a) Hassel (1991) reported two cases of hypothermia, in children, following the ingestion of erythromycin, 100 mg four times daily. Signs and symptoms resolved following withdrawal of the medication (Hassel, 1991).
b) Hypothermia was reported in three children following azithromycin administration, 150 to 200 mg/day for 2 to 3 doses. In all three patients, the hypothermia resolved within 5 days after discontinuing azithromycin therapy (Kavukcu et al, 1997).

a) CASE REPORT: A 17-year-old girl was given intravenous erythromycin lactobionate for the treatment of community-acquired pneumonia. After the second 600 mg dose of erythromycin, she presented with extreme weakness and severe hypotension. Signs and symptoms resolved following supportive treatment and discontinuation of the medication The same patient was later given 500 mg of oral erythromycin 16 hours after the last intravenous dose. The patient, 1.5 hours later, presented with extreme weakness and severe hypotension. Again, signs and symptoms resolved following supportive treatment and discontinuation of the erythromycin (Dan & Feigl, 1993).

a) CASE REPORT (CHILD): A 6.5-year-old boy presented with hematemesis several days after being placed on oral erythromycin for the treatment of otitis media. Endoscopy revealed candida esophagitis. The signs and symptoms gradually resolved following treatment with nystatin (Hachya et al, 1982).

a) CASE REPORT (CHILD): A 6-year-old boy was given 1500 mg/day of erythromycin syrup to treat tonsillitis. One week after beginning erythromycin treatment, the patient presented with gingival hyperplasia. The signs and symptoms resolved a few weeks after discontinuation of the erythromycin. One month later, an erythromycin challenge of 1500 mg/day was performed. After two days of administration, the patient presented with a new case of gingival hyperplasia, thus supporting the idea that the gingival hyperplasia was caused by the administration of erythromycin (Valsecchi & Cainelli, 1992).

