FDA Briefing Package

 

Anti-Infective Drugs Advisory Committee

 

April 26^th, 2001

 

 

 

 

 

 

 

 

 

New Drug Application (NDA) 21-144

Ketek^TM (telithromycin)

 

 

 

Executive Summary 

This FDA briefing document contains a summary of New Drug Application (NDA) 21-144 for  telithromycin tablets (KetekÔ, Aventis Pharmaceuticals; development name HMR 3647).  Telithromycin is the first in a new class of antimicrobials, ketolides, within the macrolide-lincosamide streptogramin (MLS_B) family. The FDA has reviewed the primary data provided to support the safety and efficacy of telithromycin.  Concerns regarding telithromycin will focus on the following specific areas:

·         cardiac repolarization effect (QT interval prolongation);

·         hepatotoxicity;

·         pharmacokinetic variability and drug-drug interactions;

·         resistance claims for S. pneumoniae (penicillin and macrolides).

Safety:

Recently, approvals of non-cardiac drugs with a documented effect on QT interval have come under considerable scrutiny within the FDA. Assessment of risk/benefit must be considered in the decision to approve such drugs.

Telithromycin elicited delayed repolarization in in vitro models of cardiac repolarization, and in vivo in animals. In phase I studies, telithromycin caused concentration-dependent increases in the QT_c interval. In phase III studies, telithromycin caused a consistent effect on mean QT_c duration in humans, with evidence that interactions with drugs metabolized by CYP 3A4 may further prolong QT_c duration.

Telithromycin’s effect on QTc is concentration-dependent; thus, understanding sources of pharmacokinetic variability is important. Telithromycin concentrations in human plasma are highly variable (1.99 mg/L after a single dose in phase I, up to 9.9 mg/L after multiple doses in phase III), with a significant increase in C_max in elderly subjects.  Telithromycin is a CYP 3A4 substrate, and is primarily metabolized and eliminated by the liver.  Co-administration of a 3A4 inhibitor significantly increases telithromycin concentrations. In hepatically impaired subjects, the t_½ of telithromycin was significantly increased.

Telithromycin has significant toxicologic effects on liver and heart in mice, rats, dogs and monkeys.  These include increased liver-associated enzymes, increased total bilirubin, hepatic necrosis and associated inflammation, and phospholipidosis. Toxicologic comparisons between telithromycin and clarithromycin are discussed in the briefing package.

Efficacy:

The applicant has requested approval for telithromycin in adults for the following indications:

·         tonsillitis/pharyngitis (T/P);

·         acute exacerbation of chronic bronchitis (AECB);

·         acute sinusitis;

·         community-acquired pneumonia (CAP)

Included among the requested pathogens are S. pneumoniae resistant to penicillin and erythromycin in CAP, AECB, and sinusitis.

Requests to the FDA regarding marketing claims for infections due to resistant S. pneumoniae are increasing. Levofloxacin is currently approved for the treatment of pneumonia caused by S. pneumoniae resistant to penicillin.  No agents are approved for the treatment of S. pneumoniae resistant to erythromycin.

Summary: 

Given the concerns raised regarding the safety of telithromycin, we ask the Advisory Committee to focus on the risk-benefit ratio of this new agent. This is the first time the Anti-Infectives Advisory Committee is to discuss a possible erythromycin resistance claim.  Important considerations in this discussion, in addition to safety considerations, include: in vitro evidence; potential for cross-resistance; clinical efficacy; overall weight of evidence; and public health benefit.

