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Telithromycin: A Ketolide Antibiotic for Treatment of Respiratory Tract Infections

  1. John R. Lonks1 and
  2. Donald A. Goldmann2,,3
  1. 1 Division of Infectious Diseases, Brown Medical School and Miriam Hospital, Providence, Rhode Island
  2. 2 Department of Medicine, Children's Hospital Boston, Boston
  3. 3 Institute for Healthcare Improvement, Cambridge, Massachusetts
 
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Abstract

Telithromycin, a recently approved ketolide antibiotic derived from 14-membered macrolides, is active against erythromycin-resistant pneumococci. Telithromycin has enhanced activity in vitro because it binds not only to domain V of ribosomal RNA (like macrolides do) but also to domain II. However, it is not active against streptococci and staphylococci with constitutive macrolide, lincosamide, and streptogramin B resistance. Telithromycin, available in an oral formulation, is approved by the US Food and Drug Administration for use in adults for treatment of (1) community-acquired pneumonia due to Streptococcus pneumoniae (including multidrug-resistant isolates), Haemophilus influenzae, Moraxella catarrhalis, Chlamydia pneumoniae, or Mycoplasma pneumoniae; (2) acute exacerbation of chronic bronchitis due to S. pneumoniae, H. influenzae, or M. catarrhalis; or (3) acute bacterial sinusitis due to S. pneumoniae, H. influenzae, M. catarrhalis, or methicillin- and erythromycin-susceptible Streptococcus aureus. It is not approved for treatment of tonsillitis, pharyngitis, or severe pneumococcal pneumonia. Unique visual adverse effects occurred in 0.27%–2.1% of patients receiving telithromycin therapy. Its enhanced activity against some common respiratory pathogens makes it a valuable addition to the available macrolides.

Pneumonia, acute exacerbation of chronic bronchitis (AECB), and acute bacterial sinusitis are common in outpatients. Although most patients with pneumonia receive treatment as outpatients, pneumonia is the fourth most common reason for hospitalization. Streptococcus pneumoniae is the most common cause of community-acquired pneumonia (CAP) and acute bacterial sinusitis and is a frequent cause of AECB.

Traditionally, erythromycin has been used to treat pneumococcal respiratory tract infections in patients allergic to penicillin. During the 1970s and 1980s, there was an increased awareness of the importance of “atypical” pathogens in CAP, such as Legionella species, Mycoplasma pneumoniae, and Chlamydia pneumoniae, all of which are susceptible to erythromycin. Accordingly, erythromycin was viewed as a convenient antibiotic for the empiric treatment of CAP. Clarithromycin and azithromycin have largely replaced erythromycin in clinical practice because they have fewer gastrointestinal adverse effects. Azithromycin also has improved activity against Haemophilus influenzae—an especially common pathogen in AECB and acute sinusitis. Predictably, as macrolide use increased, so did the prevalence of macrolide-resistant pneumococci. In some regions of the United States, at least 1 of 3 pneumococci isolates are erythromycin resistant [1]. Not surprisingly, infection with erythromycin resistant pneumococci is highly associated with treatment failure [2], and the clinical usefulness of these macrolides is diminishing.

In the United States, the most common mechanism of erythromycin resistance in pneumococci is efflux; the second most common is methylation of the antibiotic-binding site. Isolates with the efflux mechanism remain susceptible to clindamycin, whereas those with the methylation mechanism are clindamycin resistant. Clindamycin is not active against Legionella species, C. pneumoniae, or M. pneumoniae, which limits its use as the sole agent for empiric treatment of CAP. The newer fluoroquinolones, such as gatifloxacin and moxifloxacin, are appealing alternatives because of their increased activity against pneumococci, and they are active against “atypical” respiratory pathogens. However, there is clearly a potential for the emergence of quinolone-resistant pneumococci. Moreover, treatment failures with levofloxacin have occurred [3]. Fluoroquinolone resistance also appears to be emerging among H. influenzae strains [4–6]. New therapeutic alternatives are needed.