a) Ventricular dysrhythmias have been reported following the use of various macrolides (erythromycin, clarithromycin, roxithromycin), usually intravenously. Dysrhythmias are usually associated with QT prolongation. Most patients with ventricular dysrhythmias associated with erythromycin use have also developed a prolonged QT interval (Guelon et al, 1986; Brandriss et al, 1994; McComb et al, 1984; Gitler et al, 1994; Vogt & Zollo, 1997; Owens, 2001; Lin & Quasny, 1997; Owens, 2001). Concomitant use of other medications which prolong the QT interval may increase the risk of developing dysrhythmias (Lin & Quasny, 1997; Owens, 2001).
b) Prolongation of the QT interval has been associated with macrolide antibiotics, including azithromycin, and cases of torsade de pointes have been reported during postmarketing surveillance of azithromycin. In a randomized, placebo-controlled parallel trial in 116 healthy volunteers, coadministration of azithromycin (500, 1000, and 1500 mg once daily) with chloroquine 1000 mg increased the QT interval corrected for heart rate (QTc) in a dose- and concentration-dependent manner compared with chloroquine alone. The maximum mean increases in QTc with the coadministration of azithromycin 500, 1000, and 1500 mg were 5, 7, and 9 milliseconds (95% upper confidence bound, 10, 12, and 14 milliseconds), respectively, compared with chloroquine alone. The risk for QT prolongation should be considered prior to initiating azithromycin treatment, especially in patients with known QT prolongation or a history of torsade de pointes, bradyarrhythmias, uncompensated heart failure, proarrhythmic conditions (eg, significant bradycardia, uncorrected hypokalemia or hypomagnesemia, or patients receiving class IA or Class III antiarrhythmic agents) or patients on concomitant drugs known to prolong the QT interval (Prod Info ZITHROMAX(R) oral tablets, oral suspension, 2013; Prod Info ZITHROMAX(R) intravenous injection, 2013; Prod Info Zmax(R) oral extended release suspension, 2013).
c) CASE REPORT: A 75-year-old woman, with a medical history of chronic renal dysfunction, complete AV block managed with a chamber pacemaker, coronary artery disease, hypertension, and dyslipidemia, presented with pre-syncope, shortness of breath, nausea, and a non-productive cough after taking clarithromycin (1 g IV daily) and ceftriaxone (2 g IV daily) for 4 days during hospitalization for right lower lobe community acquired pneumonia. Her vital signs included a blood pressure of 179/107 mmHg and a heart rate of 119 beats/min while standing and a blood pressure of 188/71 mmHg and a heart rate of 63 beats/min while sitting. Laboratory results revealed hypomagnesemia, mild hypokalemia, and leukocytosis. An ECG revealed paced rhythm with a QTc interval of 514 msec. She lost consciousness about an hour later and cardiac monitoring showed torsade de pointes deteriorating into ventricular fibrillation. Following successful cardioversion and further aggressive supportive care, her condition gradually improved and she was upgraded to a dual chamber implantable cardioverter-defribillator. She was discharged with a paced QTc interval of 512 msec (Gysel et al, 2013).
d) CASE REPORT: A 29-year-old woman with idiopathic prolonged QT syndrome developed repeated episodes of torsade de pointes several days after beginning oral erythromycin 500 mg four times daily. An infusion of 250 mg erythromycin in the same patient induced T-wave alternans and frequent multifocal PVCs (Freedman et al, 1987).
e) CASE REPORT: A 56-year-old woman with cor pulmonale, pneumonia and respiratory failure developed QT prolongation, polymorphic premature ventricular complexes and torsades de pointes after intravenous administration of erythromycin (Guelon et al, 1986).
f) CASE REPORT: A 35-year-old woman developed QT prolongation, ventricular ectopy and torsades de pointes after receiving intravenous cefizoxime and erythromycin for pneumonia. Her QT interval normalized and dysrhythmias stopped after erythromycin was discontinued (Brandriss et al, 1994).
g) CASE REPORT: A 65-year-old woman who underwent mitral valve replacement for mitral stenosis developed ventricular tachycardia on 4 occasions within minutes of receiving intravenous erythromycin and cloxacillin. Dysrhythmias did not recur after erythromycin was discontinued, despite continued administration of cloxacillin (McComb et al, 1984).
h) CASE REPORT: Gitler et al (1994) reported a case of an 88-year-old woman who was given intravenous erythromycin lactobionate, 500 mg every 6 hours, to treat pneumonia. Forty minutes into the second dose of erythromycin, the patient experienced an episode of nonsustained torsades de pointes. An ECG showed QT interval prolongation. Signs and symptoms resolved after lidocaine treatment was started and the erythromycin therapy was discontinued (Gitler et al, 1994).
i) CASE REPORT: A 76-year-old man developed torsades de pointes after receiving intravenous erythromycin on two occasions. The patient had a history of myocardial infarction complicated by ventricular dysrhythmias, ventricular aneurysm and mitral insufficiency. He had developed torsades de pointes associated with quinidine use previously (Nattel et al, 1990).
j) CASE REPORTS: Two patients developed QT prolongation and torsades de pointes within one week after beginning clarithromycin therapy to treat bronchopneumonia. Signs and symptoms resolved within 7 days after discontinuing clarithromycin (Lee et al, 1998).
k) There have been reports of the occurrence of palpitations, tachycardia, and cardiac arrest with ventricular fibrillation associated with the use of roxithromycin (Anon, 1996).
l) CASE REPORT: A 27-year-old woman developed ventricular tachycardia after receiving six doses of clarithromycin. The tachycardia resolved within 4 hours after discontinuation of clarithromycin therapy (Kundu et al, 1997).
m) CASE SERIES: QTc prolongation developed in 12 of 13 drug administrations in a series of 7 consecutive critically ill patients receiving intravenous erythromycin for severe pneumonia. In 3 patients ventricular dysrhythmia (ventricular tachycardia, ventricular fibrillation and frequent premature ventricular beats) developed shortly after erythromycin infusion (Haefeli et al, 1992).

a) CASE REPORT (CHILD): A 9-month-old infant was inadvertently administered azithromycin 50 mg/kg (500 mg) (a 5 to 10-fold overdose) IV over 20 minutes instead of the prescribed ceftriaxone. The infant became unresponsive, cyanotic, and pulseless 19 minutes after the start of the infusion. The cardiac monitor showed wide-complex bradycardia, with a prolonged QTc interval, and third-degree atrioventricular block. The patient survived but with significant anoxic encephalopathy (Tilelli et al, 2006).

a) CASE REPORT: A 17-year-old girl was given intravenous erythromycin lactobionate for the treatment of community-acquired pneumonia. After the second 600 mg dose of erythromycin, she presented with extreme weakness and severe hypotension. Signs and symptoms resolved following supportive treatment and discontinuation of the medication. The same patient was later given 500 mg of oral erythromycin 16 hours after the last intravenous dose. The patient, 1.5 hours later, presented with extreme weakness and severe hypotension. Again, signs and symptoms resolved following supportive treatment and discontinuation of the erythromycin (Dan & Feigl, 1993).

a) Thrombophlebitis may occur following the intravenous administration of erythromycin (Holt & Gaskins, 1986).

