Azithromycin in Pediatrics

Macrolides
Macrolides: one of the most commonly used antibiotics. Erythromycin was discovered in 1952 by McGuire and coworkers in the metabolic products of a strain of Streptomyces erythreus. Clarithromycin & azithromycin are semisynthetic derivatives of erythromycin. Ketolides are semisynthetic derivatives of erythromycin with activity against some macrolide-resistant strains. Telithromycin (KETEK) is the only ketolide currently approved in the U.S. (for age above 18 years) Although the ketolides are promising agents against macrolideresistant organisms, substantial hepatotoxicity seen with telithromycin has limited their use.
Goodman & Gilmans The Pharmacological Basis of Therapeutics, 12 th Ed, 2011

Macrolides
Erythro base is acid labile & so is used as enteric coated capsules. Esters like stearate, estolate, & ethylsuccinate have improved acid stability, & their absorption is less altered by food. Azithro & clarithro are semisynthetic derivatives with improved acid stability, tissue penetration & broader spectrum 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 daily doses. Macrolides penetrate well into all tissues except brain and CSF. Azithro concentrations within tissue or secretions & cells (including phagocytes) exceed serum concentrations

Mechanism of Action
Inhibit protein synthesis by reversibly binding to the 50 S ribosomal subunits of microorganisms. They induce dissociation of peptidyl tRNA from the ribosome during the elongation. Thus, RNA-dependent protein synthesis is suppressed, & bacterial growth is inhibited. Macrolides are mainly bacteriostatic but can be cidal depending on sensitivity & antibiotic concentration. Their binding site is either identical or in close proximity to that for clindamycin & chloramphenicol. Azalides are a class of macrolide antibiotics which contain a nitrogen in the macrolide ring. This imparts different pharmacokinetic properties and is associated with greater stability of the molecule.

Mechanism of Action

Immunomodulatory Action

Spectrum
Spectrum of activity of macrolides is similar to that of penicillin. Cross resistance between macrolides is complete. Although they are active against Gram positive cocci, susceptibility of S aureus is not predictable. There is no activity against enteric group of Gram negative bacilli. Bacteriostatic or cidal: Varies.

Spectrum
Generally, macrolides are active against gram-positive cocci (mainly staph & 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 active against mycobacteria, mycoplasma, ureaplasma, spirochetes, and other organisms. The gram-positive activity of clarithromycin is superior to that of erythromycin & azithromycin, especially against Streptococcus pyogenes & Streptococcus pneumoniae. Gram-negative coverage is also increased with clarithromycin compared to erythromycin. Alone, clarithromycin has variable activity against H. influenzae. However, the combination of clarithromycin and its metabolite has good activity. Because of its good distribution, clarithromycin also offers excellent activity against intracellular pathogens such as Legionella & Mycoplasma species.

Spectrum
Azithromycin retains the activity of erythromycin against grampositive organisms but offers increased gram-negative coverage over erythromycin and clarithromycin. It has been demonstrated to be more active than clarithromycin against H. influenzae. However, it has variable activity against the family Enterobacteriaceae. Nonetheless, Salmonella and Shigella species have been shown to be susceptible, as have other diarrheal pathogens such as Yersinia and Campylobacter. Like clarithromycin, azithromycin also has good activity against Legionella and Mycoplasma species. Its unique feature is an excellent activity against sexually transmitted pathogens, especially Chlamydia trachomatis. Despite the improvements clarithromycin and azithromycin offer, both these agents demonstrate cross-resistance with erythromycin.

Spectrum
Clarithro & azithro have some activity against H. influenzae, with MIC breakpoints of 8 g/mL and 4 g/mL, respectively. However, these agents are not drugs of choice for documented H. influenzae infections 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.

Spectrum

Spectrum

Azithromycin
Mainly effective on G- bacteria but less active against G+ (s.pneumoniae & s.pyogenes) than erythromycin Antibacterial spectrum A. Gram- positive bacteria Staph. Aureus S. Pneumoniae S. Pyogens B. Gram- negative bacteria (> erythromycin) M. catarrhalis H. influenzae C. Intracellular organisms (> erythromycin) L. Pneumophila M. pneumoniae Chlamydia species

Preparations

Uses

FDA Safety Changes: Azithro Linked With Cardiovascular Death

Several macrolides are known to increase the risk for arrhythmias & are a/w an increased risk for sudden cardiac death. Azithro was thought to have minimal cardiotoxicity, but published reports of arrhythmias suggest that this macrolide may also be linked to an increased risk for cardiovascular death. According to an observational study published in the NEJM of Medicaid patients receiving a 5-day course of azithro, FDA issued a statement regarding a small increased risk for cardiovascular death vs patients taking amoxi/cipro/no antibiotic. The drug has been shown to cause QT-interval prolongation. Clinicians should avoid prescribing the antibiotic for patients with known QT-interval prolongation, those with low potassium levels, or those taking drugs that prolong the QT interval.

