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KETOLIDE ANTIBIOTICS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ketolide antibiotics are semi-synthetic derivatives of the macrolide erythromycin A. The mechanism of action of ketolides is similar to that of macrolides, and is related to 50S-ribosomal subunit binding with inhibition of bacterial protein synthesis; however, the ketolides appear to have greater affinity for the ribosomal binding site than the macrolides. At the time of this review, telithromycin is the only drug in this class of antibiotics that has been FDA approved. A second drug, cethromycin, is currently in clinical trials.

Specific Substances

    A) TELITHROMYCIN
    1) HMR-3647
    2) RU-647
    3) RU-66647
    4) CAS 17838-31-8
    CETHROMYCIN
    1) ABT-773

    1.2.1) MOLECULAR FORMULA
    1) TELITHROMYCIN: C43H65N5O10

Available Forms Sources

    A) FORMS
    1) Telithromycin is available as 300 mg and 400 mg film-coated tablets (Prod Info KETEK(R) oral tablets, 2010).
    B) USES
    1) Telithromycin is used for the treatment of community-acquired pneumonia of mild to moderate severity due to Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila pneumoniae, or Mycoplasma pneumoniae (Prod Info KETEK(R) oral tablets, 2010).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Telithromycin is used for the treatment of community-acquired pneumonia of mild to moderate severity due to Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila pneumoniae, or Mycoplasma pneumoniae. At the time of this review, telithromycin is the only drug in this class of antibiotics that has been FDA approved. A second drug, cethromycin, is currently in clinical trials.
    B) PHARMACOLOGY: Telithromycin, a ketolide antibiotic, is structurally related to the macrolide antibiotics. It binds domains II and V of the 23S rRNA of the 50S ribosomal subunit, thereby blocking protein synthesis. It retains gram-positive activity in the presence of methylase-mediated domain V alteration by binding at domain II. In addition, telithromycin may prevent emerging ribosomal subunit assembly.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Diarrhea, nausea, vomiting, headache, and dizziness. OTHER EFFECTS: Taste disturbance, blurred vision, diplopia, and difficulty in focusing, abdominal pain, elevated liver enzymes, pseudomembranous colitis, pancreatitis, leukopenia, thrombocytosis, acute allergic reactions.
    2) QTc prolongation, torsades de pointes, and atrial dysrhythmias have rarely been reported.
    3) Severe hepatotoxicity resulting in death has also been infrequently reported. Reactions such as fulminant hepatitis, hepatic necrosis leading to liver transplant, acute hepatic failure, and some fatal cases of severe hepatic injury have occurred during or immediately after treatment. In some cases, progress of liver injury was rapid, occurring after treatment with a few telithromycin doses. Most cases of hepatic dysfunction occurring during clinical trials and in postmarketing reports were mild to moderate and generally reversible. Severe hepatic reactions have sometimes been associated with serious underlying diseases or concurrent medications.
    4) Exacerbation of myasthenia gravis has been reported with telithromycin therapy. Patients with myasthenia gravis experienced increased muscle weakness, dyspnea, and severe acute respiratory failure within a few hours after ingestion of the first dose of telithromycin.
    E) WITH POISONING/EXPOSURE
    1) Overdose data is limited. Doses up to 2400 mg have caused taste disturbance, blurred vision, headache, diarrhea, nausea, tinnitus, confusion, and transient increases in serum aminotransferase levels in healthy subjects.
    0.2.20) REPRODUCTIVE
    A) Telithromycin is classified as FDA pregnancy category C.

