azithromycin, clarithromycin, and telithromycin

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19/08/13 zithromycin, clarithromycin, and telithromycin

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Official reprint from UpToDate

www.uptodate.com 2013 UpToDate

AuthorAmy L Graziani, PharmD

Section EditorDavid C Hooper, MD

Deputy EditorAnna R Thorner, MD

Azithromycin, clarithromycin, and telithromycin

Disclosures

All topics are updated as new evidence becomes available and ourpeer review process is complete.Literature review current through: Jul 2013. | This topic last updated: May 9, 2013.

INTRODUCTION Azithromycin (Zithromax) and clarithromycin (Biaxin) are macrolide antibiotics that are used in the

treatment of community-acquired respiratory tract infections, particularly pneumonia. They are derivatives of the older

macrolide antibiotic, erythromycin. Structural modifications of erythromycin cause a change in the spectrum of activity,

dosing, and administration of the newer macrolides and ketolides. Telithromycin (Ketek) is the first member of the

ketolide class of antimicrobials, which is related to the macrolide class. Concerns about postmarketing reports ofhepatotoxicity and exacerbations of myasthenia gravis have led to significant restrictions on the use of telithromycin.

(See 'Warnings about telithromycin' below.)

The spectrum of activity, mechanisms of action and resistance, pharmacokinetics, interactions with other drugs, and

adverse effects of these newer macrolide antibiotics will be reviewed here. The use of these drugs for community-

acquired pneumonia is discussed separately. (See "Treatment of community-acquired pneumonia in adults in the

outpatient setting" and "Treatment of community-acquired pneumonia in adults who require hospitalization".)

The macrolides are sometimes used for their antiinflammatory effects. This is discussed in detail separately. (See

"Cystic fibrosis: Overview of the treatment of lung disease", section on 'Macrolide antibiotics' and "Chronic lung

transplant rejection: Bronchiolitis obliterans", section on 'Treatment' and "Diffuse panbronchiolitis", section on 'Macrolide

antibiotics'.)

MECHANISM OF ACTION AND CHEMICAL STRUCTURE The mechanism of action of the newer macrolides is

similar to that oferythromycin. They bind to the 50S subunit of bacterial ribosomes, leading to inhibition of

transpeptidation, translocation, chain elongation and, ultimately, bacterial protein synthesis [1,2].

Clarithromycin has the same macrolide, 14-membered lactone ring as erythromycin; the only difference is that at positio

six a methoxy group replaces the hydroxyl group [1].Azithromycin, in comparison, has a 15-membered ring and a

methyl-substituted nitrogen replacing the 9A carbonyl group. For this reason, azithromycin is more precisely referred to

as an azalide rather than a macrolide [2-4].

These structural changes have made the newer macrolides more acid-stable than erythromycin, providing improved ora

absorption, tolerance, and pharmacokinetic properties. The newer macrolides also have a broader spectrum of

antibacterial activity than erythromycin [1,2].

The ketolide, telithromycin, was designed to specifically target macrolide-resistant respiratory tract pathogens. It has a

keto group substituted for the L-cladinose at C3, a methoxy group at C6, and an N-substituted carbamate at C11/C12.

These modifications enable telithromycin to bind more tightly to ribosomal RNA, which increases its potency, decreases

the selection of bacterial resistance, increases its activity against erythromycin-resistant strains, and improves the

pharmacokinetics.

RESISTANCE Acquired macrolide resistance is an increasing problem. As with resistance to other drugs, antibiotic

use has been associated with development of resistance. This relationship was directly demonstrated in a randomized,
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double-blind trial in which 224 healthy volunteers were assigned to azithromycin, clarithromycin, or placebo; the end

point was the development of pharyngeal carriage of macrolide-resistant streptococci [5]. The proportion of macrolide-

resistant streptococci was 26 to 30 percent at baseline. Both macrolides significantly increased the proportion of

macrolide-resistant streptococci compared to placebo, peaking at day four to eight, with a mean increase of about 50

percent (to an absolute proportion of over 80 percent) compared with a 4 percent increase with placebo. The increase i

resistance was greater with azithromycin, a possible reflection of its much longer half-life.

Two main mechanisms of acquired macrolide resistance have been described [6-8]:

Methylases encoded by the erm (erythromycin ribosome methylase) genes (ermA, ermB, ermC) alter the

macrolide binding site on the bacterial ribosomal RNA, usually conferring a high degree of macrolide resistance

[9]. In a study of selected resistance in volunteers, clarithromycin but not azithromycin selected for this type of

resistance [5]. This mechanism also usually confers resistance to clindamycin. (See "Clindamycin: An overview"

section on 'Resistance'.)

