum by  3 log10 cfu/lung for macrolide susceptible S. pneumoniae Azithromycin and clarithromycin were NOT able to reduce inoculum by  3 log10 cfu/lung for H influenzae or for macrolide non-susceptible S. pneumoniae (erm and mef mechanisms) At dosing comparable to dosing in humans: Azithromycin and clarithromycin were able to reduce inoculum by  3 log10 cfu/lung for macrolide susceptible S. pneumoniae Azithromycin and clarithromycin were NOT able to reduce inoculum by  3 log10 cfu/lung for H influenzae or for macrolide non-susceptible S. pneumoniae (erm and mef mechanisms) despite the high lung concentrations of these agents. M. J. Mitten, J. Meulbroek, M. Nukkala, L. Paige, K. Jarvis, A. Oleksijew, A. Tovcimak, L. Hernandez, J. D. Alder,† P. Ewing, Y. S. Or, Z. Ma, A. M. Nilius, K. Mollison, And R. K. Flamm. Efficacies Of ABT773, A New Ketolide, Against Experimental Bacterial Infections. AAC 45:2585–2593, 2001 Mitten M. et al. Antimicrob Agents Chemother 2001; 45: 2585–2593.

Azithromycin 10 mg/kg day 1; 5 mg/kg d 2–5 32 Macrolide R (ermB): MIC90 ≥ 32 g/mL; AUC:MIC ratio < 0.1 16 8 Macrolide R (mefE): MIC90 = 8 g/mL; AUC:MIC ratio 0.4 4 Serum conc. (g/mL) 2 1 Haemophilus: MIC90 = 1 g/mL; AUC:MIC ratio = 3 0.5 AUC = 3 mg.h/L 0.25 The pharmacokinetic properties of azithromycin in animal models and in humans are consistent with bacteriologic outcome studies in humans and in animal models, and explain the poor results with organisms such as H influenzae and macrolide non-susceptible S. pneumoniae (erm and mef mechanisms), which have MICs above the pharmacodynamic breakpoint of azithromycin (0.12 ug/ml). PK/PD bkpt g/mL 0.12 M. cat: MIC90 = 0.12 g/mL 0.06 Macrolide S: MIC90 = 0.06 g/mL; AUC:MIC ratio = 50 12 hr 24 hr Adapted from Drusano G. et al. J Chemother 1997; 9(suppl 3):38–44.

Pharmacodynamic vs NCCLS breakpoints (µg/mL)
Michael R. Jacobs, MD, PhD FDA Presentation Nov 7, 2001 Pharmacodynamic vs NCCLS breakpoints (µg/mL) NCCLS* PK/PD + S. pneumoniae H. influenzae ALL ORGANISMS Amoxicillin 2 – 2 Amox/clav Cefuroxime axetil Cefdinir Cefprozil Cefixime – Cefaclor Loracarbef Azithromycin Clarithromycin For antibiotics exhibiting time-dependent activity, the PK/PD parameter that should be met or exceeded is the serum concentration of unbound antibiotic that is present for 40-50% of the dosing interval. For antibiotics exhibiting concentration-dependent killing, the PK/PD parameter that should be met or exceeded is the unbound serum area-under-the-curve (AUC) time-concentration value over 24 hours divided by The highest MIC of an agent that meets the appropriate PK/PD parameter is defined as the susceptible PK/PK limit or breakpoint for the specified dosing regimen of that agent. Breakpoints should apply to ALL extracellular pathogens causing the infection, and there is no scientific validity to the differences in NCCLS breakpoints in these examples. There are some valid reasons for different breakpoints, such as for different sites of infection [systemic versus meningeal versus urine] and for intracellular versus extracellular location of pathogens. These reasons are not valid for extracellular pathogens such as S. pneumoniae and H. influenzae in respiratory tract infections. Lower breakpoints are valid for meningeal infections due to lower CSF levels of many agents. *M100-S11, National Committee for Clinical Laboratory Standards, 2001. +Sinus and Allergy Health Partnership. Otolaryngol Head Neck Surg 2000; 123(supp 1 part 2):S1–S32.

Susceptibility of Isolates at PK/PD and NCCLS breakpoints
Michael R. Jacobs, MD, PhD FDA Presentation Nov 7, 2001 Susceptibility of Isolates at PK/PD and NCCLS breakpoints Percentage of strains susceptible Agent S. pneumoniae H. influenzae M. catarrhalis Amox/clav Amoxicillin Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime Cefdinir‡ Azithromycin Clindamycin* 89 NA NA Doxycycline Levofloxacin TMP/SMX* NA 90 63 NA 46 82 NA NA NA 67 86 NA 65 98 NA 61 99 NA 68 97 NA 89 NA NA 76 NA NA NA 57 75 NA Few differences in proportions of strains of S. pneumoniae that are susceptible to these agents based on which breakpoints are used occur, and there are no NCCLS breakpoints for M. catarrhalis. However, there are several agents where PK/PD breakpoints indicate poor activity [0-2% susceptible], while NCCLS breakpoints show good activity [82-92% susceptible]. Data sources: M100-S11, National Committee for Clinical Laboratory Standards, 2001 Sinus and Allergy Health Partnership. Otolaryngol Head Neck Surg 2000; 123(supp 1 part 2):S1–S32. ‡Jacobs M. (unpublished) Based on M100-S11, National Committee for Clinical Laboratory Standards, 2001; Sinus and Allergy Health Partnership. Otolaryngol Head Neck Surg 2000; 123(supp 1 part 2):S1–S32. ‡Jacobs M. (unpublished)