Laboratory Monitoring

    A) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    B) Monitor liver enzymes, particularly in patients with pre-existing hepatic disease.
    C) Obtain an ECG and institute continuous cardiac monitoring following a significant exposure. QT interval prolongation and torsades de pointes have been reported with therapy and may occur with overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Acute toxicity, other than gastrointestinal discomfort, is not common.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. QT prolongation and torsades de pointes have been reported with therapeutic doses and may occur following overdose. Treat torsades de pointes with IV magnesium sulfate and correct electrolyte abnormalities; overdrive pacing may be necessary.
    C) DECONTAMINATION
    1) PREHOSPITAL: Severe toxicity is not expected after an overdose; prehospital decontamination is generally NOT necessary.
    2) HOSPITAL: Severe toxicity is not expected after an overdose. Gastrointestinal decontamination is not routinely warranted. Consider activated charcoal after extremely large ingestions or those involving toxic co-ingestants.
    D) AIRWAY MANAGEMENT
    1) Intubate if patient is unable to protect their airway, or if unstable dysrhythmias or severe acute allergic reactions develop.
    E) ANTIDOTE
    1) None.
    F) TORSADES DE POINTES
    1) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium, and/or atrial overdrive pacing. Correct electrolyte abnormalities (hypomagnesemia, hypokalemia, hypocalcemia). MAGNESIUM SULFATE/DOSE: ADULTS: 2 g IV over 1 to 2 min, repeat 2 g bolus and begin infusion of 0.5 to 1 g/hr if dysrhythmias recur. CHILDREN: 25 to 50 mg/kg diluted to 10 mg/mL; infuse IV over 5 to 15 min. OVERDRIVE PACING: Begin at 130 to 150 beats/min, decrease as tolerated. Avoid class Ia (quinidine, disopyramide, procainamide), class Ic (flecainide, encainide, propafenone) and most class III antidysrhythmics (N-acetylprocainamide, sotalol).
    G) HYPERSENSITIVITY REACTION
    1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    H) ENHANCED ELIMINATION PROCEDURE
    1) The effectiveness of hemodialysis following ketolide antibiotic overdose is unknown. It is unlikely to be useful given the large volume of distribution of telithromycin (2.9 L/kg).
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: Patient with inadvertent ingestions who have minimal symptoms can be observed at home.
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions should be observed in a healthcare facility.
    3) ADMISSION CRITERIA: Patients demonstrating severe fluid and electrolyte imbalance, QTc prolongation or cardiovascular instability should be admitted.
    4) CONSULT CRITERIA: Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or for whom diagnosis is unclear.
    J) PITFALLS
    1) When managing a suspected overdose of telithromycin, the possibility of multidrug involvement should be considered.
    K) PHARMACOKINETICS
    1) Telithromycin is rapidly absorbed, following oral administration, with an absolute bioavailability of approximately 57%. Protein binding: approximately 60% to 70%. Vd: 2.9 L/kg. Approximately 70% of the dose is metabolized, primarily via the liver. Approximately 50% is mediated by cytochrome P450 3A4 enzymes and 50% is cytochrome P450-independent. Renal clearance: 13 L/hr in healthy young subjects following a single 800-mg oral dose. Elimination half-life: 10 to 13 hours.
    L) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause QT interval prolongation.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established; however, severe nausea was reported following an ingestion of 1600 mg of telithromycin. Doses up to 2400 mg telithromycin caused taste perversion, blurred vision, headache, nausea, diarrhea, tinnitus, confusion, somnolence, and transient increases in serum aminotransferases in healthy subjects.