Active macrolide efflux pumps, encoded by the mef (macrolide efflux) msrA and msrB genes, confer a low to

moderate degree of macrolide resistance [9-11]

These mechanisms are responsible forerythromycin resistance in most gram-positive cocci (eg, Staphylococcus aureu

Streptococcus pneumoniae, other streptococci). In contrast to the mechanisms of acquired resistance, intrinsicresistance exhibited by Enterobacteriaceae, Pseudomonas spp, and Acinetobacter spp is due to decreased permeabili

of the outer cell envelope.

Mechanisms of resistance to azithromycin orclarithromycin are the same as or similar to those oferythromycin. There

complete cross-resistance between erythromycin, azithromycin, and clarithromycin for gram-positive organisms by the

alteration in ribosomal RNA mechanism. In contrast, resistance to telithromycin by this mechanism is as yet uncommon

as a result, telithromycin is active against many erythromycin-resistant respiratory pathogens. However, resistance due

to ketolide efflux pumps can cause resistance to telithromycin [12]. Telithromycin-resistant isolates have been isolated

vitro, and a case report has documented a telithromycin-resistant S. pneumoniae isolate recovered from blood following

telithromycin treatment [13].

The incidence of macrolide-resistant S. pneumoniae isolates increased from 10.6 percent in 1995 to 20.4 percent in

1999. However, in cities in the United States where pneumococcal vaccination of children has been widespread, there

was a distinct reduction in the overall prevalence of macrolide resistance among invasive isolates in 2002. (See

"Resistance of Streptococcus pneumoniae to the macrolides, azalides, lincosamines, and ketolides", section on

'Prevalence of resistance'.)

Azithromycin, clarithromycin, and telithromycin have enhanced gram-negative activity compared with erythromycin. As

result, selected erythromycin-resistant gram-negative organisms may be sensitive to the newer drugs.

Increasing resistance to azithromycin has been described in patients with syphilis; the frequency varies with geographic

area. (See "Pathogenesis, clinical manifestations, and treatment of early syphilis", section on 'Treatment'.)

SPECTRUM OF ACTIVITY Azithromycin, clarithromycin, and telithromycin have a broader spectrum of activity than

erythromycin [14].

The greatest use of the macrolides is in upper respiratory tract infections; azithromycin, clarithromycin, and telithromyci

have activity against erythromycin-sensitive Streptococcus pneumoniae, Haemophilus spp, Moraxella catarrhalis, and

atypical pneumonia pathogens, including Legionella pneumophila, Chlamydophila (formerly Chlamydia) pneumoniae,

and Mycoplasma pneumoniae. Telithromycin also has activity against many erythromycin-resistant S. pneumoniae.

Azithromycin is more effective in vitro against most strains of H. influenzae, and has more rapid killing and a longer pos

antibiotic effect than clarithromycin [14,15]. Despite the fact that clarithromycins 14-hydroxy metabolite has activity

against H. influenzae, in one study, only 63 percent of H. influenzae isolates were susceptible to clarithromycin, wherea
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96 percent were susceptible to azithromycin [16]. For this reason, azithromycin is preferred over clarithromycin in

outpatients with community-acquired pneumonia who have comorbidities, such as chronic obstructive pulmonary

disease [15]. Erythromycin does not have activity against H. influenzae. (See "Treatment of community-acquired

pneumonia in adults in the outpatient setting" and "Antibiotic studies for the treatment of community-acquired pneumon

in adults", section on 'Macrolide resistance'.)

These antibiotics are also usually active against other gram-positive organisms including Staphylococcus aureus (exce

for methicillin-resistant S. aureus), and Group A, B, C, and G streptococcus.

Resistance to eitherazithromycin orclarithromycin by gram-positive organisms results in cross resistance to the other

macrolides; however, this cross resistance is not necessarily true with telithromycin. As an example, telithromycin is

active against many erythromycin-resistant S. pneumoniae and Streptococcus pyogenes and is more active than

azithromycin and clarithromycin in vitro against erythromycin-sensitive S. aureus [14].

The newer macrolides have enhanced gram-negative activity compared with erythromycin. As a result, an erythromycin

resistant gram-negative organism may be sensitive to azithromycin, clarithromycin, and/ortelithromycin. The gram-

negative spectrum includes activity against Escherichia coli, Salmonella spp, Yersinia enterocolitica, Shigella spp,

Campylobacter jejuni, Vibrio cholerae, Neisseria gonorrhoeae, and Helicobacter pylori.