a) According to one study, the use of erythromycin was associated with an increased risk of sudden cardiac death. In a cohort study including 1,249,943 person-years of follow-up and 1476 cases of sudden cardiac death occurring in a community setting, researchers found that the rate of sudden death from cardiac causes was twice as high among current users of erythromycin as compared to non-users of erythromycin or amoxicillin (incidence-rate ratio, 2.01; 95% CI, 1.08 to 3.75; p=0.03). However, former use of erythromycin (incidence-rate ratio, 0.89; 95% CI, 0.72 to 1.09; p=ns) or current use of amoxicillin was not associated with a significant increased risk in sudden death (incidence-rate ratio, 1.18; 95% CI, 0.59 to 2.36; p=ns). The most marked increased risk of sudden cardiac death was seen among concurrent users of erythromycin and strong cytochrome P-450 3A (CYP3A) inhibitors (eg; ketoconazole, itraconazole, fluconazole, diltiazem, verapamil, and troleandomycin). Multivariant analysis showed that the risk of sudden cardiac death was five times higher among concurrent users of erythromycin and strong CYP3A inhibitors as compared with patients who used neither CYP3A inhibitors nor erythromycin or amoxicillin (incidence-rate ratio, 5.35; 95% CI, 1.72 to 16.64; p=0.004) (Ray et al, 2004).

a) GUINEA PIG: Daleau et al (1995) studied the effects of erythromycin on isolated guinea pig ventricular myocytes. Outward time-dependent potassium current was blocked by erythromycin. Prolongation of monophasic action potential in the isolated, buffer-perfused guinea pig heart was consistent with demonstrated selective block of I(Kr) (rapid component of the delayed rectifier). Clinically relevant concentrations were used (1 gram erythromycin IV) (Daleau et al, 1995).

a) CASE REPORT: Agitation and choreoathetosis was reported with oral azithromycin on two separate occasions in an 11-year-old boy with a history of developmental delay. The patient, who presented with an upper respiratory infection and tested positive for influenza A, was given oral azithromycin for suspected pneumonia. The patient became slightly agitated following the first dose and developed worsened agitation, insomnia, and choreoathetoid movements of the upper extremities by the third day of treatment. Despite discontinuation of azithromycin, symptoms continued and, following hospitalization and treatment with clonazepam, complete resolution of symptoms occurred within 36 hours of hospitalization. Notably, the patient had experienced similar choreoathetoid movements with azithromycin therapy 2 years prior to current presentation; discontinuation of azithromycin, and treatment with chlorpromazine and lorazepam had led to complete resolution of symptoms within 48 hours (Farooq et al, 2011).

a) In postmarketing evaluations, seizures have been reported in adult and/or pediatric patients who received azithromycin (Prod Info ZITHROMAX(R) oral suspension, oral tablets, 2011; Prod Info ZITHROMAX(R) IV infusion, 2011; Prod Info ZMAX(R) extended release oral suspension, 2009).

a) CASE REPORT: Agitation and choreoathetosis was reported with oral azithromycin on two separate occasions in an 11-year-old boy with a history of developmental delay. The patient, who presented with an upper respiratory infection and tested positive for influenza A, was given oral azithromycin for suspected pneumonia. The patient became slightly agitated following the first dose and developed worsened agitation, insomnia, and choreoathetoid movements of the upper extremities by the third day of treatment. Despite discontinuation of azithromycin, symptoms continued and, following hospitalization and treatment with clonazepam, complete resolution of symptoms occurred within 36 hours of hospitalization. Notably, the patient had experienced similar choreoathetoid movements with azithromycin therapy 2 years prior to current presentation; discontinuation of azithromycin, and treatment with chlorpromazine and lorazepam had led to complete resolution of symptoms within 48 hours (Farooq et al, 2011).

a) Nausea and vomiting are commonly reported adverse effects. Diarrhea has been reported in some cases.
b) FIDAXOMICIN: In two randomized, double-blind trials in adult patients with Clostridium difficile (C difficile)-associated diarrhea (CDAD), nausea was reported in 11% of patients who received fidaxomicin 200 mg orally twice daily for 10 days (n=564) compared with 11% of patients who received vancomycin 125 mg orally four times daily for 10 days (n=583). Vomiting was reported in 7% of patients who received fidaxomicin compared with 6% of patients who received vancomycin (Prod Info DIFICID(TM) oral tablets, 2011).
c) CASE REPORT (IV): A 44-year-old woman, diagnosed with pneumonia, was given erythromycin lactobionate, 1 g in 250 ml of normal saline infused over 20 to 30 minutes. The patient experienced severe nausea and vomiting approximately 30 minutes after the infusion was finished. The symptoms then resolved, and the patient was switched to oral erythromycin without any further episodes of nausea and vomiting (Seifert et al, 1989).
d) Seifert et al (1989) reported five other cases of patients who experienced the same symptoms of severe nausea and vomiting shortly after the relatively rapid IV administration of erythromycin lactobionate(Seifert et al, 1989a).
e) Abdominal pain and nausea were correlated with the rate of infusion of intravenous erythromycin lactobionate in one study (Downey & Chaput de Saintonge, 1986).
f) Carter et al (1987) reported that daily doses of oral erythromycin greater than 1 g frequently were associated with nausea, vomiting, diarrhea, anorexia and other gastrointestinal disturbances. The enteric-coated tablet of erythromycin base appeared to produce more severe gastrointestinal effects than the stearate or ethylsuccinate salt forms (Carter et al, 1987).