Table of Contents

Executive Summary............................................................................................................ 2

I.    Summary of Selected Microbiologic Information........................................................ 4

II.    Pre-clinical Pharmacology /Toxicology....................................................................... 5

III.  Clinical Pharmacology................................................................................................. 6

IV.  Clinical/Statistical Efficacy Analysis of Phase III trials............................................... 8

A.   Community Acquired Pneumonia........................................................................... 12

B.   Acute Bacterial Exacerbation of Chronic Bronchitis............................................. 20

C.   Acute Sinusitis........................................................................................................ 22

D.   Tonsillitis / Pharyngitis........................................................................................... 25

E.   Streptococcus pneumoniae: resistance claims and FDA regulatory history........... 27

V.  Safety Analysis............................................................................................................. 30

A.   Overview of FDA Integrated Summary of Safety Review...................................... 30

1.    Extent of Exposure.................................................................................................. 30

2.    Deaths.................................................................................................................... 30

3.    Nonfatal serious adverse events............................................................................... 30

4.    Discontinuations...................................................................................................... 33

B.   Cardiovascular Safety.............................................................................................. 34

1.    In vitro and preclinical data..................................................................................... 34

2.    Phase I data QT_c prolongation and pharmacokinetics in normal subjects...................... 35

a)    Dose-response relationship................................................................................... 35

b)    Population concentration response......................................................................... 37

3.    QT_c prolongation and pharmacokinetics in patients with cardiac disease...................... 37

4.    QT_c prolongation in drug-interaction studies (Study 1041 - cisapride)........................... 38

5.    Pharmacokinetic variability in special populations....................................................... 38

6.    Potential for drug interactions with 3A4 inhibitors...................................................... 39

7.    Summary: Pharmacokinetics.................................................................................... 39

8.    Phase III  Studies: Cardiac Safety............................................................................ 43

a)    Deaths and adverse events related to the cardiovascular system............................. 43

b)    Cardiovascular serious adverse events (SAEs)...................................................... 43

c)    Cardiovascular adverse events (AEs).................................................................... 44

d)    Electrocardiographic data..................................................................................... 44

e)    Summary: Cardiac Safety..................................................................................... 48

 C. Hepatic Safety.............................................................................................................. 51

1.   Preclinical liver abnormalities.................................................................................... 51

       2.   Phase I liver abnormalities........................................................................................ 52

3.   Phase III liver abnormalities and clinical outcome....................................................... 54

4.   Summary: Hepatic Safety......................................................................................... 61

VI. Appendices.................................................................................................................. 63

A.   FDA Cardio-Renal Consult......................................................................................... 63

B.   Patient Narratives: Efficacy Section............................................................................. 72

C.   Patient Narratives: Serious Hepatic Adverse Events..................................................... 74

D.   Review and Evaluation of Pharmacology and Toxicology Data...................................... 80

 

 

I.                   Summary of Selected Microbiologic Information

Chemistry

·        Semisynthetic

·        Belongs to the ketolide family of antimicrobials within the macrolide-lincosamide streptogramin (MLS_B) class.

Mechanism of Action

·         Inhibition of bacterial protein synthesis by action at the 23S ribosomal RNA.

Spectrum of Activity

·        In vitro activity against Gram-positive bacteria, fastidious Gram-negative bacteria, some anaerobes, and atypical pathogens (Legionella pneumophilia, Mycoplasma pneumoniae, and Chlamydiae pneumoniae).

·        MIC₉₀ (μg/ml) range for target pathogens:  

·        S. pneumoniae (including penicillin- and erythromycin-resistant strains): 0.25

·        H. influenzae: β-lactamase-negative – 2 ; β-lactamase-positive – 4

·        M. catarrhalis (including β-lactamase-positive strains) – 0.5

·        S. pyogenes: erythromycin-susceptible – 0.06; erythromycin-resistant – 8

·        Bacteriostatic against S. pyogenes, S. aureus

·        Bactericidal against penicillin- or erythromycin-susceptible and resistant S. pneumoniae, H. influenzae and M. catarrhalis.

·        None to minimal activity against methicillin-resistant S. aureus or methicillin- resistant coagulase-negative staphylococci.

Resistance

·        In vitro activity against some strains of S. pneumoniae that carry the mefE and ermB genes.