Clarithromycin and azithromycin are the primary agents used to treat Mycobacterium avium complex infections. (See

"Mycobacterium avium complex (MAC) infections in HIV-infected patients" and "Treatment of nontuberculousmycobacterial infections of the lung in HIV-negative patients".)

METABOLISM AND PHARMACOKINETICS Clarithromycin, azithromycin, and telithromycin have improved oral

absorption, longer serum half-lives, and better tissue and intracellular penetration than erythromycin. Only azithromycin

is available in an intravenous formulation.

Acid stability and food Azithromycin, clarithromycin, and telithromycin are stable at gastric pH. As a result, their

bioavailability is better than that oferythromycin base (37 versus 25 percent), and enteric coating is not required. All of

the newer tablet formulations and oral suspensions, except for extended-release clarithromycin, can be taken with or

without food [1,4,17].

The serum concentrations attained with oral azithromycin are much lower than those ofclarithromycin.

A regimen of 500 mg on day one followed by 250 mg/day for nine days leads to an average plasma azithromycin

concentration of 0.21 mcg/mL [2-4,18,19].

The extended-release oral suspension of azithromycin (Zmax, given as a single dose per week) results in a

higher peak serum concentration and more systemic exposure than can be achieved with standard regimens of

immediate-release azithromycin [20].

The oral bioavailability of the original clarithromycin (dosed every 12 hours) tablets is approximately 50 percent;

the mean steady state peak serum concentration following 500 mg orally every 12 hours is 2 to 3 mcg/mL [21].

The newer, extended-release clarithromycin tablets (Biaxin XL, dosed once daily) have inactive ingredients in th

tablet that bind to clarithromycin and slow gastric absorption. The peak serum concentration is lower than the

original clarithromycin tablets and is delayed until five to eight hours following the dose. Patients should be

instructed to take the extended-release tablets with food because fasting decreases the area under the plasma

concentration-time curve (AUC) by 30 percent.

Telithromycin is well absorbed from the GI tract (90 percent), but a third of the dose is metabolized via first pass

metabolism by the liver and intestine, resulting in an oral bioavailability of 57 percent [12]. Peak plasma levels one to tw

hours after an 800 mg oral dose are 1.8 to 2.2 mcg/mL. The plasma half-life is 9.8 hours at steady state [22]. Food doe
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not affect the rate or extent of absorption of telithromycin.

Tissue and intracellular penetration All macrolides and ketolides distribute and concentrate well in most body

tissues and phagocytic cells. Thus, the tissue levels, epithelial lining fluid, and alveolar macrophage concentrations are

usually higher than those in the plasma [1,4].

Telithromycin is the most highly concentrated in tissue, followed by azithromycin, clarithromycin, and erythromycin

[1,21]. Telithromycin achieves concentrations in lower respiratory tract infection sites that are higher than the MICs of

most respiratory pathogens [17]. As an example, telithromycin concentrates intracellularly in alveolar macrophages (at

least 400-fold higher than concomitant serum concentrations) and in polymorphonuclear cells (200 to 300-fold higher

than concomitant serum concentrations) [14,23].

Azithromycin levels in sputum and lung are 10 to 100 times those in the plasma; alveolar macrophage and neutrophil

concentrations are also higher [2,4,21]. In comparison, clarithromycin levels in the lung are only six to eight times highe

than the plasma concentration [19].

These differences in intracellular penetration and plasma concentration are two reasons that comparison of these agen

by traditional, in vitro methods (such as MIC) is difficult. The clinical significance of the better tissue penetration but low

plasma levels oftelithromycin and azithromycin is not known.

Active metabolites Azithromycin is excreted in the bile and then the feces, with very little unchanged drug appearin

in the urine [2,4]. Several azithromycin metabolites have been identified, but none is known to be biologically active

[4,24].

Clarithromycin is hydroxylated, N-demethylated, and hydrolyzed in the liver, utilizing the cytochrome P450 enzyme

system. The major metabolite, 14-hydroxy-clarithromycin, is microbiologically active [1,2], and it is more active than the

parent compound against some species. As an example, among H. influenzae isolates from patients with community-

acquired pneumonia, the concentration at which 90 percent of organisms are inhibited (MIC90) of the 14-OH metabolite

was 3 mcg/mL compared with 9 mcg/mL for the parent compound [16]. This active clarithromycin metabolite is another

variable that makes a comparison between clarithromycin and azithromycin difficult in vitro. Twenty to 30 percent of

clarithromycin is excreted unchanged in the urine [25].

