azithromycin in pediatrics

7/31/2019 Azithromycin in Pediatrics

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Azithromycin in Pediatrics


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Macrolides: one of the most commonly used antibiotics.

Erythromycin was discovered in 1952 by McGuire andcoworkers in the metabolic products of a strain of

Streptomyces erythreus. Clarithromycin & azithromycinare semisynthetic derivatives of erythromycin.

Ketolides are semisynthetic derivatives of erythromycinwith activity against some macrolide-resistant strains.

Telithromycin (KETEK) is the only ketolide currentlyapproved in the U.S. (for age above 18 years) Althoughthe ketolides are promising agents against macrolide-resistant organisms, substantial hepatotoxicity seen withtelithromycin has limited their use.

Goodman & Gilmans The Pharmacological Basis of Therapeutics, 12th Ed, 2011

Macrolides


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Erythro base is acid labile & so is used as enteric coatedcapsules. Esters like stearate, estolate, & ethylsuccinatehave improved acid stability, & their absorption is less

altered by food.Azithro & clarithro are semisynthetic derivatives withimproved acid stability, tissue penetration & broaderspectrum of activity.Clarithro may be given 12 hrly or as extended release tab

once daily. It is absorbed rapidly after oral administration.Azithro is also absorbed rapidly & is given as single dailydoses. Macrolides penetrate well into all tissues exceptbrain and CSF. Azithro concentrations within tissue or

secretions & cells (including phagocytes) exceed serumconcentrations

Macrolides


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Mechanism of Action

Inhibit protein synthesis by reversibly binding to the 50 Sribosomal subunits of microorganisms. They induce

dissociation of peptidyl tRNA from the ribosome during

the elongation. Thus, RNA-dependent protein synthesis issuppressed, & bacterial growth is inhibited.

Macrolides are mainly bacteriostatic but can be cidaldepending on sensitivity & antibiotic concentration.

Their binding site is either identical or in close proximityto that for clindamycin & chloramphenicol. Azalides are aclass of macrolide antibiotics which contain a nitrogen inthe macrolide ring. This imparts different pharmacokinetic

properties and is associated with greater stability of themolecule.


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Mechanism of Action


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Immunomodulatory Action


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Spectrum

Spectrum of activity of macrolides is similar to that ofpenicillin.

Cross resistance between macrolides is complete.

Although they are active against Gram positive cocci,susceptibility of S aureus is not predictable. There is noactivity against enteric group of Gram negative bacilli.

Bacteriostatic or cidal: Varies.


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Spectrum

Generally, macrolides are active against gram-positive cocci (mainlystaph & strepto) & bacilli, and to a lesser-extent gram-negative cocci.With the exception of Bordetella pertussis, Campylobacter,Chlamydia, Helicobacter, & Legionella species, gram-negative bacilli

are generally resistant to the macrolides. Macrolides are also activeagainst mycobacteria, mycoplasma, ureaplasma, spirochetes, andother organisms.

The gram-positive activity of clarithromycin is superior to that oferythromycin & azithromycin, especially against Streptococcus

pyogenes & Streptococcus pneumoniae. Gram-negative coverage isalso increased with clarithromycin compared to erythromycin. Alone,clarithromycin has variable activity against H. influenzae. However,the combination of clarithromycin and its metabolite has goodactivity. Because of its good distribution, clarithromycin also offers

excellent activity against intracellular pathogens such as Legionella& Mycoplasma species.


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Spectrum

Azithromycin retains the activity of erythromycin against gram-positive organisms but offers increased gram-negative coverageover erythromycin and clarithromycin. It has been demonstrated tobe more active than clarithromycin against H. influenzae. However, it

has variable activity against the family Enterobacteriaceae.Nonetheless, Salmonella and Shigella species have been shown tobe susceptible, as have other diarrheal pathogens such as Yersiniaand Campylobacter. Like clarithromycin, azithromycin also has goodactivity against Legionella and Mycoplasma species.

Its unique feature is an excellent activity against sexuallytransmitted pathogens, especially Chlamydia trachomatis.

Despite the improvements clarithromycin and azithromycin offer,both these agents demonstrate cross-resistance with erythromycin.