Telithromycin (Ketek; Sanofi-Aventis), an oral ketolide, was recently approved by the US Food and Drug Administration (FDA) for the treatment of (1) mild-to-moderately-severe CAP (but not pneumonia with bacteremia) due to S. pneumoniae (including multidrug-resistant S. pneumoniae isolates [MDRSP]), H. influenzae, Moraxella catarrhalis, C. pneumoniae, or M. pneumoniae; (2) AECB due to S. pneumoniae, H. influenzae, or M. catarrhalis; and (3) acute bacterial sinusitis due to S. pneumoniae, H. influenzae, M. catarrhalis, or Staphylococcus aureus (methicillin- and erythromycin-susceptible S. aureus isolates only). It is approved for use for individuals aged ⩾18 years.

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Structure and Activity of Macrolides and Ketolides

Erythromycin, a macrolide antibiotic, contains a 14-membered lactone ring with cladinose at position 3 (figure 1). When given orally, erythromycin is incompletely but adequately absorbed from the gastrointestinal tract. In an aqueous environment at a low pH, such as in the stomach, erythromycin slowly undergoes internal rearrangements. The products of these spontaneous rearrangements have no antimicrobial activity. Specific chemical modifications of the hydroxyl at position 6 or the macrolide ring produce derivatives such as clarithromycin and azithromycin, with increased acid stability and bioavailability. Ketolides are semisynthetic derivatives of 14-membered macrolides in which the cladinose at position 3 is replaced with a keto group. In addition, telithromycin, a ketolide, has an 11,12 carbamate bridge to which an alkyl-aryl extension is attached (figure 1). Because of these modifications, telithromycin is active against certain erythromycin-resistant gram-positive organisms, such as S. pneumoniae, and has increased bioavailability.

Figure 1
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Figure 1

A, Structures of erythromycin A (R, H) and its semisynthetic derivative, clarithromycin (R, CH3). B, Structure of telithromycin, which contains an 11,12 carbamate bridge, to which an alkyl-aryl extension is attached, and a keto group at position 3 of the macrolide ring. Reproduced with permission from [7].

Macrolides and ketolides inhibit protein synthesis by the same mode of action. They bind within the exit tunnel of the large ribosomal subunit, thus blocking the exit of nascent polypeptides. The large ribosomal subunit consists of 2 pieces of rRNA (23S and 5S) and 31 ribosomal proteins. Macrolides and ketolides bind to specific residues of 23S rRNA—namely, the adenine at positions 2058 (A2058) and 2059 (A2059). These specific adenine residues are on domain V of 23S rRNA. In addition, telithromycin binds, via the 11,12 carbamate bridge containing the alkyl-aryl extension, to a specific adenine (A752) on domain II of the 23S rRNA, a region near domain V in the 3-dimensional structure of the ribosome (figure 2). In susceptible organisms, telithromycin binds 10-fold more tightly to ribosomes than erythromycin does, because of the binding to domain II [8].

Figure 2
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Figure 2

Strutures involved in the binding of telithromycin to bacterial rRNA domains II and V. A, Schematic representation of the bacterial 23S rRNA secondary structure. B, Enlargement of part of domain II. C, Enlargement of the central loop of domain V. The circled nucleotides A752, A2058, A2059, and G2505 (Escherichia coli numbering system) constitute the binding site for ketolide and macrolide antibiotics. D, Tertiary structure of the rRNA revealed by the crystallographic data on the Haloarcula 50S ribosomal subunit. The numbered nucleotides fold into close proximity, to line the peptide exit channel. This structure is also believed to reflect the conformation of the drug site in the ribosomes of E. coli and other pathogens. The scale bar is in the plane of the figure. A752 is out of the plane of the figure and is slightly more than 15 Å from A2058. The biochemical data indicate that telithromycin spans the distance from A2058 across the peptide exit channel to make contact with A752. The absence of the C11-C12 extension in erythromycin and clarithromycin prevents them from making this contact. Reproduced with permission from [7].