Telithromycin has multiple routes of elimination: seven percent is eliminated in the feces, 13 percent is excretedunchanged in the urine, and the remainder is metabolized by hepatic CYP450 and non-CYP450 pathways. Up to four

major metabolites appear to have antibacterial activity, although the activity is weak, only about 6 percent as potent as

telithromycin [23].

DOSING AND ADMINISTRATION

Azithromycin Compared to clarithromycin, azithromycin is typically given for a shorter period because of the long

intracellular half-life (40 to 68 hours) and slow release from tissue sites. Thus, for many infections, a once-daily, five da

regimen is as effective as 10 day courses of the other macrolides.

Azithromycin is available in several different formulations, including 250, 500, and 600 mg tablets and a 100 mg/5 mL o

200 mg/5 mL pediatric preparation.

Azithromycin is also available as an intravenous formulation. The infusion volumes are relatively large (250 mL to 500

mL) and the infusion rates are long (three hours for the 1 mg/mL concentration and one hour for the 2 mg/mL

concentration).

The 2 g extended-release oral suspension ofazithromycin (Zmax) has an even shorter regimen as it is given as a singl

dose, because of the long half-life [20].

Clarithromycin Clarithromycin is available in the original tablets (250 and 500 mg) and extended release tablets

(Biaxin XL, 500 mg). There is no intravenous formulation.
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A pediatric formulation is available including tablets or granules for oral suspension (125 mg/5 mL and 250 mg/5 mL)

[24]. The suspension should not be refrigerated because it can become very viscous and difficult to shake adequately.

Warnings about telithromycin Telithromycin is available in 400 mg tablets. There is no intravenous formulation.

Because of reports of potentially fatal hepatotoxicity, potentially fatal exacerbations of myasthenia gravis, and visual

disturbances, the United States Food and Drug Administration (FDA) concluded in February 2007 that the risks

associated with telithromycin outweigh its benefits for minor illnesses, and that telithromycin should not be used to trea

sinusitis or bronchitis [26]. Even among patients with mild to moderate community-acquired pneumonia, the FDA

concluded that telithromycin should be a secondary alternative to other antimicrobial drugs. A black box warning was

added to the label stating that telithromycin should not be used in patients with myasthenia gravis. There has been som

controversy over the review and monitoring of the hepatotoxicity pre- and postmarketing [26,27].

SPECIAL POPULATIONS

Renal insufficiency Azithromycin dosing does not require adjustment with decreased creatinine clearance. In

patients with a creatinine clearance below 30 mL/min, the dose ofclarithromycin should be reduced by half or the dosin

interval should be doubled.

Telithromycin dosing does not require adjustment with mild-to-moderate renal impairment (creatinine clearance 30

mL/min). No dose has been established for patients with severe renal impairment, but the drug accumulates with

decreased renal function. As a result, dose adjustment should be considered in these patients.

Pregnancy Erythromycin should be considered the safest macrolide in pregnant women, because of the many year

of clinical experience. Of the newer macrolides, there is more experience during pregnancy with azithromycin than

clarithromycin, ortelithromycin.

Azithromycin Azithromycin is a United States Food and Drug Administration (FDA) pregnancy category B drug

(ie, no evidence of risk in pregnant humans), the same category as forerythromycin (table 1) [24,28].

There are several reports of the use ofazithromycin in pregnant women [29-31]. In two studies, patients with cervical

chlamydial infection received a 1 g dose of azithromycin and were followed for efficacy and toxicity [29,30]. Teratogenic

effects were not noted, although it is not clear if neonatal examination and follow-up were required. More recently, 123

pregnant women taking azithromycin were prospectively followed along with two groups of matched controls [31]. The

incidence of major malformations was similar in the azithromycin-exposed and unexposed groups and was not more

than the 1 to 3 percent that would be expected in the general population. All three of the malformations occurred in the

infants of azithromycin-exposed women who were treated for five days for upper respiratory tract infections. This study

was underpowered to detect a difference between the azithromycin-exposed and unexposed groups. The safety of this

agent in pregnant women is not definitively known.

Clarithromycin Clarithromycin is a pregnancy category C drug (ie, risk cannot be ruled out) (table 1) [32].

Teratogenic effects (including cleft palate, cardiovascular anomalies, and fetal growth restriction) have occurred in

monkeys, rats, mice, and rabbits with plasma clarithromycin concentrations 2 to 17 times the levels normally achieved

humans. The labeling states that no adequate and well-controlled trials in pregnant women have been performed; as a

result, clarithromycin should be used in pregnant women only if the potential benefit justifies the potential risk to the fetu

[32].