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Spectrum

Clarithro & azithro have some activity against H. influenzae, withMIC breakpoints of 8 g/mL and 4 g/mL, respectively. However, theseagents are not drugs of choice for documented H. influenzaeinfections because of their lesser activity compared to -lactams or

fluoroquinolones.Clarithromycin and azithromycin have good activity against M.catarrhalis, Chlamydia spp., L. pneumophila, B. burgdorferi,Mycoplasma pneumoniae, and H. pylori.

Azithromycin and clarithromycin have enhanced activity against M.

avium-intracellulare, as well as against some protozoa (e.g.,Toxoplasma gondii, Cryptosporidium, and Plasmodium spp.).Clarithromycin has good activity against Mycobacterium leprae.


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Spectrum


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Spectrum


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Azithromycin

Mainly effective on G- bacteria but less active against G+

(s.pneumoniae & s.pyogenes) than erythromycin

Antibacterial spectrum

A. Gram- positive bacteriaStaph. Aureus

S. Pneumoniae

S. Pyogens

B. Gram- negative bacteria (> erythromycin)

M. catarrhalis

H. influenzae

C. Intracellular organisms (> erythromycin)

L. Pneumophila

M. pneumoniaeChlamydia species


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Preparations


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Uses


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Several macrolides are known to increase the risk forarrhythmias & are a/w an increased risk for sudden cardiacdeath. Azithro was thought to have minimal cardiotoxicity, butpublished reports of arrhythmias suggest that this macrolidemay also be linked to an increased risk for cardiovascular death.According to an observational study published in the NEJM ofMedicaid patients receiving a 5-day course of azithro, FDAissued a statement regarding a small increased risk for

cardiovascular death vs patients taking amoxi/cipro/noantibiotic. The drug has been shown to cause QT-intervalprolongation. Clinicians should avoid prescribing the antibioticfor patients with known QT-interval prolongation, those with lowpotassium levels, or those taking drugs that prolong the QT

interval.

FDA Safety Changes: Azithro Linked WithCardiovascular Death


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Pertussis: even in children below 1 month (erythromycina/w IHPS) 10 mg/Kg/d for 5 days

Trachoma & eye infections d/t Chlamydia (like erythro)

Legionellosis (any macrolide)

Tx & 20 prophylaxis of disseminated MAC infection in HIVchildren (also clarithro)

2nd line drug for AOM & CAP (any macrolide)

Streptococcal infections, diphtheria etc in children withserious penicillin hypersensitivity

All macrolides possess some antiinflammatory &immunomodulatory action (like steroids/NSAIDS) esp.

Roxithro & azithro

Uses


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In children, the recommended dose of azithromycin oralsuspension for acute otitis media and pneumonia is 10mg/kg on the first day (maximum: 500 mg) and 5 mg/kg

(maximum: 250 mg per day) on days 2 through 5.The dose for tonsillitis or pharyngitis is 12 mg/kg per day,up to 500 mg total, for 5 days.

Traveler's Diarrhea: Drug of choice in children &

pregnant women, and for quinolone-resistantCampylobacter. (Dose 10 mg/kg/d 3 days) [Alsorecommended by WHO, & by experts, for the treatment oftraveller's diarrhoea if resistance to fluoroquinolones issuspected or known]

Uses


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Campylobacter gastroenteritis: Usually self limiting.Erythromycin PO 50 mg/kg/day divided tid 5 days orAzithromycin PO 5-10 mg/kg/day qid 5 days

MAC prophylaxis in HIV in children: Clarithro 7.5 mg/kg(max 500 mg) BD, or azithro 20 mg/kg (max 1,200 mg)orally weekly. Alternatively Azithro 5 mg/kg (max 250 mg)OD; children aged 6 yr rifabutin, 300 mg orally daily

M. Pneumoniae pneumonia: Clarithro (15 mg/kg/daydivided bid PO for 10 days) or azithromycin (10 mg/kgonce PO on day 1 and 5 mg/kg once daily PO on days 2-5), which eradicate M. pneumoniae in 100% of patientsstudied. Prophylaxis with azithro has been shown tosubstantially reduce the secondary attack rate in

Uses

Nelson Textbook of Pediatrics, 19th Ed, 2011


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Uses


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Acute Otitis Media: a single oral dose of 30 mg/kg ofbody weight results in similar clinical cure rates

Single dose treatment 1 gm: safe and efficacious as a 7-

day course of doxycycline for the treatment ofuncomplicated genital chlamydial infection inadolescents

Single-dose azithromycin Vs benzathine benzylpenicillin

for treatment of yaws in children: effective @ 30 mg/KgSingle dose azithromycin (20 mg/kg) is superior tociprofloxacin (20 mg/Kg) for treating cholera in children

Azithromycin 2.0 g & ceftriaxone 250 mg are equally

effective in the treatment of uncomplicated gonorrhea.