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Mechanisms of Resistance to Macrolides

The 2 main mechanisms of macrolide resistance are ribosomal modification by methylation, and efflux. Some strains of streptococci, including pneumococci, and staphylococci contain an enzyme that methylates a specific adenine residue (A2058). Bacteria with methylated A2058 do not bind macrolides and are resistant to these agents. Methylation of A2058 causes cross-resistance to clindamycin, a lincosamide, and to streptogramin type B antibiotics (e.g., quinupristin), thus producing the macrolide, lincosamide, and streptogramin B (MLSB) resistance phenotype. The methylase is encoded by the erythromycin-resistance methylase genes (erm genes), many of which have been described. The erm genes are expressed either constitutively or by induction. When expressed constitutively, the bacteria test positive for MLSB resistance. When expressed by induction, the isolates test positive for resistance to macrolides but not lincosamides or streptogramins. Inducible MLSB resistance is demonstrated by using a disk approximation test. An erythromycin disk is placed ∼15 mm from a clindamycin disk on the culture medium. If, after incubation, the clindamycin zone adjacent to the erythromycin disk is flattened (the so-called D zone) because of induction of clindamycin resistance by erythromycin, then the organism has inducible MLSB resistance. The erm gene in pneumococci is usually expressed constitutively.

Efflux is the other common mechanism of macrolide resistance in pneumococci. Strains with this resistance mechanism contain the macrolide efflux pump, which uses energy to remove macrolides from the interior of the bacteria. Hence, the macrolide can not reach its intracellular target, the ribosome. The efflux pump is encoded by the macrolide efflux gene (mef).

Rarer mechanisms of macrolide resistance include mutations that affect 23S rRNA or ribosomal proteins. For example, some clinical strains contain point mutations of A2059 [9]. These strains are resistant because macrolides do not bind to their ribosomes. Certain mutations or amino acid insertions affecting ribosomal proteins L4 and L22, located near the macrolide-binding site of the ribosome, can produce macrolide resistance [9, 10].

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Mechanism of Action of Ketolides Against Macrolide-Resistant Bacteria

The telithromycin-binding site overlaps the macrolide-binding site of domain V of 23S rRNA. In addition, telithromycin binds to domain II of 23S rRNA. Hence, because of its binding to domain II, telithromycin is active against pneumococci with MLSB resistance due to the methylase mechanism. Furthermore, ketolides are active against pneumococci that have a macrolide efflux pump. Hence, telithromycin is active against macrolide-resistant pneumococci that contain either the methylase or the efflux mechanism of resistance. In general, S. aureus and Streptococcus pyogenes strains with inducible MLSB resistance are susceptible to telithromycin, whereas strains with constitutive expression of MLSB resistance are telithromycin resistant. An in vitro model with Escherichia coli ribosomes showed that although ketolides bind to ribosomes that are monomethylated, they do not bind to ribosomes that are dimethylated [11]. Hence, different methylases, different levels of expression, and different degrees of methylation may produce isolates that are telithromycin resistant.

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In Vitro Activity

Pneumococci are categorized as susceptible to telithromycin if the MIC is ⩽1 µg/mL, intermediately resistant (hereafter, “intermediate”) if the MIC is 2 µg/mL, and resistant if the MIC is ⩾4 µg/mL (table 1). A study of 13,874 pneumococcal isolates showed that 99.85% were susceptible, 0.08% were intermediate, and 0.07% were resistant. Most (71%) of the isolates had an MIC of 0.008 µg/mL or 0.015 µg/mL [12]. For erythromycin-susceptible pneumococci, the MIC of telithromycin is ∼10-fold lower than the MIC of erythromycin. However, telithromycin is 4- to 8-fold less active against erythromycin-resistant isolates; the MIC50 and MIC90 values for erythromycin-susceptible pneumococci are 0.016 and 0.03, and for erythromycin-resistant pneumococci they are 0.06 and 0.25 [13]. Although erythromycin-resistant pneumococci have higher MICs of telithromycin, ∼99.6% remain classified as telithromycin susceptible (MIC, ⩽1 µg/mL) [12]. When pneumococci with characterized mechanisms of resistance were tested, the telithromycin MIC90 was 0.06 µg/mL (range, ⩽0.02 to 1) for isolates with an erm gene and 0.06 µg/mL (range, ⩽0.02 to 1) for isolates with the mef gene, compared with an MIC90 of 0.008 µg/mL (range, ⩽0.002 to 0.008) for susceptible isolates [14]. Erythromycin-resistant pneumococci with a variety of single L4 ribosomal protein mutations or point mutations involving the adenine at position 2058 (A2058G) or 2059 (A2059G) are susceptible to telithromycin [15, 16].