·        In vitro activity against S. pyogenes that do not carry ermB gene. Increased MIC₉₀s in S. pyogenes that carry ermB.

Other microbiologic characteristics of telithromycin

·        Synergism: no data available

·        Antagonism: no data available

·        Post-Antibiotic effect: Telithromycin has been shown to have a PAE ranging from approximately 1 h to 8 h at 10x MIC against the pathogens of interest.

·        pH effect: A decrease in pH from 7 to 5.5 increases the telithromycin  MIC for S. pneumoniae by approximately 15-fold.

·        Inoculum effect: Increasing inoculum size from 10⁴ to 10⁶ cfu/mL does not affect the MIC. If the inoculum size is 10⁷ or greater, the telithromycin MIC for S. pneumoniae goes up approximately 2 to 4-fold.

 

 

II.                Pre-clinical Pharmacology /Toxicology

The pre-clinical pharmacology/toxicology review of the telithromycin NDA submission included a side-by-side comparison with pre-clinical data for clarithromycin.  (See Appendix D of this briefing document for the complete report.) The review evaluated the original source data submitted to the FDA in support of all clarithromycin applications, since the NDA for telithromycin compares its hepatic and cardiac effects to those of clarithromycin.  Summary comments are listed below, and additional data regarding potential he­patic and cardiac toxicity are included in the Safety section (section V) of this briefing package.

            Dr. John Koerner of the Division of Cardio-Renal Drug Products has reviewed the preclinical electrophysiologic data for telithromycin. He concluded that “[Telithromycin] demonstrated a potential to affect ventricular repolarization . . . The absence of an effect on absolute QT interval in the presence of a heart rate increase strongly supports the con­clusion of a drug-related effect on ventricular repolarization since, in the absence of drug, a heart rate increase should shorten the QT.  All of the above mentioned effects were concentration- or dose-related.”

As the applicant has suggested that telithromycin has a risk profile no worse than that of clarithromycin, it is critical to consider the effects of each drug in each species evaluated.  The applicant for clarithromycin considered the monkey the most appropriate animal model for toxicologic studies.  After 2 weeks of dosing with telithromycin or clarithromycin, increased LFTs were seen with both compounds.  In addition, telithromy­cin elicited renal tubular atrophy and increased total bilirubin levels.  After 4 weeks of dosing in the monkey, both compounds elicited increased LFTs, but more significant in­creases were seen with telithromycin.  Telithromycin-treated monkey showed increased total bilirubin levels during this entire dosing period.

In the rat, after 4 weeks of dosing, although both drugs increased LFTs (clarithromycin 2-3x; telithromycin 2-15x), the qualitative and quantitative effects were quite different.  Clarithromycin primarily affected multinucleated hepatocytes (significance to humans unknown) with minimal to mild hepatic necrosis at >50 mg/kg/d.  Telithromycin caused moderate to severe hepatic necrosis with steatosis/phospholipidosis at >50 mg/kg/d (lowest dose tested).  After 13 weeks of dosing, multinucleated hepatocytes were reported for clarithromycin while telithromycin elicited increased LFTs, increased N-acetyl-ß-glucosamidase (3x) in urine, and phospholipidosis.

In dogs, LFTs were increased with both compounds (clarithromycin 4-5x; telithromycin 6x) but telithromycin elicited one premature decedent with acute liver and renal failure, and phospholipidosis in mid- and high-dose groups.  EKGs showed no drug-related differences from controls/baseline with clarithromycin, while telithromycin caused a markedly increased heart rate and increased QTc interval (27-30 msec).  In the only comparative study performed, clarithromycin and erythromycin each increased the QTc interval by 17 msec while telithromycin increased it by 30 msec. 

The applicant for clarithromycin stated that dogs are exquisitely sensitive to the toxicologic effects of clarithromycin. Of note, it appears that the incidence and severity of significant changes in LFTs, histopathology, and QT intervals were increased in telithromycin-treated dogs when compared to clarithromycin-treated dogs.  In addition, more species appeared to be adversely affected by telithromycin treatment than by clarithromycin treatment.