Telithromycin Telithromycin is a pregnancy category C drug (table 1). In rats and rabbits at high doses, materna

toxicity may result in delayed fetal maturation; in rats, it is excreted in breast milk [33].

ADVERSE REACTIONS The newer macrolides are generally better tolerated than erythromycin. Because of its mor

frequent gastrointestinal side effects and risk of QT prolongation and sudden death, erythromycin is now rarely

recommended. Erythromycin was the first macrolide to be associated with QT prolongation, but subsequent reports and

studies have also described QT prolongation with clarithromycin, azithromycin, as well as the ketolide, telithromycin.
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The following provides a brief summary of some of the major adverse effects associated with these drugs. Detail about

specific interactions is available by using the Lexi-Interact program included with UpToDate.

Hepatotoxicity

Azithromycin Postmarketing reports have identified various hepatic abnormalities in patients receiving

azithromycin, including abnormal liver function tests, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failur

some of these cases have resulted in death [34]. Azithromycin is therefore contraindicated in patients with a history of

cholestatic jaundice or hepatic dysfunction associated with prior azithromycin use. It should be discontinued immediate

if signs or symptoms of hepatitis occur.

Telithromycin Severe hepatotoxicity reported in three patients receiving telithromycin prompted an FDA Public

Health Advisory

(www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm107824.htm) [35]. All

three patients developed jaundice and abnormal liver function. One patient recovered, one required an organ transplan

and one died. Liver histology in the latter two patients showed massive tissue death. Although two patients reported

some alcohol use, all three had been previously healthy and were not using other prescription drugs. There have been

additional reports of hepatotoxicity, 42 of which were reviewed in detail and published [36]. The onset was short (media

10 days) and mortality was high.

Clinicians are cautioned to monitor patients taking telithromycin for signs and symptoms of liver dysfunction and areadvised to stop the medication in any patient who develops evidence of liver disease. Telithromycin should not be

readministered to patients with a previous history of hepatitis and/or jaundice associated with the use of telithromycin o

any macrolide antibiotic.

Due to postmarketing reports of hepatotoxicity and other toxicities, the FDA rescinded its approval oftelithromycin for

bronchitis and sinusitis. It is still approved for the treatment of mild to moderate community-acquired pneumonia, but th

FDA concluded that telithromycin should be a secondary alternative to other antimicrobial drugs. (See 'Warnings about

telithromycin' above.)

Other gastrointestinal Gastrointestinal side effects (nausea, diarrhea, abdominal pain) occur in 2 to 5 percent of

patients with oral azithromycin and clarithromycin and about 12 percent with telithromycin [14,33]. Clarithromycin does

not form the anhydrohemiketal degradation product thought to be responsible for some of the gastrointestinal side

effects associated with erythromycin [19]. Macrolides have a dose-related effect on motilin receptors and can thereby

stimulate the smooth muscle of the gastrointestinal tract. In fact, they have been used clinically to stimulate gastric

motility [37].

The intravenous formulation ofazithromycin also causes gastrointestinal side effects including: nausea (4 to 7 percent)

vomiting (1.4 percent), diarrhea (4 to 9 percent), and abdominal pain (2 to 3 percent).

The response to one drug does not necessarily predict that to the other. Some patients, for example, have intolerable

side effects with clarithromycin but not azithromycin, and vice versa. Abdominal cramping with subsequent loose stools

is common with high doses of azithromycin [4,19].

Dysgeusia seems to be a relatively frequent complaint in patients who are treated with clarithromycin, less so with

telithromycin, and not with azithromycin. The clarithromycin pediatric suspension is bitter-tasting.

QT interval prolongation Erythromycin was the first macrolide to be associated with QT interval prolongation, but

subsequent reports and studies have also described QT interval prolongation with clarithromycin and azithromycin, as

well as the ketolide, telithromycin. Clinicians should assess the risk of torsades de pointes when considering a macrolid

and other antibiotic treatment options for patients at risk for cardiovascular events [38]. In addition to macrolides, certai

non-macrolides, such as fluoroquinolones, also have the potential for prolonging the QT interval. (See

"Fluoroquinolones", section on 'QT interval prolongation and arrhythmia' and "Acquired long QT syndrome", section on

'Incidence with specific drugs'.)
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In addition, each patient's medication list should be reviewed to determine if he or she is taking more than one drug tha

can prolong the QT interval (eg, methadone) since such patients are at increased risk of torsades de pointes (table 2).