    B) THERAPEUTIC DOSE: TELITHROMYCIN: ADULTS: 800 mg once daily for 7 to 10 days. CHILDREN: The safety and efficacy of telithromycin in pediatric patients have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Telithromycin is used for the treatment of community-acquired pneumonia of mild to moderate severity due to Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila pneumoniae, or Mycoplasma pneumoniae. At the time of this review, telithromycin is the only drug in this class of antibiotics that has been FDA approved. A second drug, cethromycin, is currently in clinical trials.
    B) PHARMACOLOGY: Telithromycin, a ketolide antibiotic, is structurally related to the macrolide antibiotics. It binds domains II and V of the 23S rRNA of the 50S ribosomal subunit, thereby blocking protein synthesis. It retains gram-positive activity in the presence of methylase-mediated domain V alteration by binding at domain II. In addition, telithromycin may prevent emerging ribosomal subunit assembly.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Diarrhea, nausea, vomiting, headache, and dizziness. OTHER EFFECTS: Taste disturbance, blurred vision, diplopia, and difficulty in focusing, abdominal pain, elevated liver enzymes, pseudomembranous colitis, pancreatitis, leukopenia, thrombocytosis, acute allergic reactions.
    2) QTc prolongation, torsades de pointes, and atrial dysrhythmias have rarely been reported.
    3) Severe hepatotoxicity resulting in death has also been infrequently reported. Reactions such as fulminant hepatitis, hepatic necrosis leading to liver transplant, acute hepatic failure, and some fatal cases of severe hepatic injury have occurred during or immediately after treatment. In some cases, progress of liver injury was rapid, occurring after treatment with a few telithromycin doses. Most cases of hepatic dysfunction occurring during clinical trials and in postmarketing reports were mild to moderate and generally reversible. Severe hepatic reactions have sometimes been associated with serious underlying diseases or concurrent medications.
    4) Exacerbation of myasthenia gravis has been reported with telithromycin therapy. Patients with myasthenia gravis experienced increased muscle weakness, dyspnea, and severe acute respiratory failure within a few hours after ingestion of the first dose of telithromycin.
    E) WITH POISONING/EXPOSURE
    1) Overdose data is limited. Doses up to 2400 mg have caused taste disturbance, blurred vision, headache, diarrhea, nausea, tinnitus, confusion, and transient increases in serum aminotransferase levels in healthy subjects.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Visual abnormalities, including blurred vision, diplopia, and difficulty in focusing, have been reported with telithromycin therapy. Although the visual effects may occur at any time during therapy, the majority of patients experienced the abnormalities following the first or second dose of telithromycin. The visual adverse effects appeared to last for several hours and have recurred with subsequent dosing of telithromycin (Prod Info KETEK(R) oral tablets, 2010; Zhanel et al, 2002). The peak incidence appeared to occur within 2 hours of dosing (Bearden et al, 2001).
    2) INCIDENCE: Visual abnormalities appeared to occur more frequently in female patients 40 years of age or younger (2.1%, n=682) as compared with female patients over 40 years of age (1%, n=703), male patients 40 years of age or younger (1.2%, n=563), and male patients over 40 years of age (1.1%, n=702) (Prod Info Ketek, 2004).
    B) WITH POISONING/EXPOSURE
    1) BLURRED VISION: Blurred vision has been reported in healthy subjects receiving doses up to 2400 mg of telithromycin (Hade MJ, 2004).
    3.4.4) EARS
    A) WITH POISONING/EXPOSURE
