Macrolide Antibiotics - Medical University of South...

Macrolides and Related AntibioticsJohn A. Bosso, Pharm.D.

PHRMP732.macrld.bosso.rev 7.06 1

Macrolide AntibioticsTherapeutics/PHRMP-732

John A. Bosso, Pharm.D.

CASE:

FZX, a 41 year old white female, is seen in theoutpatient department for complaints of low grade fever,cough, and mild respiratory distress. CXR shows light, patchyinfiltrates. The attending physician suspects mycoplasmapneumonia and wishes to treat the patient with erythromycin.However, before writing a prescription, she seeks your advice.She explains that she has heard a lot lately from thepharmaceutical company representatives about the “newerythromycins” and asks for your appraisal and advice inselecting appropriate macrolide therapy for this patient.

QUESTIONS TO ADDRESS:

1. What are the differences between the three major macrolides (erythromycin, clarithromycin and azithromycin) in terms ofspectrum of antibacterial activity?

2. Are there important pharmacokinetic properties which distinguishone macrolide from another? If so, what are they?

3. Are there important differences in side effect profiles that helpdistinguish between the various macrolides?

4. Are there important drug interactions to avoid with erythromycin?Do these interactions, or others, occur with the other macrolides?

5. Based upon the above discussion, are there differences in clinicalindications of the various macrolides of which the pharmacist shouldbe aware?

Macrolides

16-membered ring(spiramycin)

12-membered ring(methymycin)

14-membered ring 15-membered ring(azithromycin)

Natural erythromycin

A, B, C, etc.

Semi syntheticclarithromycindirithromycinflurithromycinroxithromycin

ketolides

Bryskier A. Macrolides: Chemistry, Pharmacology and Clinical Uses. Oxford,England: Blackwell Scientific Publications; 1993.



Structures of Macrolides

Azithromycin

Clarithromycin

Erythromycin

Mechanism of Action

• Bind to 50s subunit of ribosomes causingthem to dissociate from the mRNAresulting in premature termination of theamino acid chain & cessation of proteinsynthesis

Microbiologic Activity of Macrolides

*literature-derived means

Microbiologic Activity of Macrolides

*literature-derived means



Streptococcus pneumoniae Macrolide Resistance

• erm B– Methylation of 23S rRNA– High level macrolide resistance (MICs > 64)– Prevalence (in USA) ≅ 25%

• mef A– Efflux pump– Mid-range macrolide resistance (MICs 1 to 32)– Prevalence (in USA) ≅ 75%

Macrolide MIC Frequency Distributions VersusStreptococcus pneumoniae (n = 1531), 1999-2000

ERYTHROMYCIN

S R

≤

Macrolide MIC Frequency Distributions forS. pneumoniae (n = 1531), 1999-2000

Clarithromycin

S R

≤

G Doern. Personal Communication.

Macrolide MIC Frequency Distributions forS. pneumoniae (n = 1531), 1999-2000

Azithromycin

S R

≤

G Doern. Personal Communication.



Erythromycin-resistant S. pneumoniae 1999-2000

Lower respiratory tract(177/681, 26.0%)

Middle ear fluid (54/105, 51.4%)

Sinus(17/48, 35.4%)

S I+R

Other upperrespiratory

(51/173, 29.5%)

Blood/CSF/Bodyfluid

(94/491, 19.1%)

Other(11/33, 33.3%)

*Total number of isolates, n = 1531

Streptococcus pneumoniae, 1999-2000

S I R

0 - 5 years(148/447, 33.1%)

6 - 20 years(28/87, 32.2%)

21 - 64 years(145/643, 22.6%)

≥65 years(78/339, 23.0%)

*Total number of isolates, n = 1531

Erythromycin

Erythromycin Salts

• Base– Inactivated by acid; absorption delayed by

food• Stearate

– More acid stable; absorption decreased byfood

• Estolate– Acid stable; absorption not affected by food

Erythromycin Salts

• Ethylsuccinate– Acid stable; absorption delayed by food

• Lactobionate– IV form



Pharmacokinetics of Macrolides Active Metabolites

• Clarithromycin:– 14-hydroxyclarithromycin

• Activity often not accounted for in vitro testing

• Dirithromycin:– erythromycylamine

Serum Concentrations of Macrolides

µg/

mL

1 2 3 4 5 6 7 8 9 10 11 12 Time (hours)