Information regarding the risk of QT prolongation with each macrolide and telithromycin is summarized as follows:

Erythromycin Erythromycin is associated with an approximate two-fold increase in the risk of sudden cardiac

death overall and a five-fold increase in patients also taking CYP3A4 inhibitors [39]. (See "Acquired long QT

syndrome".)

Azithromycin In 2013, the US Food and Drug Administration issued a warning about the risk of QT interval

prolongation and potentially fatal torsades de pointes among patients taking azithromycin [38]. Patients at

particular risk include those with existing QT interval prolongation, hypokalemia, hypomagnesemia, significant

bradycardia, bradyarrhythmias, uncompensated heart failure, and those receiving certain antiarrhythmic drugs

(eg, class IA [quinidine, procainamide] or class III [dofetilide, amiodarone, sotalol] antiarrhythmic drugs)

[38,40,41]. Elderly patients may also be more susceptible to drug-associated QT interval prolongation. The

warning was based on a review that followed the publication of a study that showed an increased risk of death in

patients receiving azithromycin [42].

In a large database analysis of adults aged 30 to 74 years enrolled in Medicaid in Tennessee, patients receiving

five-day course of azithromycin had an increased risk of cardiovascular mortality (hazard ratio [HR] 2.88, 95% C1.79-4.63) and all-cause mortality (HR 1.85, 95% CI 1.25-2.75) compared with those who took no antibiotics [42

Patients receiving azithromycin also had an increased risk of cardiovascular mortality (HR 2.49, 95% 1.38-4.50)

and all-cause mortality (HR 2.02, 95% CI 1.24-3.30) compared with those receiving amoxicillin. In contrast, there

was no increase in the risk of death in patients receiving amoxicillin orciprofloxacin. The risk of cardiovascular

mortality and all-cause mortality were similar for azithromycin and levofloxacin.

The absolute increase in cardiovascular mortality was small; patients who received azithromycin had an

estimated 47 additional cardiovascular deaths per million courses of therapy compared with amoxicillin [42]. The

risk of cardiovascular mortality was highest among patients with elevated cardiovascular risk scores; compared

with patients receiving amoxicillin, in patients receiving azithromycin, there were nine excess cardiovascular

deaths per million five-day courses of antibiotics among those in the lowest cardiovascular risk category versus

245 excess cardiovascular deaths among those in the highest category. Among the 29 cardiovascular deaths th

occurred during a five-day course of azithromycin, 22 were sudden cardiac deaths. Although the investigators

used propensity analysis to adjust for baseline risk, residual confounding remains a concern since patients

prescribed azithromycin may have had a higher risk of death because of their underlying disease and/or

comorbidities.

A large cohort study used Danish national healthcare data to evaluate the association between azithromycin use

and cardiovascular death in adults between the ages of 18 and 64 [43]. The risk of death from cardiovascular

causes was significantly increased with current use of azithromycin (defined as a five-day course) compared wit

no use of antibiotics (rate ratio [RR] 2.85, 95% CI 1.13-7.24). However, in a propensity adjusted analysis, currenazithromycin use was not associated with an increased risk of death from cardiovascular causes compared with

penicillin V (RR 0.93, 95% CI 0.56-1.55). These results suggest that the increased risk of cardiovascular death

observed in patients receiving azithromycin compared with no antibiotic use was attributable to underlying patien

factors that led to the prescription of antibiotics.

Because there were few events, there was limited power to examine the risk of cardiovascular death in

subgroups, including the subgroup of patients with known cardiovascular disease (RR 1.35, 95% CI 0.69-2.64)

[43]. Of note, the population in this study was healthier than the Medicaid population evaluated in the database

analysis described above [42,44]. The cardiovascular mortality rate in the Medicaid population was 85.2 deaths
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per million courses of azithromycin compared with 15.4 deaths per million courses in the Danish population. This

study suggests that azithromycin does not increase the risk of cardiovascular death in young and middle-aged

members of the general population, at least those without preexisting cardiovascular disease.

Clarithromycin Clarithromycin has also been associated with QT interval prolongation [45,46], and is

metabolized by CYP3A4. Torsades de pointes has primarily been described when clarithromycin is given with

other drugs that prolong the QT interval. A few case reports have described torsades de pointes with

clarithromycin alone [47].

Telithromycin Telithromycin can also prolong the QT interval. The product labeling specifies that telithromycin

should be avoided in patients with congenital long QT syndrome, ongoing proarrhythmic conditions, significant

bradycardia, and those taking class 1A or III antiarrhythmic agents (eg, quinidine, procainamide, dofetilide).