III.             Clinical Pharmacology

Standard pharmacokinetic parameters for oral telithromycin are given in Table 1.  Clinical pharmacology concerns of particular importance include:

·        Pharmacokinetic variability: drug exposure may be significantly increased in the elderly and hepatically impaired patients.

·        Drug-drug interactions: telithromycin exposure may be significantly increased by co-administration of a CYP 3A4 inhibitor such as ketoconazole.

·        Cardiac repolarization effects: telithromycin prolongs the QT interval in a concentration-dependent fashion.

·        The potential for these factors to act in an additive or synergistic fashion, leading to an increased risk of torsades de pointes.

            Specific details are discussed in the Safety section (section V) of this document.

 

Table 1.  Summary of oral telithromycin pharmacokinetics

IV.       Clinical/Statistical Efficacy Analysis of Phase III trials

This section summarizes the FDA analyses of pivotal and supportive phase III trials contained in the NDA.  The applicant has requested labeling of oral telithromycin for the treatment of the following infections (indications) in adults:

 

·        Community-acquired pneumonia due to S. pneumoniae, including strains resistant to penicillin and erythromycin, H. influenzae, H. parainfluenzae, M. catarrhalis, C. pneumoniae, L. pneumophila, and/or M. pneumoniae.

 

·        Acute bacterial exacerbation of chronic bronchitis due to S. pneumoniae, H. influenzae, H. parainfluenzae, M. catarrhalis, S. aureus, C. pneumoniae, and/or M. pneumoniae.

 

·        Acute sinusitis due to S. pneumoniae, including strains resistant to penicillin and erythromycin, H. influenzae, H. parainfluenzae, M. catarrhalis, and/or S. aureus.

 

·        Tonsillitis/pharyngitis due to S. pyogenes in patients 13 years old and above.

The NDA for telithromycin presents efficacy and safety data from 9 phase III pivotal trials and 4 phase III supportive trials. While some studies included patients from the US, there were no studies that enrolled US patients only. Phase III studies were conducted between 1997 and 2000. There were a total of 6113 patients enrolled, 5193 randomized and 5169 actually treated. There were 3390 subjects exposed to telithromycin and 1779 to comparators as shown by study protocol and indication in Table 2.

Study populations

Table 3 shows the definitions of the various study populations used in the analysis of efficacy; Table 4 shows the sizes of the populations for the various indications. The definition of the mITT is different from the classic definition of intent-to-treat (ITT, i.e., all randomized patients). The purpose behind analyzing mITT rather than ITT populations was to exclude subjects with a clear misdiagnosis and to provide a more conservative approach to establish statistical and clinical equivalence between telithromycin and the comparators under study. The difference between the ITT and mITT populations was largely explained by subjects who did not meet the predefined radiologic criteria as specified for the various infections.

 

 

Seven clinical trial sites were inspected at random by the FDA’s Division of Scientific Investigation. Six of these sites failed to meet good clinical practice guidelines and were therefore censored by the Agency due to data integrity issues. A total of 186 subjects from these sites were excluded from all analyses for efficacy and safety. Table 5 summarizes the number of subjects censored by the FDA.

 

The following outcome definitions were applied in all studies:

·        Clinical Cure: all infection-related signs and symptoms had disappeared or had returned to the pre-infection state and (for CAP) Chest X-ray findings showed improvement or lack of progression; OR

Infection-related signs and symptoms had improved,  (for CAP) chest X-ray findings showed improvement or lack of progression and NO subsequent antibiotic therapy was started for the treatment of the disease under investigation.