Uses
Pertussis: even in children below 1 month (erythromycin a/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 HIV children (also clarithro) 2nd line drug for AOM & CAP (any macrolide) Streptococcal infections, diphtheria etc in children with serious penicillin hypersensitivity All macrolides possess some antiinflammatory & immunomodulatory action (like steroids/NSAIDS) esp. Roxithro & azithro

Uses
In children, the recommended dose of azithromycin oral suspension for acute otitis media and pneumonia is 10 mg/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-resistant Campylobacter. (Dose 10 mg/kg/d 3 days) [Also recommended by WHO, & by experts, for the treatment of traveller's diarrhoea if resistance to fluoroquinolones is suspected or known]

Uses
Campylobacter gastroenteritis: Usually self limiting. Erythromycin PO 50 mg/kg/day divided tid 5 days or Azithromycin 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/day divided bid PO for 10 days) or azithromycin (10 mg/kg once PO on day 1 and 5 mg/kg once daily PO on days 25), which eradicate M. pneumoniae in 100% of patients studied. Prophylaxis with azithro has been shown to substantially reduce the secondary attackTextbook of Pediatrics, 19 Ed, 2011 Nelson rate in
th

Uses

Uses: Single Dose Tx

Acute Otitis Media: a single oral dose of 30 mg/kg of body weight results in similar clinical cure rates Single dose treatment 1 gm: safe and efficacious as a 7day course of doxycycline for the treatment of uncomplicated genital chlamydial infection in adolescents Single-dose azithromycin Vs benzathine benzylpenicillin for treatment of yaws in children: effective @ 30 mg/Kg Single dose azithromycin (20 mg/kg) is superior to ciprofloxacin (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: Malaria
Azithro in combination with artemisinins or quinine exerts additive to synergistic interactions, shows no cross-sensitivity with traditional antimalarials, & has substantial antimalarial activity on its own
Antimicrob Agents Chemother. 2007 Feb;51(2):651-6

Currently, there is no evidence for the superiority/equivalence of azithro monotherapy/combination therapy for the Tx of P. falciparum or P. vivax compared with other antimalarials or with the current 1st line antimalarial combinations. Available evidence suggests that azithro 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 is less effective than clinda. There were no published data identified on the 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 from the malarial region.

Use: Enteric Fever

Enteric Fever: reduces the clinical failure rate and duration of hospital stay in comparison to fluoroquinolones & relapse rate in comparison to ceftriaxone, when used in the treatment of typhoid fever in populations with multidrug resistant typhoid fever Indian
Pediatrics Vol 46 Jan, 2009

Defervescence time similar to chloramphenicol with lesser SE

Dose is 10 20 mg/Kg/day for 7 days.

Use: Enteric Fever

Nelson Textbook of Pediatrics, 19th Ed, 2011

Roxithromycin
Effective & safe oral antibiotic to treat children with upper & lower respiratory tract and skin infections due to 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 5-10 days (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 in streptococcal infections, urethritis, cervicitis, and cervicovaginitis. Efficacy essentially equivalent to erythromycin, with better plasma concentrations, higher tissue concentrations and less AEs & drug interactions

Off-label & Investigational Uses

Pelvic inflammatory disease (PID) Infectious diarrhea Dental infections: Abscess & allergic to penicillins Acne: 83% of patients showed at least a 60% improvement in only 4 weeks & the majority achieved 80% clearance in 12 weeks. Prostatitis Syphilis: as a multidose treatment in early syphilis Mediterranean spotted fever (Rickettsiosis): or Doxy Endocarditis: prophylaxis in allergic to penicillin Non-infectious diseases: Atherosclerosis & Cystic fibrosis

Pros & Cons: Advantages

Excellent efficacy Low potential for drug interactions Low rate of side effects Sustained antimicrobial activity Active against intracellular bacteria (Chlamydia pneumoniae & 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 the transport with WBCs, azithro possesses a unique property - targeted activity at the site of infection. In infected tissues, azithro achieves high & sustained therapeutic concentrations that last 5 7 days after the last dose.