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Table 1

Interpretive criteria for testing susceptibility to telithromycin.

The mechanism of telithromycin resistance is known for 2 pneumococcal isolates. One clinical isolate (MIC, 16 µg/mL) contained both an amino acid insert in ribosomal protein L22 and a point mutation at A2058; the other (MIC, 256 µg/mL) contained both an erm gene with a truncated leader peptide and a mutation involving the ribosomal protein L4 [17, 18].

Telithromycin is not always active against erythromycin-resistant gram-positive organisms other than pneumococci. For example, telithromycin is active against erythromycin-susceptible S. aureus (MIC90, 0.06 µg/mL; range, 0.008–0.5 µg/mL) but is inactive against S. aureus with constitutive MLSB resistance (MIC for most isolates, >32 µg/mL). The MICs of telithromycin for S. aureus isolates with inducible MLSB resistance are 4- to 8-fold higher than those for erythromycin-susceptible isolates (MIC90, 0.5 µg/mL; range 0.03–0.5 µg/mL). Similarly, telithromycin is active against erythromycin-susceptible isolates of S. pyogenes, whereas it is less active against isolates with inducible MLSB resistance and markedly less active against isolates with constitutive MLSB resistance [15]. One reason in vitro activity against S. pyogenes and S. aureus strains with consitutive expression of ribosomal methylase differs from the activity against strains with inducible expression is that telithromycin does not induce the erm gene [19].

Telithromycin is active against H. influenzae (MIC range, ⩽0.12 to ⩾32 µg/mL; MIC50, 2 µg/mL; MIC90, 4 µg/mL) and M. catarrhalis (MIC range, ⩽0.06 to 2 µg/mL; MIC50, 0.06 µg/mL; MIC90, 0.12 µg/mL) [20, 21]. H. influenzae is categorized as susceptible when the MIC of telithromycin is ⩽4 µg/mL, intermediate when the MIC is 8 µg/mL, and resistant when the MIC is ⩾16 µg/mL (table 1). The in vitro activity of telithromycin against H. influenzae is about the same as that of azithromycin, and both of these agents are 4-fold more active than clarithromycin.

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Pharmacokinetics and Pharmacodynamics

The oral dose of telithromycin is 800 mg, given as two 400-mg tablets, once a day. For patients with severe renal impairment (creatinine clearance, <30 mL/min), including those receiving hemodialysis, the dose is 600 mg, given as two 300-mg tablets, once a day. For patients receiving hemodialysis, telithromycin should be given after dialysis on the days that dialysis is performed. The bioavailability is ∼57% and is unaffected by food. The peak serum concentration occurs at ∼1 h, averaging ∼2 µg/mL. Approximately 60%–70% of the drug is protein bound. The terminal half-life, after multiple doses, is ∼10 h, which permits once-a-day dosing. Approximately 70% of a dose is metabolized. About half of the metabolism is done by the cytochrome P450 3A4 system, and the other half is done by cytochrome P450—independent mechanisms. Of the systemically available drug, 7% is excreted in the feces, 13% is excreted in the urine, and 37% is metabolized by the liver. There is an increase in renal elimination in patients with hepatic insufficiency; hence, no dosage adjustment is recommended for these patients. However, for patients with hepatic impairment and severe renal impairment (creatinine clearance, <30 mL/min), the dosage should be reduced to 400 mg once a day. There is an increase in the area under the concentration-time curve (AUC) in patients aged ⩾65 years, but no dosage adjustment is recommended on the basis of age alone. The availability of multiple routes of elimination mitigates the impact of isolated renal or hepatic insufficiency on drug accumulation. Telithromycin is concentrated in WBCs, reaching a peak intracellular concentration of 72.1 µg/mL. High intracellular concentrations may help treat intracellular pathogens.

Telithromycin is bactericidal against S. pneumoniae, H. influenzae, and M. catarrhalis and bacteriostatic against S. pyogenes and S. aureus [22]. The major determinant of in vivo efficacy is probably the 24-h AUC-to-MIC ratio.