Other Severe reactions are rare but possible with all three macrolides. These include anaphylaxis, Stevens-Johnson

syndrome, and pseudomembranous colitis [24,32]. A severe reaction to azithromycin may persist for several days due

its long half-life. Irreversible hearing loss has been reported with azithromycin, clarithromycin, and erythromycin [48,49]

Reversible hearing loss has also been reported following macrolide use, especially when they have been given at high

doses [50-53]. Interstitial nephritis has been reported with erythromycin [54].

In addition, several other rare side effects have occurred with telithromycin, including fatal hepatotoxicity, fatal

exacerbation of myasthenia gravis, loss of consciousness, and acute interstitial nephritis [33,55-58]. Visual disturbance

(eg, blurry vision, diplopia, difficulty focusing) can also occur and may be related to telithromycin's effects on nicotinic

acid receptors [59]. Telithromycin is contraindicated in patients with myasthenia gravis. (See 'Warnings about

telithromycin' above.)

DRUG INTERACTIONS The macrolides have a variety of drug interactions, many of which are mediated by inhibitio

of hepatic cytochrome CYP (P450) 3A enzymes [60]. In contrast to the other macrolides, azithromycin does not appear

to affect hepatic enzymes significantly, leading to fewer documented drug interactions. However, several clinically-

important drug interactions have been reported with all of these agents. For example, fatalities have been reported in

patients receiving clarithromycin and colchicine and there are now specific colchicine dose reduction recommendations

published [61,62]. Detail about specific interactions is available by using the Lexi-Interact program included with

UpToDate.

Specific interactions between any two medications may be determined using the drug interaction tool (Lexi-Interact

Online). This tool can be accessed from the UpToDate online search page or through the individual drug information

topics, section on Drug interactions.

SUMMARY

Azithromycin (Zithromax) and clarithromycin (Biaxin) are macrolide antibiotics that are used in the treatment of

community-acquired respiratory tract infections. They are derivatives of the older macrolide antibiotic,

erythromycin. Telithromycin (Ketek) is the first member of the ketolide class of antimicrobials, which is related to

the macrolide class. Concerns about postmarketing reports of hepatotoxicity and exacerbations of myastheniagravis have led to significant restrictions on the use of telithromycin. (See 'Introduction' above and 'Warnings

about telithromycin' above.)

The mechanism of action of the newer macrolides is similar to that oferythromycin. They bind to the 50S subuni

of bacterial ribosomes, leading to inhibition of transpeptidation, translocation, chain elongation and, ultimately,

bacterial protein synthesis. (See 'Mechanism of action and chemical structure' above.)

Structural changes have made the newer macrolides more acid-stable than erythromycin, providing improved or

absorption, tolerance, and pharmacokinetic properties. The newer macrolides also have a broader spectrum of

antibacterial activity than erythromycin. (See 'Mechanism of action and chemical structure' above and 'Dosing an
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administration' above.)

Two main mechanisms of acquired macrolide resistance have been described:

Methylases encoded by the erm (erythromycin ribosome methylase) genes (ermA, ermB, ermC) alter the

macrolide binding site on the bacterial ribosomal RNA, usually conferring a high degree of macrolide

resistance as well as resistance to clindamycin.

Active macrolide efflux pumps, encoded by the mef (macrolide efflux) msrA and msrB genes, confer a low to

moderate degree of macrolide resistance These mechanisms are responsible forerythromycin-resistance in

most gram-positive cocci (eg, Staphylococcus aureus, Streptococcus pneumoniae, Staphylococcus aureus,

other streptococci). In contrast to the mechanisms of acquired resistance, intrinsic resistance exhibited by

Enterobacteriaceae, Pseudomonas spp, and Acinetobacter spp is due to decreased permeability of the oute

cell envelope. (See 'Resistance' above.)

Azithromycin and clarithromycin have a broader spectrum of activity than erythromycin, and include activity

against respiratory tract pathogens such as Streptococcus pneumoniae, Haemophilus spp, Moraxella catarrhalis

and atypical pneumonia pathogens, as well as against various other gram-negative bacteria and Mycobacterium

avium complex. (See 'Spectrum of activity' above.)

Because of its more frequent gastrointestinal side effects and the earlier appreciation of the risk of QT

prolongation and sudden death, erythromycin is rarely recommended. However, subsequent reports and studies

have also described QT prolongation with clarithromycin, azithromycin, as well as the ketolide, telithromycin.

Postmarketing reports have also identified various hepatic abnormalities in patients receiving azithromycin,

including cases that have resulted in death. (See 'Adverse reactions' above.)