1.0

2.0

3.0

(Clari)

(Ery)(Azi)

Differences in IntrapulmonaryAntimicrobial Disposition

Single- Dose Studies

Wise et al, Conte et al, various sources

05

10152025303540

ELFSerum

amoxicillincefuroxime

clarithromycin

ciproCon

cent

ratio

n (µ

g/m

l)

Time of Sampling Post-dose (hr)1-2 4-6 66

levofloxacin

66

Azithro



MACROLIDE INTRAPULMONARYDISTRIBUTION

0.01

0.1

1

10

100

4 8 12

PlasmaELF

Azi Clari Azi Clari Azi Clari

Rodvold et al. AAC. 1997;41:1399.

Macrolide Pharmacodynamics

• Erythromycin– Time-dependent

(%T>MIC)• Clarithromycin & Azilides

– Time- and concentration-dependent(AUC/MIC)

Major Macrolide Drug InteractionsMediated though inhibition of CYP3A4

• Astemizole• Carbamzepine• Cyclosporin• Disopyramide• Midazolam• Quinidine

• Terfenadine• Theophylline• Triazolam• Zidovudine

Major Macrolide Drug InteractionsMediated though enzyme induction

• Rifampin• Rifabutin



Macrolide Drug Interactions

• Mostly likely with erythromycin• Much less likely with clarithromycin and

dirithromycin• Rare if any with azithromycin

Macrolide Side Effects• General

– Gastrointestinal (30% with erythromycin)– Ototoxicity

• Dose-related; usually reversible• Auditory or vestibular

– Hepatoxicity (rare)– QTc prolongation

• Specific– Taste perversion with clari- and erythro-– Phlebitis (4%) with IV form of erythro-

Torsades de pointes• A polymorphic ventricular tachycardia

related to prolongation of the QT interval• Risk factors for occurrence with macrolides:

– Patients with electrolyte disturbances– Elderly females– Concomitant diseases (e.g., caridac)– Concomitant drugs

• Certain antiarrhymics and others that prolong the QTinterval

Shaffer et al. CID 2002;35:197-200.

Indications for MacrolidesINDICATION Erythromycin Clarithromycin Azithromycin Dirithromycin

Approved in pediatrics? + + + -Upper respiratory tract infexn

Pharyngitis + + + +Sinusitis ± +Otitis ± + +

Lower respiratory tract infexn

Chronic bronchitis + + +*

Pneumonia S. pneumoniae + + + + H. influenzae + anaerobes + C. trachomatis + + L. pneumophila + + M. pneumoniae + + +

*does not include H. influenzae



Indications for Macrolides

Sexually transmitted diseases

Lymphogranuloma venereum +

Chancroid +

Syphilis +

NGU + +

Uncomplicated skin & skin structure + + + +

Miscellaneous

Diphtheria +Acne vulgaris +Disseminated MAC + +Helicobacter pylori +*

(ulcer)

*co-administered with omeprazole and amoxicillin

INDICATION Erythromycin Clarithromycin Azithromycin Dirithromycin

Misc. Issues

• Controversy regarding role in empirictherapy of respiratory tract infectionsdue to apparent S. pneumoniae resistance

• Non-antibacterial effects– Anti-inflammatory– Mucolytic– Ciliary effects– Immunomodulatory

Macrolide Immunopharmacologic Effects Effects upon bacterial virulence

• Clarithromycinreduces productionof:– DNAase– protease– Endotoxin A– Exoenzymes

• Clarithromycinreduces:– the potential for

adhesion– reduces motility– alters cellular

morphology– reduces activity of

beta haemolysin

Shryock TR et al. J Antimcrob Chemother. 1998;41:505-512

Macrolides / Azalides

• Good activity against– typical* and

– atypical pathogens

• Can be used in penicillin-allergic patients

• Generally safe and welltolerated

• No activity against erythromycin-resistant S. pneumoniae

• Penicillin resistance inS. pneumoniae is often associatedwith cross-resistance to macrolides

• Tissue accumulation withazithromycin

• Multiple-daily dosing with mostmacrolides

• Once-daily dosing not supported bypharmacokinetics

*Erythromycin and clarithromycin have relatively low activity against H. influenzae.