·        Bacteriologic Eradication was defined as either of the following:

1.) proven eradication (the causative pathogen was absent in a culture obtained during the post therapy/TOC time window and no subsequent antibiotic therapy was started prior to the culture being obtained, AND

2.) presumed eradication (the subject had improved clinically to such an extent that a proper follow-up culture could not be obtained and no subsequent antibiotic therapy had been started up to the end of the post therapy/TOC time window.

 

A.      Community Acquired Pneumonia

The applicant submitted five clinical studies in support of community-acquired pneumonia indication for KetekÔ (telithromycin) tablets in the original NDA submission on February 28, 2000. Three of the clinical studies were pivotal (3001, 3006, 3009OL and two studies were supportive (3000 and 3009OL).  The applicant submitted an additional clinical study (3010) on March 1, 2001, primarily to supplement the efficacy data on resistance claims. Table 6 summarizes all submitted studies of CAP.

Table 6.  Community-Acquired Pneumonia: Pivotal and Supportive Studies

STUDY	DESIGN	TREATMENT		DAYS	N	GEOGRAPHIC REGION
Pivotal Comparative Studies
3001	Multicenter,double-blind,randomized, active-controlled, comparative,2-arm parallel group		Telithromycin 800 mg po qd   Amoxicillin 1000 mg po tid	7 - 10 d   7 - 10 d	404	Argentina, Australia, Austria, Finland, France, Germany, Hungary, New Zealand, South Africa, Spain, Sweden, UK, Uruguay
3006	Multicenter,double-blind,randomized, active-controlled, comparative		Telithromycin 800 mg po qd   Clarithromycin 500 mg po bid	7 - 10 d   7 - 10 d	449	USA, Canada, Argentina, Chile
3009*	Multicenter,double-blind,ranndomized, active-controlled, comparative		Telithromycin 800 mg  po qd Trovafloxacin 200 mg  po qd	7 - 10 d   7 - 10 d	204	USA, Canada, South Africa
Supportive Non-Comparative Studies
3000	Multicenter,open-label,non-comparative		Telithromycin 800 mg po qd	7 - 10 d	240	Argentina, Australia, Austria, Belgium, Finland, France, Germany, Hungary, Israel, New Zealand, Norway, South Africa, Sweden
3009OL	Multicenter,open-label,Non-comparative		Telithromycin 800 mg po qd	7 - 10 d	221	South Africa
3010	Open-label, non- comparative		Telithromycin 800 mg po qd	7 d	432	USA, South America, South Africa, Canada

* This study was terminated prematurely because of safety concerns with the comparator, trovafloxacin.

The primary efficacy variable was clinical response (cure, failure or indeterminate) assessed by the investigator at the posttherapy/TOC visit, 7 to 10 days after the end of therapy. The primary analysis study population was the per protocol population (PPc). The PPc population was defined as all protocol-compliant subjects who received study medication and remained in the study. Clinical outcome was also analyzed for the modified-intent-to treat population (mITT) who were all subjects treated with a confirmed diagnosis of CAP (as defined in the protocol) and received at least one dose of study drug.  Clinical cures include patients who had complete resolution of symptoms and those who had improved.

Tables 7A-7C summarize the clinical and bacteriologic efficacy data for all studies of CAP at the TOC visit in both per-protocol and mITT populations.

 

 

 

 

Table 7C.  Overall eradication rates of Baseline Pathogens Pooled from all CAP Studies at posttherapy/TOC- PPb population

All Combined Studies	Telithromycin	Comparator
Pathogen	N          n              %	N          n              %
S. pneumoniae	174     166          95.4	50       44            88.0
H. influenzae	105       94          89.5	28       26            92.8
M. catarrhalis	30        27          90.0	6         6           100.0
H. parainfluenzae	60        53          88.3	10         9             90.0
S. aureus	19         15          79.0	3         3           100.0
Other	46         37          80.4	16       13              81.2

 

Penicillin-resistant S. pneumoniae (PRSP)/Erythromycin-resistant S. pneumoniae (ERSP)