a) CASE REPORT: A 19-year-old woman who acutely ingested approximately 6.6 grams of erythromycin base developed severe epigastric pain, nausea and vomiting 3 hours later. The patient recovered with supportive care (Gumaste, 1989).

a) FIDAXOMICIN: In two randomized, double-blind trials in adult patients with Clostridium difficile (C difficile)-associated diarrhea (CDAD), abdominal pain was reported in 6% of patients who received fidaxomicin 200 mg orally twice daily for 10 days (n=564) compared with 4% of patients who received vancomycin 125 mg orally four times daily for 10 days (n=583) (Prod Info DIFICID(TM) oral tablets, 2011).
b) CASE REPORT (CHILD): A 4-year-old boy ingested erythromycin estolate liquid, 125 mg every 6 hours, for acute otitis media. Within 15 hours of the first dose, the patient experienced nausea and severe right upper-quadrant abdominal pain. The symptoms dissipated over 8 hours (Rogers, 1972).
c) Karachalios (1973) reported similar symptoms in a 7-year-old boy 12 hours after ingesting 125 mg erythromycin estolate. The patient was given a second tablet 8 hours later with the same results. The symptoms dissipated over 6 hours (Karachalios, 1973).
d) Abdominal pain following therapeutic doses of erythromycin estolate has been reported in several other patients (Greico, 1969).

a) CASE REPORT: A 19-year-old woman who acutely ingested approximately 6.6 grams of erythromycin base developed severe epigastric pain, nausea and vomiting 3 hours later. The patient recovered with supportive care (Gumaste, 1989).

a) CASE REPORT (IV): Pancreatitis was reported in a 22-year-old woman who was given 2 g intravenous erythromycin lactobionate mixed with 500 ml of isotonic saline infused over an hour. Severe epigastric pain radiating to the back occurred forty minutes after the start of the infusion. An elevated serum amylase level confirmed the diagnosis of pancreatitis. Symptoms resolved following supportive treatment (Hawksworth, 1989).
b) CASE REPORT (ROXITHROMYCIN): A 54-year-old woman, who had been given 300 mg/day of oral roxithromycin, experienced severe epigastric pain and meteorism 24 hours after initiating therapy. Elevated pancreatic enzyme levels and the ultrasonographic data suggested moderate pancreatitis. Symptoms resolved 24 hours after roxithromycin was stopped (Souweine et al, 1991).

a) Pancreatitis has been reported in patients who have ingested large amounts of erythromycin in a short period of time. Signs and symptoms resolved following supportive care (Gumaste, 1989; Berger et al, 1992).
b) CASE REPORT: A 15-year-old girl developed nausea, vomiting, epigastric pain and tenderness, with an elevated serum lipase after ingesting 16 tablets (333 mg) of erythromycin base. She recovered with supportive care (Tenenbein & Tenenbein, 2005).

a) Rigauts et al (1988) reported a case of a 67-year-old woman who presented with pruritus, vomiting, abdominal pain and jaundice after taking erythromycin estolate (500 mg four times daily for 2 weeks) to treat an upper respiratory infection. Liver enzyme levels and bilirubin levels were elevated. A liver biopsy revealed cholestasis and inflammation, confirming the diagnosis of cholestatic hepatitis. Signs and symptoms resolved upon the discontinuation of the antibiotic (Rigauts et al, 1988).
b) CASE REPORT: A 62-year-old man developed cholestatic hepatitis after PO clarithromycin, 1 g twice daily, for treatment of a lung infection. The cholestatic hepatitis resolved after withdrawal of the medication. A 1 g challenge dose of clarithromycin, resulted in development of the same signs and symptoms as experienced previously, thereby supporting the diagnosis of clarithromycin-induced cholestatic hepatitis (Yew et al, 1994).

a) Other drugs which have been associated with interstitial nephritis were taken in some cases, but erythromycin use was most closely associated with the development of nephritis (Singer et al, 1988; Rosenfeld et al, 1983).

a) Leukopenia has rarely (less than 1%) been reported in adult/pediatric patients who received azithromycin during clinical trials. Leukopenia appeared to be reversible in cases where follow-up was provided (Prod Info ZITHROMAX(R) oral suspension, oral tablets, 2011; Prod Info ZITHROMAX(R) IV infusion, 2011; Prod Info ZMAX(R) extended release oral suspension, 2009).