Advantages Disadvantages



ExperimentalRoxithromycin

– (Phase III)

KETOLIDES

• Macrolide-like compounds• Inhibitors of protein synthesis• Spectrum

– H. influenzae, M. catarrhalis, C. pneumoniae,M. pneumoniae, macrolide-resistant Gram-positives

– Less active vs. L. pneumophila• Telithromycin and ABT-773

KETEK® (telithromycin)CHEMICAL STRUCTURE1,2

O

O O

O

OCH3ON

O

O

O

O HN

N

N N

• C3-keto– Lack of induction of macrolide

type (ermB) resistance– Acid stability

• C6-methoxy– Acid stability

• C11-12 carbamateextension

– Potent antimicrobialactivity against resistant andsusceptible pathogens

– Innovative mechanism of action

1. Douthwaite S. Clin Microbiol Infect. 2001;7(suppl 3):11–17. 2. Douthwaite S, Champney WS. J Antimicrob Chemother. 2001;48:1–8.

TELITHROMYCIN IN VITRO ACTIVITYAGAINST TYPICAL PATHOGENS1

• MIC (µg/mL)•Organism (N) MIC50 MIC90 Range•S pneumoniae (16,672) 0.015 0.5 0.002–8•H influenzae (8064) 1.0 2.0 0.002–32• (ß-lactamase positive; 1631) 2.0 4.0 0.008–16•M catarrhalis (1156) 0.06 0.12 0.004–0.5• (ß-lactamase positive; 1071) 0.06 0.12 0.008–0.5•S aureus (methicillin-susceptible; 1775) 0.06 0.06 0.015–64•S pyogenes (3918) 0.03 0.03 <0.015–>16

1. Data on file. (PROTEKT Studies). Aventis Pharmaceuticals. Bridgewater, NJ.



TELITHROMYCIN IN VITRO ACTIVITYAGAINST ATYPICAL PATHOGENS

MIC (µg/mL)Pathogen MIC50 MIC90 RangeM pneumoniae1 0.008 0.008 0.008–0.06(N=47)C pneumoniae2 0.0625 0.25 0.031–2(N=19)L pneumophila*3 0.008 0.015 <0.004–0.015(N=26)

1. Kenny GE, Cartwright FD. Antimicrob Agents Chemother. 2001;45:2604–2608.2. Hammerschlag MR, Roblin PM, Bébéar CM. J Antimicrob Chemother.2001;48:25–31. 3. Data on file (PROTEKT Studies). Aventis Pharmaceuticals.Bridgewater, NJ.

TELITHROMYCIN IN VITRO ACTIVITY AGAINSTANTIBIOTIC-RESISTANT S. PNEUMONIAE1

• MIC (µg/mL)•Resistance Phenotype (N) MIC50 MIC90 Range•Macrolide-susceptible (11,384) 0.015 0.015 <0.002–1•Macrolide-resistant (5,288) 0.12 1.0 0.008–8• ermB (657) 0.06 0.5 0.008–8• mefA (436) 0.12 0.5 0.008–1• mefA + ermB (71) 0.5 0.5 0.06–1•Penicillin-resistant (4,027) 0.12 1.0 0.004–8•Levofloxacin-resistant (154) 0.03 0.5 0.004–1•Multi-drug resistant (1,500)* 0.12 1.0 0.008–8

*Resistant to penicillin, the macrolides, TMP/SXT, and tetracycline1. Data on file (PROTEKT Studies) [N=16,672]). AventisPharmaceuticals. Bridgewater, NJ.

IN VITRO ACTIVITY AGAINSTMACROLIDE-RESISTANT S. PNEUMONIAE

Susceptibility of Resistant S pneumoniae to Telithromycin1

Efflux ermB Efflux + ermB

Telithro Telithro TelithroAzithro Azithro Azithro

1. Data on file (PROTEKT study HMR 3647A/005–2002/2003). Aventis Pharmaceuticals. Bridgewater, NJ.

IN VITRO ACTIVITY AGAINSTH. INFLUENZAESusceptibility of H. influenzae

Telithromycin Amoxicillin/clavulanate Clarithromycin

1. Data on file (PROTEKT US study report 2002–2003). Aventis Pharmaceuticals. Bridgewater, NJ. 2. KETEK® (telithromycin) PrescribingInformation. Aventis Pharmaceuticals. Bridgewater, NJ.