The macrolides have a variety of drug interactions, many of which are mediated by inhibition of hepatic

cytochrome CYP (P450) 3A enzymes. In contrast to the other macrolides, azithromycin does not appear to affec

hepatic enzymes significantly, leading to fewer documented drug interactions. (See 'Drug interactions' above.)

Use of UpToDate is subject to the Subscription and License Agreement.

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Topic 474 Version 13.0
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GRAPHICS

Drug ratings in pregnancy (US Food & Drug Administration)

Category Interpretation

A Controlled human studies show no risk

Controlled studies in pregnant women fail to demonstrate a risk to the fetus in the

first trimester with no evidence of risk in later trimesters. The possibility of fetal

harm appears remote.

B No evidence of risk in studies

Either animal-reproduction studies have not demonstrated a fetal risk but there are

no controlled studies in pregnant women, or animal-reproduction studies have

shown an adverse effect (other than a decrease in fertility) that was not confirmed

in controlled studies in women in the first trimester and there is no evidence of a

risk in later trimesters.

C Risk cannot be ruled out

Either studies in animals have revealed adverse effects on the fetus (teratogenic or

embryocidal effects or other) and there are no controlled studies in women, or

studies in women and animals are not available. Drugs should be given only if the

potential benefits justify the potential risk to the fetus.

D Positive evidence of risk

There is positive evidence of human fetal risk, but the benefits from use in pregnant

women may be acceptable despite the risk (eg, if the drug is needed in a life-

threatening situation or for a serious disease for which safer drugs cannot be used

or are ineffective).

X Contraindicated in pregnancy

Studies in animals or human beings have demonstrated fetal abnormalities or there

is evidence of fetal risk based on human experience, or both, and the risk of the use

of the drug in pregnant women clearly outweighs any possible benefit. The drug is

contraindicated in women who are or may become pregnant.

Reproduced with permission from: Lexicomp Online. Copyright 1978-2013 Lexicomp, Inc. All Rights

Reserved.


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Some reported causes and potentiators of the long QT syndrome*

Congenital

Jervell and Lange-Nielsen syndrome (including

"channelopathies")

Romano-Ward syndrome

Idiopathic

Acquired

Metabolic disorders

Hypokalemia

Hypomagnesemia

Hypocalcemia

Starvation

Anorexia nervosa

Liquid protein diets

Hypothyroidism

Bradyarrhythmias

Sinus node dysfunction

AV block - second or third degree

Antiarrhythmic drugs

Quinidine

Procainamide or N-acetylprocainamide

Disopyramide

Amiodarone and dronedarone

Sotalol

Dofetilide, ibutilide, azimilide, sematilide

Antimicrobial drugs

Erythromycin, clarithromycin, telithromycin,azithromycin

Pentamidine

Some azole antifungals - voriconazole,

posaconazole

Some fluoroquinolones (eg, sparfloxacin,

gatifloxacin, levofloxacin, moxifloxacin)

Other - spiramycin, chloroquine, halofantrine

mefloquine

Acquired (continued)

Antihistamines

Terfenadine

Astemizole

Psychotropic drugs

Thioridazine

Phenothiazines

Tricyclic or tetracyclic antidepressants

Haloperidol and other butyrophenones

Antineoplastic agents

Crizotinib, dasatinib, eribulin, nilotinib,

romidepsin, sorafenib, sunitinib, vandetanib,

vemurafenib, vorinostat

Other drugs

Selective serotonin reuptake inhibitors

Risperidone

Opioids (methadone, oxycodone)

Vasodilators - prenylamine, bepridil,

mibefradil

Diuretics - via electrolyte changes (esp.hypokalemia or hypomagnesemia)

5HT3-antagonists - ondansetron, granisetron,

and dolasetron

Motility drugs - cisapride, domperidone

Droperidol - may be safe at the low doses

used by anesthesiologists (0.625 to 1.25 mg)

Ranolazine

HIV protease inhibitors

Miscellaneous - organophosphate insecticides,

probucol, cocaine, terodiline, papaverine,

certain Chinese herbs, chloral hydrate, arsenic

trioxide, cesium chloride, levomethadyl

Other factors

Myocardial ischemia or infarction, esp. with

prominent T wave inversions

Intracranial disease


15/15


HIV infection

Hypothermia

Connective tissue diseases with anti-Ro/SSA

antibodies

* The long and growing list of medications and other factors capable of prolonging the QT(U) represents

an evolving area of clinical research. In some cases of long QT-U two or more factors may be involved.

Additional clinical information is provided at the Arizona Center for Education and Research on

Therapeutics (CERT) website: http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm.
http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm

azithromycin, clarithromycin, and telithromycin

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