The applicant is requesting the indication of community-acquired pneumonia due to S. pneumoniae, including penicillin- and erythromycin-resistant strains.  Table 8 summarizes the efficacy of telithromycin across the five CAP studies in the PPb population that contained resistant organism.  The definition of the breakpoints for S. pneumoniae is as follows:

Penicillin                                                         Erythromycin

            Sensitive           < 0.6 µg/ml                               Sensitive           < 0.25 µg/ml

            Intermediate     0.12 < MIC < 1 µg/ml              Intermediate     0.25 < MIC < 1 µg/ml

            Resistant           ≥ 2 µg/ml                                  Resistant           > 1 µg/ml

It should be noted that the majority of subjects were treated as outpatients with oral therapy, and were classified as having mild to moderate pneumonia upon entry into the studies.

Table 8.  Summary of Outcomes by Resistance patterns for Streptococcus pneumoniae (single and mixed cultures) – Telithromycin (PPb population, 5 studies combined*)

	Outcome- Cured
	Pen-S	PRSP	Ery-S	Ery-R	PRSP+EryR
TOTAL	125/128 (97.6%)	14/17 (82%)	135/137 (99%)	14/17 (82%)	6/9 (66.6%)
Blood	27/29 (93%)	4/6 (66.7%)	32/34 (94%)	4/6 (66.7%)	1/3 (33.3%)
Sputum	98/99 (98.9%)	10/11 (91%)	103/103 (100%)	10/11 (91%)	5/6 (83.3%)
Mixed**	33/34 (97.1%)	5/7 (71.4%)	33/34 (97.1%)	5/7 (71.4%)	3/5 (60%)

* Studies 3000, 3001, 3006, 3009OL, 3010

** mixed = cultures which contained bacterial pathogens in addition to S. pneumoniae

Overall, the cure rate in telithromycin-treated patients was 97.6% for those with S. pneumoniae penicillin-sensitive isolates compared to 82% for those with PRSP isolates.  PRSP was isolated from 17 telithromycin-treated patients; six of these had documented S. pneumoniae bacteremia.  Of the six patients with PRSP bacteremia, the cure rate was 66.7%.  There was only one PRSP isolated from the sputum in a comparator-treated patient, who was reported as cured.

Erythromycin resistance was seen in 17 telithromycin-treated patients.  The cure rate for telithromycin-treated patients with erythromycin-sensitive isolates was 99%, compared to 82% for patients with erythromycin-resistant isolates.  Only 6 telithromycin-treated patients had ERSP isolated from the blood.  The cure rate in patients with ERSP bacteremia was 66.7%.

ERSP was isolated from 3 patients among the comparator-treated patients, all of whom were cured. Of note, 5 of these patients had telithromycin MICs greater than the suggested FDA resistance breakpoint for telithromycin (0.25 µg/mL).

Outcomes in patients with erythromycin-resistant isolates of different genotypes were examined.   There were 9 ermB isolates with MICs ranging from 4.0 to 32.0 ug/mL.  The cure rate was 77.8% (7/9). The two patients who failed had severe pneumonia, were hospitalized and had penicillin-resistant S. pneumoniae.  Ten patients had S. pneumoniae isolates with the mefE genotype (two of the 17 patients had both genes).  Only one patient, who was bacteremic, was a clinical failure.  The telithromycin MICs of these isolates ranged from 0.3 to 1.0 µg/mL.  Using the FDA breakpoint for telithromycin, 5 of these patients’ isolates were resistant to telithromycin.

Of PRSP isolates, 52.9% (9/17) were also resistant to erythromycin.  Although these are small numbers, patients with a PRSP+EryR isolate were more likely to have poorer clinical outcomes that those with either a PSRP or Ery-R phenotype alone.  All of these isolates were sensitive to telithromycin with a MIC or < 0.5 µg/ml.  All of the MICs reported for the isolates classified as PRSP were < 2.0 µg/ml (final MICs are pending). 