S. pneumoniae: oral agents approved or recommended for AOM with 90% of recent US strains susceptible at NCCLS or PK/PD breakpoints (µg/mL) NCCLS* PK/PD+ Bkpt %S Bkpt %S Amoxicillin Amoxicillin/clav Clindamycin NA NA Clindamycin at 89% was included here as the value was very close to 90% Data sources: M100-S11, National Committee for Clinical Laboratory Standards, 2001 Sinus and Allergy Health Partnership. Otolaryngol Head Neck Surg 2000; 123(supp 1 part 2):S1–S32. ‡Jacobs M. (unpublished) *M100-S11, National Committee for Clinical Laboratory Standards, 2001. +Sinus and Allergy Health Partnership. Otolaryngol Head Neck Surg 2000; 123(supp 1 part 2):S1–S32.

H. influenzae: oral agents approved or recommended for AOM with 90% of recent US strains susceptible at NCCLS or PK/PD breakpoints (µg/mL) NCCLS* PK/PD+ Bkpt %S Bkpt %S Amoxicillin/clav Cefdinir‡ Cefixime Cefpodoxime Cefuroxime axetil Cefprozil Loracarbef Azithromycin The first group has =>90% susceptible by both PK/PD and NCCLS breakpoints, while the second group has =>90% susceptible by only NCCLS breakpoints. Data sources: M100-S11, National Committee for Clinical Laboratory Standards, 2001 Sinus and Allergy Health Partnership. Otolaryngol Head Neck Surg 2000; 123(supp 1 part 2):S1–S32. ‡Jacobs M. (unpublished) *M100-S11, National Committee for Clinical Laboratory Standards, 2001. +Sinus and Allergy Health Partnership. Otolaryngol Head Neck Surg 2000; 123(supp 1 part 2):S1–S32. ‡ Data from Jacobs M. (unpublished).

Azithromycin MICs (S. pneumoniae and H. influenzae)
Michael R. Jacobs, MD, PhD FDA Presentation Nov 7, 2001 Azithromycin MICs (S. pneumoniae and H. influenzae) MIC that includes 90% of H. influenzae MIC that includes 90% of S. pneumoniae The azithromycin MICs required cover 90% of current isolates of the two major otitis media pathogens, S pneumoniae [32 ug/ml]and H influenzae [2 ug/ml], are shown here. The reason for the high MICs of H. influenzae compared to those of macrolide susceptible S pneumoniae is a cell-membrane based efflux pump recently described by Sanchez. A H. influenzae mutant lacking this efflux pump has been shown to have an azithromycin MIC of 0.06 ug/ml, which is in the same range as that seen with macrolide susceptible S pneumoniae (Bozdogan et al, 2001). Sanchez et al. acrAB chromosomal genes encoding for efflux in H. influenzae. J. Bacteriol. 1997, 179: B. Bozdogan, C. Clark, M. Peric, P. C. Appelbaum. Combination of Efflux and Ribosomal Mutations in H. influenzae Mutants Resistant to Macrolides Selected In Vitro. Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Chicago, Dec 2001. Jacobs et al. ICAAC 1999 poster C-61.

Azithromycin MICs (S. pneumoniae and H. influenzae)
Michael R. Jacobs, MD, PhD FDA Presentation Nov 7, 2001 Azithromycin MICs (S. pneumoniae and H. influenzae) Efficacy animal models equivalent to current dosing Efficacy in animal models equivalent to 4X current dosing PK/PD breakpoint based on current approved dosing Based on PK/PD parameters, animal models and human studies, azithromycin has inadequate activity against macrolide resistant S pneumoniae and all H influenzae. Increasing dosing regimen by four-fold in animal models has been shown to improve the activity of azithromycin against H influenzae, but not against macrolide resistant S pneumoniae. Jacobs et al. ICAAC 1999 poster C-61.

Conclusions: Antibacterial choice for empiric use in acute otitis media Most clinical studies are too small to show clinical differences between agents PK/PD parameters correlate with bacteriological and clinical outcome in animal models and in humans, and can be used to select agents with maximum potential for bacterial eradication Currently available agents vary significantly in achieving PK/PD parameters necessary for bacterial eradication Few oral agents approved for pediatric use are active against 90% of current US strains of the key otitis media pathogens at approved dosing regimens Bacteriologic outcome studies in children and animal studies have repeatedly validated these conclusions Conclusions: Most clinical studies are too small to show clinical differences between agents PK/PD parameters correlate with bacteriological and clinical outcome in animal models and in humans, and can be used to select agents with maximum potential for bacterial eradication Currently available agents vary significantly in achieving PK/PD parameters necessary for bacterial eradication Few oral agents approved for pediatric use are active against 90% of current US strains of the key otitis media pathogens at approved dosing regimens Bacteriologic outcome studies in children and animal studies have repeatedly validated these conclusions

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Michael R. Jacobs, MD, PhD FDA Presentation Nov 7, 2001

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