    1) TINNITUS: Tinnitus has been reported in healthy subjects receiving doses up to 2400 mg of telithromycin (Hade MJ, 2004).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) QTc interval prolongation (7 msec or less) has been infrequently reported following therapeutic administration of telithromycin (Quinn et al, 2003; Iannini, 2002; Shain & Amsden, 2002). The development of a prolonged QTc interval appears to be dose- and concentration-dependent, potentiated by the concomitant administration of cytochrome P450 3A4 enzyme inhibitors and decreased telithromycin clearance in elderly or those patients with hepatic impairment (Anonymous, 2002; Shain & Amsden, 2002; Bearden et al, 2001); however, no cardiovascular morbidity or mortality attributable to QTc prolongation occurred with telithromycin in 4780 patients in clinical trials, including 204 patients with prolonged QTc at baseline (Prod Info KETEK(R) oral tablets, 2010).
    B) TORSADES DE POINTES
    1) WITH THERAPEUTIC USE
    a) During postmarketing exposure, cases of torsades de pointes have been reported in patients using telithromycin (Prod Info KETEK(R) oral tablets, 2010).
    C) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) During postmarketing exposure, atrial dysrhythmias were reported in patients using telithromycin (Prod Info KETEK(R) oral tablets, 2010).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) TELITHROMYCIN: Headaches have been frequently reported with telithromycin therapy (Prod Info KETEK(R) oral tablets, 2010; Clark & Langston, 2003; Shain & Amsden, 2002; Hagberg et al, 2002).
    b) CETHROMYCIN: Seven of 12 healthy volunteers, involved in a cethromycin clinical trial, reported the development of mild headaches following administration of the drug (Pletz et al, 2003).
    2) WITH POISONING/EXPOSURE
    a) Headache has been reported in healthy subjects receiving doses up to 2400 mg of telithromycin (Hade MJ, 2004).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness may be a common occurrence with telithromycin therapy (Prod Info KETEK(R) oral tablets, 2010; Clark & Langston, 2003; Shain & Amsden, 2002; Hagberg et al, 2002; Balfour & Figgitt, 2001).
    b) INCIDENCE: Dizziness was reported in 5.3% of patients (n=244) and 5.1% of patients (n=254) after receiving 800 mg telithromycin once daily for 5 days and 800 mg telithromycin once daily for 10 days, respectively, during a randomized, double-blind, multicenter clinical efficacy trial (Luterman et al, 2003).
    C) CLOUDED CONSCIOUSNESS
    1) WITH POISONING/EXPOSURE
    a) Confusion has been reported in healthy subjects receiving doses up to 2400 mg of telithromycin (Hade MJ, 2004).
    D) DROWSY
    1) WITH POISONING/EXPOSURE
    a) Somnolence has have been reported in healthy subjects receiving doses up to 2400 mg of telithromycin (Hade MJ, 2004).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting, and diarrhea are common occurrences during telithromycin therapy (Prod Info KETEK(R) oral tablets, 2010; Dunbar et al, 2004; Carbon et al, 2003; Quinn et al, 2003; Clark & Langston, 2003) and are typically mild to moderate in severity (Zhanel et al, 2002; Shain & Amsden, 2002; Balfour & Figgitt, 2001).
    b) INCIDENCE: Following oral administration of once-daily (800 mg) doses of telithromycin for 5 (n=244) and 10 (n=254) days, nausea was reported in 11.9% and 9.4% of the patients, respectively, and diarrhea was reported in 19.3% and 20.5% of the patients, respectively (Luterman et al, 2003).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Severe nausea occurred in one patient, involved in a randomized clinical trial, who ingested a single 1600-mg dose of telithromycin (Hade MJ, 2004).
    b) Nausea and diarrhea have been reported in healthy subjects receiving doses up to 2400 mg of telithromycin (Hade MJ, 2004).
    B) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain has been infrequently reported following telithromycin therapy (Luterman et al, 2003; Hagberg et al, 2002).
    C) ANTIBIOTIC ENTEROCOLITIS
    1) WITH THERAPEUTIC USE
    a) Pseudomembranous colitis has been reported with telithromycin therapy (Prod Info KETEK(R) oral tablets, 2010; Luterman et al, 2003; Zhanel et al, 2002) and can range in severity from mild to life-threatening (Prod Info Ketek, 2004).
    D) ESOPHAGITIS
    1) WITH THERAPEUTIC USE