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Drug-Drug Interactions

Telithromycin is a strong inhibitor of the cytochrome P450 3A4 system. Hence, levels of several drugs are increased by its use (table 2). It is contraindicated to give telithromycin to individuals receiving pimozide or cisapride. If telithromycin is prescribed, then simvastatin, lovastatin, and atorvastatin should be stopped during the course of treatment. Coadministration of telithromycin and theophylline may worsen gastrointestinal adverse effects (e.g., nausea and vomiting). If it is necessary to give both drugs, then they should be administered 1 h apart. Telithromycin decreases levels of sotalol by decreasing its absorption. Itraconazole and ketoconazole increase the blood level of telithromycin, and rifampin decreases it. Concomitant use of telithromycin and rifampin should be avoided. There is no interaction between telithromycin and warfarin, oral contraceptives, ranitidine, or antacids. However, postmarketing reports suggest that telithromycin may potentiate the effect of oral anticoagulants.

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Table 2

Drug-drug interactions with telithromycin.

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Adverse Events

The incidence of adverse events due to telithromycin appears to be similar to that for comparators (amoxicillin, amoxicillin-clavulanate, cefuroxime axetil, clarithromycin, and trovafloxacin) used in phase III clinical studies. These adverse events include (given as percentage incidence with telithromycin/percentage incidence with comparator): diarrhea (10.8%/8.6%), nausea (7.9%/4.6%), headache (5.5%/5.8%), dizziness (3.7%/2.7%), vomiting (2.9%/2.2%), loose stools (2.3%/1.5%), and dysgeusia (1.6%/3.6%). Less common events (incidence, <2% but>0.2%) categorized as possibly drug related include abnormal liver function, such as increased transaminase levels, which are usually asymptomatic and reversible. Hepatitis with or without jaundice occurs in 0.07% of patients who receive telithromycin and is reversible.

Telithromycin has unique visual adverse effects. Visual adverse effects, including reversible blurred vision, diplopia, or difficulty focusing, occurred in 1.1% of individuals receiving telithromycin and 0.28% of those receiving a comparator antibiotic (table 3). The highest incidence occurred among women aged ⩽40 years. Among men aged >40 years, the rate of visual adverse events for those receiving telithromycin was similar to that for those receiving a comparator. Visual adverse events were most often mild to moderate in severity. However, severe adverse events have been reported. The majority (65%) of adverse visual events occurred after the first or second dose and usually lasted several hours. Some patients had a resolution of visual adverse events while receiving treatment, whereas others continued to have symptoms throughout the course of treatment. Patients should be cautioned about these visual adverse effects and the potential impact on their ability to drive a vehicle, operate machinery, or engage in other activities that would be potentially dangerous.

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Table 3

Associations between the age and sex of patients and the visual adverse effects that occurred during phase III studies of telithromycin and comparator antibiotics.

Telithromycin has a modest effect on the corrected QT interval (QTc). In therapeutic doses, it is associated with a mean QTc increase of 1.5–3.8 ms. No cardiovascular morbidity or mortality due to QTc prolongation occurred among 4780 patients in clinical trials who were receiving telithromycin, including 204 patients with a prolonged QTc at baseline. An FDA review of postmarketing data from outside the United States did not find any unusual cardiac safety issues. Like other macrolides, telithromycin can cause exacerbation of myasthenia gravis.