Uses: Single Dose Tx


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Azithro in combination with artemisinins or quinine exerts additive tosynergistic interactions, shows no cross-sensitivity with traditional

antimalarials, & has substantial antimalarial activity on its ownAntimicrob Agents Chemother. 2007 Feb;51(2):651-6

Currently, there is no evidence for the superiority/equivalence ofazithro monotherapy/combination therapy for the Tx of P. falciparumor P. vivax compared with other antimalarials or with the current 1stline antimalarial combinations. Available evidence suggests thatazithro is a weak antimalarial with some appealing safety

characteristics.Cochrane Database Syst Rev. 2011 Feb 16;(2)Slow acting & weak antimalarial against P. falciparum & vivax. It isless effective than clinda. There were no published data identified onthe use of azithromycin as an antimalarial in pregnant women.

Prophylaxis: If used, requires daily dosing (adult dose: 1 tab/day)

starting the day before exposure, & for 4 weeks after departure fromthe malarial re ion.

Uses: Malaria


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Enteric Fever: reduces the clinical failure rate andduration of hospital stay in comparison tofluoroquinolones & relapse rate in comparison toceftriaxone, when used in the treatment of typhoid feverin populations with multidrug resistant typhoid fever IndianPediatrics Vol 46 Jan, 2009

Defervescence time similar to chloramphenicol with

lesser SEDose is 10 20 mg/Kg/day for 7 days.

Use: Enteric Fever


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Nelson Textbook of Pediatrics, 19th Ed, 2011

Use: Enteric Fever


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Effective & safe oral antibiotic to treat children withupper & lower respiratory tract and skin infections dueto common pathogens J. Antimicrob. Chemother. (1987) 20 (suppl B): 171-177

Dose: 150 mg BD or 300 mg OD for 10 days. Children:Usual doses are 2.5 to 5 mg/kg every 12 hours for 5-10days (max 4 wks), hr before or 2 hrs after meals.Therapy should be continued for at least 2 days after

resolution of symptoms, & for at least 10 days instreptococcal infections, urethritis, cervicitis, andcervicovaginitis.

Efficacy essentially equivalent to erythromycin, withbetter plasma concentrations, higher tissueconcentrations and less AEs & drug interactions

Roxithromycin


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Pelvic inflammatory disease (PID)

Infectious diarrhea

Dental infections: Abscess & allergic to penicillins

Acne: 83% of patients showed at least a 60% improvementin only 4 weeks & the majority achieved 80% clearance in12 weeks.

Prostatitis

Syphilis: as a multidose treatment in early syphilisMediterranean spotted fever (Rickettsiosis): or Doxy

Endocarditis: prophylaxis in allergic to penicillin

Non-infectious diseases: Atherosclerosis &

Cystic fibrosis

Off-label & Investigational Uses


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Excellent efficacy

Low potential for drug interactions

Low rate of side effects

Sustained antimicrobial activityActive against intracellular bacteria (Chlamydiapneumoniae & trachomatis, Mycoplasma, Legionella spp.).Since azithromycin is a weak base, it easily penetrates the

cell membrane and stays within the cell.Targeted activity at the site of infection. Because of thetransport with WBCs, azithro possesses a unique property- targeted activity at the site of infection. In infectedtissues, azithro achieves high & sustained therapeutic

concentrations that last 5 7 days after the last dose.

Pros & Cons: Advantages


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Suitable choice for empirical therapy. Since azithromycinhas a good activity against the most common pathogens itis used as a choice for empirical therapy.

Good compliance: short once daily dosing regimen.Azithromycin's short dosing regimen is convenient andimproves patient compliance. For the majority ofinfections, azithromycin is administered once daily for

three days. In the treatment of sexually transmitteddiseases, azithromycin is administered as a single dose.