    a) A case report described pill esophagitis in a 43-year-old man following telithromycin treatment for acute sinusitis (Buyukberber et al, 2006).
    E) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) Pancreatitis has been observed during the postmarketing use of telithromycin (Prod Info KETEK(R) oral tablets, 2010).
    F) TASTE SENSE ALTERED
    1) WITH THERAPEUTIC USE
    a) TASTE PERVERSION: Taste perversion has been reported as a rare occurrence following telithromycin therapy (Dunbar et al, 2004; Perret et al, 2002).
    2) WITH POISONING/EXPOSURE
    a) TASTE DISTURBANCE: Taste disturbance has been reported in healthy subjects receiving doses up to 2400 mg of telithromycin (Hade MJ, 2004).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Elevated liver enzyme levels have been frequently reported following therapeutic administration of telithromycin and were typically asymptomatic and reversible (Prod Info KETEK(R) oral tablets, 2010; Dunbar et al, 2004; Carbon et al, 2003; Anonymous, 2002; Hagberg et al, 2002).
    b) CASE REPORT: One patient, involved in a telithromycin clinical efficacy trial, developed elevated liver enzyme levels (ALT, AST, and lactate dehydrogenase levels increased to 2.9-, 7.6-, and 2.5-fold the upper limit of normal, respectively) 3 days after completing telithromycin therapy, 800 mg once daily for 10 days. The enzyme levels returned to baseline within 2 weeks (Quinn et al, 2003).
    2) WITH POISONING/EXPOSURE
    a) Transient increases in serum aminotransferases have been reported in healthy subjects receiving doses up to 2400 mg of telithromycin (Hade MJ, 2004).
    B) TOXIC LIVER DISEASE
    1) WITH THERAPEUTIC USE
    a) Hepatotoxicity has been reported with telithromycin treatment. Reactions such as fulminant hepatitis, hepatic necrosis leading to liver transplant, acute hepatic failure, and some fatal cases of severe hepatic injury have occurred during or immediately after treatment. In some cases, progress of liver injury was rapid, occurring after treatment with a few telithromycin doses. Most cases of hepatic dysfunction occurring during clinical trials and in postmarketing reports were mild to moderate and generally reversible. Severe hepatic reactions have sometimes been associated with serious underlying diseases or concurrent medications (Prod Info KETEK(R) oral tablets, 2010).
    b) Severe hepatotoxicity was reported in three patients following telithromycin therapy (Clay, 2006).
    1) The first patient was a 46-year-old man who presented with a 4-day history of dark urine, jaundice, and malaise that began 2 days after starting telithromycin therapy for treatment of an ear and sinus infection. The patient reported fatigue and mild pruritus and laboratory data showed elevated liver enzyme levels. The patient recovered following withdrawal of telithromycin therapy.
    2) The second patient was a 51-year-old woman who became jaundiced after beginning a 5-day course of telithromycin. The patient also reported consuming 2 glasses of wine daily. Laboratory data showed elevated liver enzyme levels and a CT scan of the abdomen revealed a small liver with varices and splenomegaly. Over the next month, the patient's condition deteriorated with the development of severe fatigue and muscle weakness, with persistent jaundice, necessitating a liver transplantation. The histologic findings of the explanted liver appeared to be consistent with a diagnosis of hepatic necrosis.
    3) The third patient was a 26-year-old man who presented with an 8-day history of jaundice, fever, melena, and hematemesis. The symptoms began after completing a 5-day course of telithromycin. The patient's history included consumption of 8 12-ounce beers every 2 weeks. Laboratory data revealed elevated liver enzyme levels and a CT scan of the abdomen showed moderate ascites and bowel-wall thickening. The patient became hypotensive and developed cardiopulmonary failure, necessitating resuscitation, during an upper endoscopy procedure. The patient's clinical condition continued to deteriorate with the development of refractory metabolic acidosis and worsening respiratory status. Despite aggressive supportive care, the patient died on hospital day 3. The autopsy showed hepatomegaly and hepatic necrosis with lymphocytic inflammation indicative of a hypersensitivity reaction (Clay, 2006).