a) In postmarketing evaluations, thrombocytopenia was reported in patients who received azithromycin (Prod Info ZITHROMAX(R) oral suspension, oral tablets, 2011; Prod Info ZITHROMAX(R) IV infusion, 2011; Prod Info ZMAX(R) extended release oral suspension, 2009).
b) CASE REPORT: A 74-year-old man presented with pneumonia and atrial fibrillation and was treated with oral clarithromycin, 250 mg every 12 hours, and digoxin. Seven days later, the patient experienced petechiae on the roof of his mouth and on his tongue, arms and legs. The patient's platelet count greatly decreased and a diagnosis of thrombocytopenic purpura was made. Clarithromycin was discontinued and the patient received several platelet transfusions over the next few days, causing an increase in platelet count and the disappearance of the petechiae (Oteo et al, 1994).
c) CASE REPORT: Price and Tuazon (1992) reported a case of thrombocytopenia following the administration of clarithromycin, 2 g/day, to treat mycobacterium avium complex infection in an AIDs patient. The platelet count greatly decreased as the clarithromycin therapy was continued. Following a platelet transfusion and discontinuation of the clarithromycin, the patient's platelet count increased and then stabilized. Other drugs administered in the course of treatment included zidovudine, clofazimine, amikacin and pentamidine (Price & Tuazon, 1992).

a) CASE REPORT: A 60-year-old man experienced severe respiratory distress shortly after ingestion of two tablets of erythromycin stearate. The severe respiratory distress was most likely due to an allergic reaction from the erythromycin. This was determined by positive results obtained from the indirect mast cell degranulation test using erythromycin stearate. The patient recovered following treatment with intravenous prednisolone (Abramov et al, 1978).

a) CASE REPORT: Handa (1972) reported a case of Schonlein-Henoch syndrome in a patient after the ingestion of 6 tablets of erythromycin over a period of 36 hours. The Schonlein-Henoch syndrome is an allergic reaction characterized by an erythematous rash, arthralgia, and abdominal pain, accompanied later by gastrointestinal bleeding and renal insufficiency, usually due to glomerulonephritis. This is an extremely unusual toxic effect to be associated with the administration of erythromycin (Handa, 1972).

a) A large, population-based registry study of women in Norway who used antibacterial agents during pregnancy found that use of erythromycin (n=1786) during the first trimester of pregnancy, which is the most crucial period for fetal heart formation, was not associated with a significantly higher risk of cardiovascular malformations (adjusted odds ratio [aOR], 1.2; 95% CI, 0.8 to 1.8). Of the 1786 patients exposed to erythromycin in the first trimester, 21 women (1.2%) had an infant with a cardiovascular malformation and 90 (5%) had an infant with at least 1 nonchromosomal congenital malformation (aOR, 1.04; 95% CI, 0.84 to 1.29). Ten out of 611 (1.6%) women who received erythromycin during the crucial heart formation period, gave birth to infants with cardiovascular malformations, and six (1%) had atrial or ventricular septal defects (ASD/VSD). No significant associations between erythromycin use and ASD/VSD (aOR, 1.41; 95% CI, 0.63 to 3.17) or cardiovascular malformations (aOR, 1.62, 95% CI, 0.86 to 3.02) were found with erythromycin use during days 28 through 56 of pregnancy. In adjusted subanalyses, no increased risk for any of 17 predefined specific malformations was observed for erythromycin use compared with no antibiotic use during the first trimester (Romoren et al, 2012).
b) Cardiovascular malformations were reported at a higher rate in infants who were prenatally exposed to erythromycin (n=1844), primarily during the first trimester, compared with those exposed to penicillin V and compared with all subjects in a study of Swedish Medical Birth Registry data (n=677,028). Of the erythromycin-exposed group, 34 (1.8%) had a cardiovascular malformation (excluding chromosomal abnormalities, patent ductus arteriosus or single umbilical artery) compared with 0.9% of infants exposed to penicillin and 1% of infants in the entire registry. The odds ratio for cardiovascular defects after erythromycin exposure (controlling for maternal age, parity, smoking and number of early miscarriages) was 1.84 (95% confidence interval, 1.29 to 2.62) (Kallen et al, 2005).
c) A prospective study using data from the Swedish Medical Birth Registry from 1996 to 2011 showed a statistically significant association between erythromycin use during pregnancy and infant cardiovascular defects. The study included 1,575,847 infants, of which 2,531 were exposed to erythromycin during early pregnancy. Of the infants exposed, 43 were born with a cardiovascular defect with an odds ratio of 1.70 (95% confidence interval, 1.26 to 2.29). The most common cardiovascular defects were ventricular septum defect (n=13) and atrial septum defect (n=5), and coarctation of aorta (n=3) (Kallen & Danielsson, 2014).