Tables 9A and 9B display details regarding the individual patients with PRSP isolates.  It should be noted that the bmITT patients were listed in order to give the reader an understanding of the types of outcomes that were recorded.  It is particularly interesting to note that of the 5 patients who were in the bmITT group and were not included in the PPb subgroup, 3 were classified as having Indeterminate outcomes. One patient died due to aspiration pneumonia on day 5 after showing improvement on a chest X-ray on day 4.

Table 9A. Subjects with S. pneumoniae penicillin resistant (PRSP)[ MIC ³2 mg/mL)]–bmITT+PPb Populations:   ALL CAP  Studies – Telithromycin group

Study Number/ Investigator No./ Subject Number/ Location	Fine Score/ Severity	Pathogen/ (Single or Mixed)/ Genotype	Source	MIC to Pen G (ug/ml)	MIC to Ery A (ug/ml)	MIC to Ketek (ug/ml)	Clinical Outcome	Bacteriological Outcome
bmITT 3000/101/1365 Argentina 3001/0111/010 Argentina/ 3001/0902/002 New Zealand 3010/0473/009 USA 3010/0526/002 South America  Total = 5	I         III         III         V         II	S. pneumoniae/ (Single)/ NA S. pneumoniae/ (Single)/ NA S. pneumoniae/ (Single)/ NA S. pneumoniae/ (Mixed)/mefE S. pneumoniae/ (Single)	BLOOD   BLOOD   SPUTUM   SPUTUM   SPUTUM	2.000   2.000   2.000   2.000   2.000	0.030   0.060   0.060   8.000   0.250	0.015   0.015   0.015   2.000   0.030	Indeterminate   Indeterminate   Failure   Indeterminated   Cure	Indeterminate   Indeterminate   Eradication   Indeterminate   Presumed eradication
PPb 3000/603/1081 France 3000/605/1091 France 3000/610/1110 France 3001/1002/027 South Africa 3001/1401/002 Australia 3006/0008/031 USA 3006/0008/039 USA 3006/0012/019 USA 3009OL/0355/104 South Africa 3009OL/0368/105 South Africa 3009OL/0369/105 South Africa 3010/0483/008 USA 3010/0494/036 USA 3010/0503/001 USA 3010/0526/001 South America 3010/0533/007 South Africa 3010/0534/059 South Africa Total = 17	II         III         I         IV    Moderate              I         I         I         II         I         II         I        III         II        III         I         I	S. pneumoniae/ (Single)/ NA S. pneumoniae/ (Mixed)/ermB S. pneumoniae/ (Single) /NA S. pneumoniae/ (Mixed)/ermB S. pneumoniae/ (Single)/ NA S. pneumoniae/ (Single) /NA S. pneumoniae/ (Single)/mefE S. pneumoniae/ (Mixed)/ NA S. pneumoniae/ (Single)/mefE S. pneumoniae/ (Single)/ NA S. pneumoniae/ (Single)/mefE S. pneumoniae/ (Mixed)/mefE S. pneumoniae/ (Mixed)/ermB S. pneumoniae/ (Mixed)/ NA S. pneumoniae/ (Single)/ NA S. pneumoniae/ (Single)/ermB/mefE S. pneumoniae/ Mixed)/ermB/mefE	BLOOD   BLOOD   SPUTUM   SPUTUM   SPUTUM   BLOOD   SPUTUM   SPUTUM   BLOOD   BLOOD   BLOOD   SPUTUM   SPUTUM   SPUTUM   SPUTUM   SPUTUM   SPUTUM	2.000   2.000   2.000   2.000   ND*   2.000   2.000   2.000   2.000   2.000   2.000   2.000   2.000   2.000   2.000   2.000   2.000	0.030   32.000   0.030   32.000   ND   0.060   4.000   0.060   4.000   0.060   4.000   4.000   8.000   0.060   0.250   8.000   8.000	0.015   0.030   0.015   0.030   ND   0.008   0.030   0.008   0.060   0.030   0.120   0.060   0.250   0.030   0.030   0.500   0.500	Cure   Failure   Cure   Failure   Cure   Cure   Cure   Cure   Cure   Cure   Failure   Cure   Cure   Cure   Cure   Cure   Cure	Eradication   Pres.persistence   Pres. eradication   Pres.persistence   Pres. eradication   Eradication   Pres. eradication   Pres. eradication   Pres. eradication   Pres. eradication   Pres. persistence   Pres. eradication   Pres. eradication   Pres. eradication   Pres. eradication   Pres. eradication   Pres. eradication