    c) CASE REPORT: Hepatitis occurred in one patient who received 800 mg telithromycin once daily for 7 to 10 days during a clinical efficacy trial. The patient had elevated liver enzyme levels prior to study enrollment and developed fever, vomiting, and diarrhea 12 days following the last day of study treatment. During this time, the patient also had contact with family members who had a gastroenteritis-like disease with fever; however, a specific causative agent could not be identified, therefore a causal relationship between telithromycin administration and the development of hepatitis could not be discounted at the time of this episode. The patient developed a second episode of hepatitis 9 months after the first episode. At this time, the patient had not been taking telithromycin, suggesting that both episodes may have been unrelated to telithromycin therapy (Carbon et al, 2003).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia has been rarely reported following therapeutic administration of telithromycin (Carbon et al, 2003; Shain & Amsden, 2002).
    B) THROMBOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) Thrombocytosis occurred in 11% of patients (n=199) who received telithromycin therapy, 800 mg once daily, during a clinical efficacy trial (Hagberg et al, 2002).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE WEAKNESS
    1) WITH THERAPEUTIC USE
    a) Exacerbation of pre-existing myasthenia gravis has been reported in several patients during telithromycin therapy. Increased muscle weakness, dyspnea, and severe acute respiratory failure have occurred in these patients within hours of taking the first telithromycin dose (Prod Info KETEK(R) oral tablets, 2010; Perrot et al, 2006; Anonymous, 2004; Nieman et al, 2003).
    b) Myasthenic crisis associated with telithromycin was reported in a 46-year-old woman with history of myasthenia gravis and hypertension. She experienced sudden onset of shortness of breath shortly after receiving telithromycin for a sinus infection. Her pulse oximetry on room air was 94% during the initial evaluation at the emergency room where she received methylprednisolone, diphenhydramine, albuterol and ipratropium nebulized treatments for anaphylactic reaction. Although her condition appeared to improve after receiving intravenous glycopyrrolate 0.2 mg, her pulse oximetry on room air declined to 70% to 80%. She was given propofol, succinylcholine, followed by midazolam and vecuronium prior to rapid intubation, and was admitted to the medical intensive care unit for myasthenic crisis. Despite a negative acetylcholine receptor antibody level (0.1 nanomoles/liter (nmol/L); positive value, 0.5 nmol/L or greater), she underwent plasmapheresis on days 2 and 4 of hospitalization, and resumed her pyridostigmine 60 mg 4 times daily on days 4. She was extubated on day 3, followed by initiation of methylprednisolone, then prednisone titration for a target dose of 60 mg daily. She remained in the medical intensive care unit for 5 days and was discharged from the hospital after 8 days (Jennett et al, 2006).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) During postmarketing exposure, rare cases of severe allergic reactions, including angioedema and anaphylaxis, have been reported (Prod Info KETEK(R) oral tablets, 2010).
    b) An allergic reaction, consisting of chest pain, dyspnea, throat swelling, and rash, was reported in one patient on day 1 of telithromycin therapy. The patient completely recovered following discontinuation of therapy (Quinn et al, 2003). Allergic reactions has also been infrequently reported in other patients (Shain & Amsden, 2002; Zhanel et al, 2002).