a) Pyloric stenosis was reported at a higher rate in infants who were prenatally exposed to erythromycin (n=1844), primarily during the first trimester, compared with those exposed to penicillin V and compared with all subjects in a study of Swedish Medical Birth Registry data (n=677,028). Pyloric stenosis was diagnosed in 4 (0.2%) infants exposed to erythromycin prior to the first antenatal visit, 6 infants (0.06%) exposed to penicillin V, and 458 infants (0.06%) of the entire group. The odds ratio for pyloric stenosis after erythromycin exposure was 3.03 (95% CI 1.10-8.50). An additional two infants with pyloric stenosis who had been exposed to erythromycin after the first antenatal visit were identified (Kallen et al, 2005).
b) Infantile hypertrophic pyloric stenosis (IHPS) occurred at an increased rate in infants prescribed systemic erythromycin (n=469), particularly in the first 2 weeks of life, compared with those not prescribed erythromycin in a retrospective cohort study of 14,876 infants born between June 1993 and December 1999 at a single hospital. IHPS was reported in 0.29% of the infants (n=43). At age 1 week or less, IHPS was reported in 2.75% of erythromycin prescription infants compared with 0.26% of non-erythromycin prescription infants (relative risk (RR), 10.62; 95% confidence interval (CI), 4.2 to 26.7). At age 2 weeks or less, IHPS occurred in 2.65% of prescription infants compared with 0.25% of nonprescription infants (RR, 10.51; 95% CI, 4.5 to 24.7). At age 3 months or less, IHPS occurred in 1.28% of prescription infants compared with 0.26% of nonprescription infants (RR, 4.98; 95% CI, 2.1 to 11.7). The 6 infants with a systemic erythromycin prescription and IHPS diagnosis had a gestational age of 35 to 39 weeks, birthweight of 2.5 to 3.8 mg, gender of male (n=5) and female (n=1); prescriptions of 14 days (n=5) and 15 days (n=1), and daily doses of 20 to 50 mg/kg. Among the 416 prescriptions specifying treatment duration, IHPS risk increased for 14 days or greater compared with less than 14 days (3% vs 0%, p less than 0.5). IHPS risk was not increased by maternal systemic erythromycin prescriptions (RR, 1.19; 95% CI, 0.6 to 2.3) or infant prescriptions for topical erythromycin ophthalmic ointment (crude RR, 1.12; 95% CI, 0.31 to 2.69) regardless of whether the infant had a systemic erythromycin prescription (Mahon et al, 2001).

a) A retrospective cohort study conducted in Israel found that use of macrolide antibiotics during the first trimester of pregnancy was not associated with major malformations and third trimester exposure is not likely to increase neonatal risks for pyloric stenosis or intussusception in a clinically meaningful manner. This study identified 105,492 pregnancies and 1112 pregnancy terminations. Overall, 1033 fetuses were exposed to macrolides (azithromycin, clarithromycin, erythromycin, or roxithromycin) during the first trimester. After adjusting for maternal age, parity, ethnic group, pregestational diabetes, and year of birth or pregnancy termination, macrolide exposure during the first trimester did not increase the risk of major malformations (adjusted OR, 1.074; 95% CI, 0.839 to 1.376). During the third trimester, 959 fetuses were exposed to macrolides. There was no association between such exposure and increased risk of pyloric stenosis or intussusception (Bahat Dinur et al, 2013).

a) There were no cases of infantile hypertrophic pyloric stenosis (IHPS) in 6 infants prescribed systemic azithromycin at 48 days of age or older in a retrospective cohort study of data from macrolide antibiotic (azithromycin or erythromycin) prescriptions in 14,876 infants born between June 1993 and December 1999 at a single hospital (Mahon et al, 2001).
b) Azithromycin did not cause an increased rate of congenital anomalies when used during pregnancy in a series of observational cohort studies. Of 29 pregnant women who received azithromycin, 16 discontinued the drug before the last menstrual period, 11 were exposed during the first trimester, and 2 had unknown exposure. Of the 11 exposed during the first trimester, there were 10 births without congenital anomalies, and one pregnancy intentionally terminated (Wilton et al, 1998).

a) A nationwide cohort study in Denmark examined if an increased risk of miscarriage and congenital malformations were associated with clarithromycin use during the first trimester of 931,504 pregnancies (705,837 live births, 77,553 miscarriages, and 148,114 induced abortions). Ten percent of 401 pregnant women exposed to clarithromycin miscarried compared with 8.3% of 77,513 unexposed pregnant women (hazard ratio (HR) = 1.56; confidence interval (CI) 95%, 1.14-2.13). Overall, 9 (3.6%) out of 253 live births exposed to clarithromycin had a major malformations compared with 24,808 (3.5%) children in the unexposed group. No significant difference in malformations was observed in the children of pregnant women exposed to clarithromycin in comparison to those who were unexposed (odds ratio = 1.03 (CI) 95%, 0.52-2.00). These results indicate that clarithromycin increases the risk of miscarriage, but not congenital malformations, in the first trimester of pregnancy (Andersen et al, 2013).
b) A retrospective cohort study conducted in Israel found that use of macrolide antibiotics during the first trimester of pregnancy was not associated with major malformations and third trimester exposure is not likely to increase neonatal risks for pyloric stenosis or intussusception in a clinically meaningful manner. This study identified 105,492 pregnancies and 1112 pregnancy terminations. Overall, 1033 fetuses were exposed to macrolides (azithromycin, clarithromycin, erythromycin, or roxithromycin) during the first trimester. After adjusting for maternal age, parity, ethnic group, pregestational diabetes, and year of birth or pregnancy termination, macrolide exposure during the first trimester did not increase the risk of major malformations (adjusted OR, 1.074; 95% CI, 0.839 to 1.376). During the third trimester, 959 fetuses were exposed to macrolides. There was no association between such exposure and increased risk of pyloric stenosis or intussusception (Bahat Dinur et al, 2013).
c) Exposure to clarithromycin during the first trimester of pregnancy was not associated with an excess of major birth malformations, based on a retrospective surveillance study using 5 year (1991 to 1995) hospital claims data and medical records. Overall, 143 women were identified who had filled at least one prescription for clarithromycin during their first trimester of pregnancy. There were 149 babies born to these 143 women. Among the 149 neonates, 5 had major malformations, translating to a 3.4% rate of major malformations. The expected rate of major birth defects was 2.8% using national historical data. The rate found in the study was not statistically significantly different from the expected rate (p=0.61) (Drinkard et al, 2000).
d) First-trimester exposure to clarithromycin did not result in major or minor congenital malformations in a prospective, multicenter, controlled study of clarithromycin use during pregnancy (Einarson et al, 1998).