Active against most respiratory tract infections.Betalactams lack activity against atypical pathogens.Among macrolides, azithromycin shows the best activity

against H. influenzae.

Pros & Cons: Advantages


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Food reduces azithromycin absorption rate. Azithromycincapsules should not be mixed with or taken with food,however tablets may be taken without regard to food

Present product labelling indicates that azithromycincapsules should not be taken with food. However, threerecent studies demonstrated that food does notsignificantly decrease the bioavailabilities of new

formulations of azithromycin.

Pros & Cons: Disdvantages


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Comparison

AgeApproval

DailyDosing

Few GI SideEffects,Tissue

Penetration

DrugInteractions-CYP3A

Erythromycin 3-4 times ++ +++

Azithromycin Once daily +++ +-

Clarithromycin 6 mo Twice +++ +++

Roxithromycin 6 mo Twice +++ +


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Comparison

Bioavailability

Half life FoodInteractions

FDAPregnancyCategory

Erythromycin 25% 1- 1 hour Yes B

Azithromycin 38% 40-60 hrs Yes B

Clarithromycin 55% 3-7 hrs No C

Roxithromycin 50% 5 hrs Yes B1 (ADEC)

Telithromycin 10 hrs


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Comparison

Erythromycin is least expensive followed by azithromycinand clarithromycin. All three have unpleasant taste, buterythromycin is the most palatable.

Parenteral preparations have limited use in children andthe use is associated with thrombophlebitis.


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Key Differences

Azithro & clarithromycin have improved tolerability &fewer GI side effects than erythromycin.

Azithromycin is considered to have much lower potential

for interactions than erythromycin & clarithroAzithro & clarithromycin have improvedpharmacokinetics - better bioavailability, better tissuepenetration, prolonged half-lives.

Clarithro & azithromycin have advantages overerythromycin in dosing regimen.

The gram-positive activity of clarithro is superior to thatof erythromycin & azithromycin.

Azithromycin offers increased gram-negative coverage

over erythro & clarithromycin.


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Suspension IV Injection

Drops 40 mg/mL

Susp. 100 mg/5 mL:15 mL & 30 mL

Susp. 200 mg/5 mL:15 mL & 30 mL

Stat preparations: 1gm & 2 gm per 30mL

500 mg/5 mL

Tablets

100 mgDT

250 mg

500 mg

1 gm

Azithromycin Preparations

Combinations

With Cefixime

With fluconazole &secnidazole


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Adverse Events


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Adverse Effects

Epigastric distress: This side effect is common and canlead to poor patient compliance for erythromycin.

Clarithromycin and azithromycin seem to be better

tolerated by the patient, but gastrointestinal problemsare their most common side effects.

Cholestatic jaundice: This side effect occurs especiallywith the estolate form of erythromycin, presumably asthe result of a hypersensitivity reaction to the estolateform (the lauryl salt of the propionyl ester oferythromycin). It has also been reported for other formsof the drug.

Ototoxicity: Transient deafness has been associated

with erythromycin, especially at high dosages.


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Drug Interactions


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Resistance

Resistance to erythromycin is becoming a serious clinicalproblem. Most strains of staph in hospital isolates areresistant to this drug.

Several mechanisms have been identified: 1) the inabilityof the organism to take up the antibiotic or the presenceof an efflux pump, both of which limit the amount ofintracellular drug; 2) a decreased affinity of the 50Sribosomal subunit for the antibiotic, resulting from the

methylation of an adenine in the 23S bacterial ribosomalRNA; & 3) the presence of a plasmid-associatederythromycin esterase. Both clarithromycin andazithromycin show cross-resistance with erythromycin,

but telithromycin can be effective against macrolide-resistant or anisms.


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Conclusions

Azithromycin is more active than erythromycin againstgram-negative bacteria, showing potentially usefulactivity against H. influenzae. Azithromycin

concentrations in infected tissue have also been shownto be higher than those in noninfected tissue. The hightissue-to-serum level and extended elimination half-lifeallow for once-daily dosing and short-course therapy.

Although both azithromycin and clarithromycin are welltolerated by children, azithromycin has the advantage ofshorter treatment regimens and improved tolerance,potentially improving compliance in the treatment ofrespiratory tract and skin or soft tissue infections.


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azithromycin in pediatrics

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