Reproductive

    3.20.1) SUMMARY
    A) Telithromycin is classified as FDA pregnancy category C.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) At doses estimated to be 1.8 times (900 mg/m(2)) and 0.49 times (240 mg/m(2)) the daily human dose of 800 mg (492 mg/m(2)) in the rat and rabbit, respectively, there was no evidence of teratogenicity (Prod Info Ketek, 2004).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Telithromycin is classified by the manufacturer as FDA pregnancy category C (Prod Info Ketek, 2004).
    B) ANIMAL STUDIES
    1) Delayed fetal maturation may occur following maternal doses greater than 900 mg/m(2) and 240 mg/m(2) in the rat and rabbit, respectively (Prod Info Ketek, 2004).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known whether telithromycin is excreted in human breast milk (Prod Info Ketek, 2004).
    B) ANIMAL STUDIES
    1) In rats, telithromycin is excreted in breast milk (Prod Info Ketek, 2004).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    B) Monitor liver enzymes, particularly in patients with pre-existing hepatic disease.
    C) Obtain an ECG and institute continuous cardiac monitoring following a significant exposure. QT interval prolongation and torsades de pointes have been reported with therapy and may occur with overdose.

Methods

    A) CHROMATOGRAPHY
    1) CETHROMYCIN: A high-performance liquid chromatographic-tandem mass spectrometric method was used to determine cethromycin concentrations in human plasma, bronchoalveolar lavage (BAL) fluid, and alveolar cells. The detection limits, using this method, were as follows: 1 ng/mL for plasma and 0.2 ng/mL for BAL fluid and a suspension consisting of alveolar cells (Ren et al, 2003).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients demonstrating severe fluid and electrolyte imbalance, QTc prolongation or cardiovascular instability should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) HOME CRITERIA: Patient with inadvertent ingestions who have minimal symptoms can be observed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity (ie, dysrhythmias) or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions should be observed in a healthcare facility.

Monitoring

    A) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    B) Monitor liver enzymes, particularly in patients with pre-existing hepatic disease.
    C) Obtain an ECG and institute continuous cardiac monitoring following a significant exposure. QT interval prolongation and torsades de pointes have been reported with therapy and may occur with overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Severe toxicity is not expected after an overdose; prehospital decontamination is generally NOT necessary.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY: Severe toxicity is not expected after overdose. Gastrointestinal decontamination is not routinely warranted. Consider activated charcoal after extremely large ingestions or those involving toxic co-ingestants.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    2) Monitor liver enzymes, particularly in patients with pre-existing hepatic disease.
    3) Obtain an ECG and institute continuous cardiac monitoring following a significant exposure. QT interval prolongation and torsades de pointes have been reported with therapy and may occur with overdose.
    B) TORSADES DE POINTES
    1) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    2) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    3) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    4) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    5) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    6) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    7) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.
    C) ACUTE ALLERGIC REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

Enhanced Elimination

    A) HEMODIALYSIS
    1) The effectiveness of hemodialysis following ketolide antibiotic overdose is unknown. It is unlikely to be useful given the large volume of distribution of telithromycin (2.9 L/kg).

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established; however, severe nausea was reported following an ingestion of 1600 mg of telithromycin. Doses up to 2400 mg telithromycin caused taste perversion, blurred vision, headache, nausea, diarrhea, tinnitus, confusion, somnolence, and transient increases in serum aminotransferases in healthy subjects.
    B) THERAPEUTIC DOSE: TELITHROMYCIN: ADULTS: 800 mg once daily for 7 to 10 days. CHILDREN: The safety and efficacy of telithromycin in pediatric patients have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) TELITHROMYCIN: The recommended oral dose is 800 mg once daily for 7 to 10 days (Prod Info KETEK(R) oral tablets, 2010).
    7.2.2) PEDIATRIC
    A) TELITHROMYCIN: The safety and efficacy of telithromycin in pediatric patients have not been established (Prod Info KETEK(R) oral tablets, 2010).

Minimum Lethal Exposure

    A) At the time of this review, a minimum lethal dose in humans is unknown.

Maximum Tolerated Exposure

    A) Severe nausea was reported in one patient, involved in a randomized clinical trial, following ingestion of a single 1600-mg dose of telithromycin (Hade MJ, 2004).
    B) Doses up to 2400 mg telithromycin caused taste perversion, blurred vision, headache, nausea, diarrhea, tinnitus, confusion, somnolence, and transient increases in serum aminotransferases in healthy subjects (Hade MJ, 2004).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Telithromycin, a ketolide antibiotic, is structurally related to the macrolide antibiotics. It binds domains II and V of the 23S rRNA of the 50S ribosomal subunit, thereby blocking protein synthesis. It retains gram-positive activity in the presence of methylase-mediated domain V alteration by binding at domain II. In addition, telithromycin may prevent emerging ribosomal subunit assembly (Prod Info KETEK(R) oral tablets, 2010).

Physicochemical

Physical Characteristics

    A) TELITHROMYCIN - a white to off-white crystalline powder (Prod Info KETEK(R) oral tablets, 2007) .

Molecular Weight

    1) TELITHROMYCIN: 812.03 (Prod Info KETEK(R) oral tablets, 2007)

References

General Bibliography

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