a) Erythromycin use during pregnancy did not increase the risk of pyloric stenosis in infants in a case-control surveillance of data collected between 1976 and 1998. Infants diagnosed with pyloric stenosis (n=1044), a control group of infants with no malformations (n=1704), and a control group with malformations other than pyloric stenosis (n=15,356). were identified in a database of infants born with birth defects. Women who reported using an unknown antibiotic during pregnancy were excluded. Odds ratios using comparisons from each control group were close to 1, all confidence intervals included 1, and all upper 95% confidence bounds were less than 2 demonstrating no association between maternal erythromycin use and pyloric stenosis in infants (Louik et al, 2002).
b) Erythromycin use during pregnancy did not increase teratogenic risk to the infant, particularly during the second and third months of pregnancy, in a population-based, case-control teratologic study of data collected from the Hungarian Case-Control Surveillance of Congenital Abnormalities between 1980 and 1996. A population control group of infants without any congenital abnormalities (n=38,151) and a group of infants or fetuses with congenital abnormalities (n=22,865) were identified. Erythromycin was used during pregnancy in 172 (0.5%) of the infants in the control group compared with 113 (0.5%) of those in the group with congenital abnormalities (crude odds ratio, 1.1; 95% confidence interval, 0.9 to 1.4) (Czeizel et al, 1999).

a) When pregnant animals were given oral azithromycin at doses up to moderately maternally toxic dose levels of 200 mg/kg/day (4 and 2 times the oral human daily dose of 500 mg, respectively), no evidence of teratogenicity was observed, despite maternal toxicity (Prod Info ZMAX(R) oral extended release suspension, 2015).

a) In four rat teratogenicity studies, clarithromycin did not result in teratogenicity following oral administration of clarithromycin in 3 studies and 1 study with intravenous administration of up to 160 mg/kg/day during the period of organogenesis. In two additional studies with a different strain of rat, oral clarithromycin doses up to 150 mg/kg/day (2-fold the human serum levels) administered during gestation days 6 to 15 resulted in a low incidence of cardiovascular anomalies. In two rabbit studies, oral doses up to 125 mg/kg/day (about 2-fold the maximum recommended human dose (MRHD) based on mg/m(2) or intravenous doses of 30 mg/kg/day administered during gestation days 6 to 18 did not demonstrate any teratogenicity. In four mouse studies, a variable incidence of cleft palate was noted following oral doses of 1000 mg/kg/day (2- and 4-fold the MRHD based on mg/m(2), respectively, and equivalent to plasma levels 17-fold the human serum levels) during gestation days 6 to 15. Cleft palate was also reported at 500 mg/kg/day doses (Prod Info BIAXIN(R) Filmtab(R) oral tablets, 2014; Prod Info BIAXIN(R) XL Filmtab(R) oral extended-release tablets, 2014; Prod Info BIAXIN(R) Granules oral suspension, 2014).

a) RATS: In rat studies, there was no evidence of teratogenicity or any other adverse events in female rats that received erythromycin base up to 0.25% of their diet before and during mating, during gestation, and through weaning of 2 consecutive litters (Prod Info PCE(R) Dispertab(R) oral tablets, 2008).

a) RATS AND RABBITS: No evidence of fetal harm was observed when pregnant rats and rabbits were given IV fidaxomicin at doses up to 12.6 and 7 mg/kg, respectively. This represented approximately 200 times and 66 times the human plasma exposure, respectively (AUC(0 to t)) (Prod Info DIFICID(TM) oral tablets, 2011).