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Clinical Efficacy Studies

CAP

Four randomized, double-blind studies and 4 open-label studies of patients with mild-to-moderate CAP that compared the efficacy of telithromycin (800 mg once a day for 7–10 days) to that of other antibiotics (clarithromycin, 500 mg twice a day for 10 days; trovafloxacin, 200 mg once a day for 7–10 days; and amoxicillin, 1000 mg 3 times a day for 10 days) were submitted to the FDA. Patients were excluded if they had severe pneumonia, which was diagnosed if there was an admission to the intensive care unit, a need for parenteral administration of antibiotics, a respiratory rate of >30 breaths/min, hypotension, an altered mental status, an oxygen saturation rate of <90% by pulse oximetry, or a peripheral WBC count of <4000 cells/mm3. The clinical cure rate for telithromycin ranged from 88.3% to 94.6%, whereas that for the comparators ranged from 88.5% to 94.2%. These studies showed that telithromycin was not inferior to the comparator antimicrobial agents. By pathogen, the clinical cure rates (given as percentage cure rate with telithromycin/percentage cure rate with comparator) were 93.6%/90.0% for S. pneumoniae, 83.0%/95.5% for H. influenzae, 85.7%/77.8% for M. catarrhalis, 92.0%/94.7% for C. pneumoniae, and 95.7%/90.9% for M. pneumoniae. Blood cultures were performed for all patients with mild-to-moderate pneumonia. The clinical cure rate for telithromycin was 88% among the 76 patients with pneumococcal bacteremia and 91.7% among the 36 patients with MDRSP infection. MDRSP isolates are penicillin-resistant pneumococci that are also resistant to at least 1 of the following agents: second-generation cephalosporins, macrolides, tetracyclines, or trimethoprim-sulfamethoxazole. The clinical cure rate for telithromycin among 28 patients infected with macrolide-resistant pneumococci was 89.3%. Of the 6 patients with erythromycin-resistant bacteremic pneumococcal pneumonia, 4 had their condition cured.

One of the 2 patients with bacteremia who experienced treatment failure was a 78-year-old woman whose bronchial aspirate sample yielded pneumococcus, H. influenzae, and M. catarrhalis. A blood culture for this patient grew an erythromycin-resistant pneumococcus (erythromycin MIC, >32 µg/mL, ermB; telithromycin MIC, 0.03 µg/mL). On a subsequent visit by the patient, the signs and symptoms of pneumonia had improved, a sputum sample grew Citrobacter freundii (considered colonization), and blood cultures were sterile. Then, fever and dyspnea recurred. S. aureus was isolated from a urine sample, and treatment with additional antibiotics was started. The outcome was classified as telithromycin treatment failure because of the use of additional antibiotics [23, 24]. The other patient who experienced telithromycin treatment failure was a 37-year-old woman with erythromycin-resistant pneumococcal bacteremia. The MICs of erythromycin and telithromycin were 4 µg/mL and 0.12 µg/mL, respectively. The isolate had the mef E gene. Culture of a blood sample obtained on day 3 of treatment grew pneumococcus with decreased susceptibility to telithromycin (MIC, 0.5 µg/mL). On day 5 of treatment, additional antibiotics were added to the regimen because the patient's symptoms had not improved adequately [23, 24]. More data on the clinical efficacy of telithromycin against erythromycin-resistant bacteremic pneumococcal pneumonia are needed.

Acute bacterial sinusitis

Two randomized double-blind comparative studies of patients with acute bacterial sinusitis showed that telithromycin at a dosage of 800 mg once a day for 5 days had clinical cure rates similar to those of amoxicillin-clavulanate at a dosage of 500 mg of amoxicillin and 125 mg of clavulanate 3 times a day for 10 days (telithromycin/comparator, 75.3%/74.5%) and cefuroxime axetil at a dosage of 250 mg twice a day for 10 days (85.2%/82.0%). These studies showed that telithromycin was not inferior to the comparator antimicrobial agents. A separate study that compared a 5-day with a 10-day course of telithromycin therapy showed clinical cure rates of 91.1% and 91.0%, respectively. Analyzed by specific pathogen, the clinical cure rates were similar for S. pneumoniae (87.1%/87.5%), H. influenzae (82.4%/86.7%), and M. catarrhalis (100%/100%).

AECB due to bacteria

Data from 3 randomized, double-blind clinical trials showed that clinical cure rates for telithromycin (800 mg once a day for 5 days) were similar to those for cefuroxime axetil (500 mg twice a day for 10 days) (telithromycin/comparator, 86.4%/83.1%), amoxicillin-clavulanate (500 mg of amoxicillin and 125 mg of clavulanate 3 times a day for 10 days) (86.1%/82.1%), and clarithromycin (500 mg twice a day for 10 days) (85.8%/89.2%). These studies showed that telithromycin was not inferior to the comparator antimicrobial agents. Analyzed by specific pathogen, the clinical cure rate (telithromycin/comparator) was similar for S. pneumoniae (81.5%/78.9%), H. influenzae (73.3%/84.9%), and M. catarrhalis (93.1%/85.3%).