d - death due to aspiration pneumonia.

* ND – not done

 

 

 

 

Table 9B.  Subjects with S. pneumoniae erythromycin-resistant (ERSP) [MIC ³1 mg/mL], alone and combination with PRSP–bmITT+PPb Populations: All CAP Studies –Telithromycin Group

Study Number/ Investigator No./Subject Number/Location	Fine Score/ Severity	Pathogen/ (Single or  Mixed)/ Genotype	Source	MIC to Pen G (mg/mL)	MIC to Ery A (ug/ml)	MIC to Ketek (ug/ml)	Clinical Outcome	Bacteriologic Outcome
BmITT 3000/605/1090/France   3010/0473/009/USA   3010/0494/026/USA   Total = 3	III         V          I	S. pneumoniae/ (Single)/ermB S. pneumoniae/ (Mixed)/mefE S. pneumoniae/ (Mixed)/ermB	SPUTUM   SPUTUM   SPUTUM	0.120   2.000   0.500	0.030   8.000   8.000	0.030   2.000   0.030	Cure   Indeterminate   Cure	Pres. eradication   Indeterminate   Pres. eradication
PPb 3000/605/1091/ France 3001/1002/027 South Africa 3001/1401/002/* Australia 3001/1101/005/ Sweden 3006/0008/039 USA 3006/0425/008 Argentina 3009OL/0355/104 South Africa 3009OL/055/154 South Africa 3009OL/055/157 South Africa 3009OL/0369/105 South Africa 3010/0483/008/ USA 3010/0494/036/ USA 3010/0523/001/ South America 3010/0533/007/ South Africa 3010/0523//059 South Africa 3010/0536/014/ South Africa 3010/0536/031/ South Africa Total = 17	III          IV    Moderate              IV         I         I         II         II             I         II         I        III          I         I         I         I         1	S. pneumoniae/ (Mixed)/ermB S. pneumoniae/ (Mixed)/ermB S. pneumoniae/ (Mixed)/ermB S. pneumoniae/ (Single)/ ermB S. pneumoniae/ (Single) /mefE S. pneumoniae/ (Single)/mefE S. pneumoniae/ (Single)/mefE S. pneumoniae/ (Single)/ermB S. pneumoniae/ (Single)/ mefE S. pneumoniae/ (Single)/mefE S. pneumoniae/ (Mixed)/mefE S. pneumoniae/ (Mixed)/ermB S. pneumoniae/ (Single)/ ermB S. pneumoniae/ (Single)/ermB/mefE S. pneumoniae/ (Mixed)/ermB/mefE S. pneumoniae/ (Mixed)/mefE S. pneumoniae/ (Mixed)/mefE	BLOOD   SPUTUM   SPUTUM   blood   SPUTUM   SPUTUM   BLOOD   SPUTUM   SPUTUM   BLOOD   SPUTUM   SPUTUM   SPUTUM   SPUTUM   SPUTUM   BLOOD   BLOOD	2.000   2.000   ND**   0.008   2.000   0.500   2.000   0.250   0.030   2.000   2.000   2.000   2.000   0.030   2.000   0.250   0.500	32.000   32.000   ND**   32.000   4.000   8.000