Pros & Cons: Advantages

Suitable choice for empirical therapy. Since azithromycin has a good activity against the most common pathogens it is used as a choice for empirical therapy. Good compliance: short once daily dosing regimen. Azithromycin's short dosing regimen is convenient and improves patient compliance. For the majority of infections, azithromycin is administered once daily for three days. In the treatment of sexually transmitted diseases, 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: Disdvantages

Food reduces azithromycin absorption rate. Azithromycin capsules should not be mixed with or taken with food, however tablets may be taken without regard to food Present product labelling indicates that azithromycin capsules should not be taken with food. However, three recent studies demonstrated that food does not significantly decrease the bioavailabilities of new formulations of azithromycin.

Comparison
Age Daily Approval Dosing Few GI Side Effects, Tissue Penetration ++ +++ +++ +++ Drug Interactions -CYP3A +++ ++++ +

Erythromycin Azithromycin Clarithromycin Roxithromycin 6 mo 6 mo

3-4 times Once daily Twice Twice

Comparison
Bioavaila Half life bility Erythromycin Azithromycin 25% 38% 1- 1 hour 40-60 hrs Food Interactions Yes Yes FDA Pregnancy Category B B

Clarithromycin
Roxithromycin Telithromycin

55%
50%

3-7 hrs
5 hrs 10 hrs

No
Yes

C
B1 (ADEC)

Comparison
Erythromycin is least expensive followed by azithromycin and clarithromycin. All three have unpleasant taste, but erythromycin is the most palatable. Parenteral preparations have limited use in children and the use is associated with thrombophlebitis.

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 & clarithro Azithro & clarithromycin have improved pharmacokinetics - better bioavailability, better tissue penetration, prolonged half-lives. Clarithro & azithromycin have advantages over erythromycin in dosing regimen. The gram-positive activity of clarithro is superior to that of erythromycin & azithromycin. Azithromycin offers increased gram-negative coverage over erythro & clarithromycin.

Azithromycin Preparations

Tablets

Suspension
Drops 40 mg/mL Susp. 100 mg/5 mL: 15 mL & 30 mL Susp. 200 mg/5 mL: 15 mL & 30 mL Stat preparations: 1 gm & 2 gm per 30 mL

IV Injection
500 mg/5 mL

100 mgDT 250 mg 500 mg 1 gm

Combinations
With Cefixime With fluconazole & secnidazole

Adverse Events

Adverse Effects
Epigastric distress: This side effect is common and can lead to poor patient compliance for erythromycin. Clarithromycin and azithromycin seem to be better tolerated by the patient, but gastrointestinal problems are their most common side effects. Cholestatic jaundice: This side effect occurs especially with the estolate form of erythromycin, presumably as the result of a hypersensitivity reaction to the estolate form (the lauryl salt of the propionyl ester of erythromycin). It has also been reported for other forms of the drug. Ototoxicity: Transient deafness has been associated with erythromycin, especially at high dosages.

Drug Interactions

Resistance
Resistance to erythromycin is becoming a serious clinical problem. Most strains of staph in hospital isolates are resistant to this drug. Several mechanisms have been identified: 1) the inability of the organism to take up the antibiotic or the presence of an efflux pump, both of which limit the amount of intracellular drug; 2) a decreased affinity of the 50S ribosomal subunit for the antibiotic, resulting from the methylation of an adenine in the 23S bacterial ribosomal RNA; & 3) the presence of a plasmid-associated erythromycin esterase. Both clarithromycin and azithromycin show cross-resistance with erythromycin, but telithromycin can be effective against macrolideresistant organisms.

Conclusions
Azithromycin is more active than erythromycin against gram-negative bacteria, showing potentially useful activity against H. influenzae. Azithromycin concentrations in infected tissue have also been shown to be higher than those in noninfected tissue. The high tissue-to-serum level and extended elimination half-life allow for once-daily dosing and short-course therapy. Although both azithromycin and clarithromycin are well tolerated by children, azithromycin has the advantage of shorter treatment regimens and improved tolerance, potentially improving compliance in the treatment of respiratory tract and skin or soft tissue infections.

Thank you!