Tonsillitis and/or pharyngitis

Telithromycin is not approved by the FDA for this indication. Two studies on the efficacy of telithromycin for treatment of tonsillitis and/or pharyngitis due to group A streptococci were submitted to the FDA. In one study, telithromycin did not show equivalence to penicillin, and in the other study, the cure rate was <85% in the modified intention-to-treat analysis [22]. The reduced efficacy of telithromycin is attributable to the failure of telithromycin to eradicate erythromycin-resistant group A streptococci; the eradication rate for erythromycin-resistant group A streptococci was 1 (16.7%) of 6 cases for telithromycin, compared with 8 (88.9%) of 9 cases for penicillin.

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Emergence of Resistance

Isolates of S. pneumoniae resistant to telithromycin have been created in vitro by sequential subcultures in subinhibitory concentrations of telithromycin [25]. More importantly, there are clinical isolates resistant to telithromycin (MIC, ⩾4 µg/mL), although they are rare. An international surveillance study showed that 10 of 13,874 pneumococci isolates were telithromycin resistant [12]. Of these 10 isolates, 7 had an MIC of 4 µg/mL, and 3 had an MIC of 8 µg/mL. The telithromycin-resistant isolates were from France (4 isolates), Italy (2), Japan (2), Spain (1), and Hungary (1). A study of pneumococci from the United States showed that 4 (0.04%) of 10,103 isolates were telithromycin resistant [20]. Studies with adults have not included susceptibility testing of nasopharyngeal isolates to look for the development of telithromycin resistance during treatment.

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Conclusions

Telithromycin, a ketolide, differs chemically from the classic macrolide antibiotics. It is more active in vitro against macrolide-susceptible organisms than erythromycin is. It is active against erythromycin-resistant pneumococci. However, telithromycin is inactive against many erythromycin-resistant S. aureus and S. pyogenes strains. The in vitro activity of telithromycin against H. influenzae is similar to that of azithromycin. However, the clinical efficacy of macrolides to treat infections due to H. influenzae is controversial [26, 27].

Clinical studies support the use of telithromycin for treatment of mild-to-moderate CAP (but not pneumonia with bacteremia), AECB, and acute bacterial sinusitis. More clinical data supporting its use for treatment of serious infections due to erythromycin-resistant pneumococci are needed. Telithromycin is FDA approved for the treatment of CAP due to MDRSP. Other antimicrobial agents that are approved for the treatment of CAP due to MDRSP include gemifloxacin, gatifloxacin, and levofloxacin.

The adverse-events profile of telithromycin is similar to that of other commonly used oral antimicrobial agents. However, telithromycin has unique visual adverse effects that occur most frequently in women and in people aged ⩽40 years. Drug-drug interactions with telithromycin, a strong inhibitor of the cytochrome P450 3A4 system, are similar to those that occur with clarithromycin and erythromycin.

There is no way to accurately predict the emergence of telithromycin resistance. Rare telithromycin-resistant pneumococci were found in the United States before telithromycin was available for use. Although the emergence of resistance was not noted in clinical trials, it would be surprising if widespread use of this agent were not accompanied by increasing resistance to it.

Clinicians now have an additional oral antibiotic treatment option for patients with mild-to-moderate CAP, AECB, and acute sinusitis. Like the newer quinolones, telithromycin has activity against the common bacterial pathogens that cause these diseases, as well as against C. pneumoniae and M. pneumoniae. We recommend the use of telithromycin for treatment of cases in which there is a high clinical suspicion of an atypical respiratory pathogen and the need to provide coverage against the pneumococcus.

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Acknowledgments

We graciously thank Dr. Antone A. Medeiros for critically reading this manuscript and for providing his astute insight.

Potential conflicts of interest. J.R.L. has received recent research funding from Bristol-Myers Squibb and Aventis and is a consultant for Aventis. D.A.G.: no conflicts.

  • Received December 16, 2004.
  • Accepted February 1, 2005.
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  1. Clin Infect Dis. (2005) 40 (11): 1657-1664. doi: 10.1086/430067
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