From the PROTEKT US surveillance program, more than 19,250 clinical isolates were collected nationwide(3367 H influenzae) during the year of 2002–2003.1

Telithromycin clinical cure rates by pathogen for H influenzae in acutebacterial sinusitis, AECB, and CAP were 82%, 73%, and 83%, respectively.2



TELITHROMYCINPHARMACOKINETIC OVERVIEW1

Mean Pharmacokinetics of QD 800-mg Doses in 18 Healthy Adults

– 57% absolute bioavailability– Absorption not affected by food– Total in vitro protein binding is approximately 60% to 70% and is primarily

due to human serum albumin– Metabolism accounts for approximately 70% of the dose– Elimination is by multiple pathways: 7% by biliary and/or intestinal secretion;

13% unchanged by renal excretion; and 37% by the liver

*Median values.

Parameter

0.070.03C24h (μg/mL)9.817.16Terminal t1/2 (h)12.58.25AUC(0–24) (μg•h/mL)1.01.0Tmax (h)*2.271.9Cmax (μg/mL)

Multiple dose (7days)Single dose

1. KETEK® (telithromycin) Prescribing Information. Aventis Pharmaceuticals. Bridgewater, NJ.

FDA-APPROVEDRESPIRATORY INDICATIONS1

•Acute Bacterial Sinusitis– S pneumoniae– H influenzae– M catarrhalis– S aureus

•Acute Bacterial Exacerbation of Chronic Bronchitis– S pneumoniae– H influenzae– M catarrhalis

•Community-Acquired Pneumonia of Mild to Moderate Severity– S pneumoniae– S pneumoniae (multi-drug resistant)– H influenzae– M catarrhalis– C pneumoniae– M pneumoniae

•No Enteric Gram-Negative Coverage1. KETEK® (telithromycin) Prescribing Information. Aventis Pharmaceuticals.Bridgewater,NJ.

Dosing andDrug Interaction Issues

• Chiefly removed via metabolism (CYP3A4)

• No dosing adjustment needed in hepaticimpairment or elderly

• Proper dosing with severe renal dys-function unknown

• CYP-drug interactions!– Discontinue simvastatin, lovastatin and

atorvastatin during telithromycin therapy

All Treatment-emergent Adverse Events Reported in Phase III ControlledClinical Trials

ADVERSE EVENT PROFILESIMILAR TO COMPARATORS

1.5%2.3%Loose Stool

2.7%3.7%Dizziness

3.6% 1.6%Dysgeusia

2.2% 2.9%Vomiting

5.8% 5.5%Headache4.6% 7.9%Nausea8.6%10.8%Diarrhea

Comparators†

n=2139Telithromycin

n=2702Adverse Event*

<1% discontinuation rate due to distinct GI adverse events, including diarrhea.*Based on the frequency of possibly related adverse events >2% in KETEK or comparator groups.†Includes the comparators from all combined Phase III studies–amoxicillin, amoxicillin/clavulanate, cefuroxime, clarithromycin, trovafloxacin.



Telithromycin and Hepatotoxicity

• In June of 2006 the FDA required achange in the PI regarding the potentialfor serious hepatic toxicity based onseveral case reports

http://www.fda.gov/bbs/topics/NEWS/2006/NEW01401.html

CASE:

FZX, a 41 year old white female, is seen in theoutpatient department for complaints of low grade fever,cough, and mild respiratory distress. CXR shows light, patchyinfiltrates. The attending physician suspects mycoplasmapneumonia and wishes to treat the patient with erythromycin.However, before writing a prescription, she seeks your advice.She explains that she has heard a lot lately from thepharmaceutical company representatives about the “newerythromycins” and asks for your appraisal and advice inselecting appropriate macrolide therapy for this patient.

QUESTIONS TO ADDRESS:

1. What are the differences between the three major macrolides (erythromycin, clarithromycin and azithromycin) in terms ofspectrum of antibacterial activity?

2. Are there important pharmacokinetic properties which distinguishone macrolide from another? If so, what are they?

3. Are there important differences in side effect profiles that helpdistinguish between the various macrolides?

4. Are there important drug interactions to avoid with erythromycin?Do these interactions, or others, occur with the other macrolides?

5. Based upon the above discussion, are there differences in clinicalindications of the various macrolides of which the pharmacist shouldbe aware?

Macrolide Antibiotics - Medical University of South...

Documents

Transcript of Macrolide Antibiotics - Medical University of South...