a) The manufacturer has classified azithromycin as FDA category B (Prod Info ZMAX(R) oral extended release suspension, 2015).
b) Use during pregnancy only if clearly needed (Prod Info ZMAX(R) oral extended release suspension, 2015)

a) Manufacturers have classified erythromycin, and fidaxomicin as FDA category B (Prod Info DIFICID(TM) oral tablets, 2011; Prod Info PCE(R) Dispertab(R) oral tablets, 2008).

a) The manufacturer has classified clarithromycin as FDA category C (Prod Info BIAXIN(R) Filmtab(R) oral tablets, 2014; Prod Info BIAXIN(R) XL Filmtab(R) oral extended-release tablets, 2014; Prod Info BIAXIN(R) Granules oral suspension, 2014).

a) The amoxicillin/clarithromycin/lansoprazole oral combination is classified as FDA pregnancy category C (Prod Info PREVPAC(TM) oral delayed-release capsules, oral capsules, oral tablets, 2014).

a) The amoxicillin/clarithromycin/omeprazole oral combination is classified as FDA pregnancy category C (Prod Info Omeclamox-Pak(TM) oral kit, 2015).

a) A nationwide cohort study in Denmark examined if an increased risk of miscarriage and congenital malformations were associated with clarithromycin use during the first trimester of 931,504 pregnancies (705,837 live births, 77,553 miscarriages, and 148,114 induced abortions). Ten percent of 401 pregnant women exposed to clarithromycin miscarried compared with 8.3% of 77,513 unexposed pregnant women (hazard ratio (HR) = 1.56; confidence interval (CI) 95%, 1.14-2.13). Overall, 9 (3.6%) out of 253 live births exposed to clarithromycin had a major malformations compared with 24,808 (3.5%) children in the unexposed group. No significant difference in malformations was observed in the children of pregnant women exposed to clarithromycin in comparison to those who were unexposed (odds ratio = 1.03 (CI) 95%, 0.52-2.00). These results indicate that clarithromycin increases the risk of miscarriage, but not congenital malformations, in the first trimester of pregnancy (Andersen et al, 2013).
b) There were four spontaneous abortions, four voluntary terminations of pregnancy, one infant death due to prematurity, and twenty physically normal newborns in 34 exposures to clarithromycin during the first and early second trimesters of pregnancy from 1991 to 1996 identified by a teratogen information service. Pregnancy outcome was pending in five cases at the time of the publication. The spontaneous abortion rate was not greater than expected (Schick et al, 1996).

a) In monkeys, oral doses of 70 mg/kg/day (about equivalent to the maximum recommended human dose (MRHD) and plasma levels 2-fold the human serum levels) resulted in fetal growth retardation. In other monkey studies, monkeys given 150 mg/kg/day (equal to 2.4 times the MRHD and 3-fold the human serum levels) resulted in embryonic loss. In rabbits, in utero fetal loss was observed at oral doses of 33 mg/m(2) (17-fold less than the proposed maximum recommended human dose of 618 mg/m(2)) (Prod Info BIAXIN(R) Filmtab(R) oral tablets, 2014; Prod Info BIAXIN(R) XL Filmtab(R) oral extended-release tablets, 2014; Prod Info BIAXIN(R) Granules oral suspension, 2014).

a) Azithromycin is excreted into human breast milk in small amounts. Exercise caution when administering azithromycin to a lactating woman (Prod Info ZMAX(R) oral extended release suspension, 2015).

a) In a prospective observational study, 55 breastfed infants of mothers who were taking macrolide antibiotics (6 of which were taking clarithromycin) were compared with 36 breastfed infants of mothers who were taking amoxicillin. Both groups had comparable adverse effects. Adverse reactions (eg, rash, diarrhea, loss of appetite, and somnolence) were observed in 12.7% of infants in the macrolides group (Prod Info BIAXIN(R) Filmtab(R) oral tablets, 2014; Prod Info BIAXIN(R) XL Filmtab(R) oral extended-release tablets, 2014; Prod Info BIAXIN(R) Granules oral suspension, 2014).

a) Two infants experienced minor diarrhea and 2 mothers reported irritability in their infants in a prospective study of mother-infant pairs in which 17 mothers were treated with erythromycin while breastfeeding (Ito et al, 1993).

a) CASE REPORT: A case report described hypertrophic pyloric stenosis in a 3-week-old nursing infant following erythromycin administration to the mother for mastitis. The mother had received therapy for 5 days, at which time the infant developed irritability, persistent vomiting, and an orange-red discoloration of the stools. Although there was no supporting documentation, it was postulated that the stool discoloration was attributable to the dye in the tablets and evidence of the excretion of erythromycin into the breast milk. Subsequently, erythromycin was discontinued. However, vomiting and subsequent weight loss persisted in the infant. Upper GI studies revealed hypertrophic pyloric stenosis, and a pyloromyotomy was successfully performed. No further sequelae were observed and breastfeeding was resumed, with an increase in weight of the infant (Stang, 1986).

a) A nursing infant whose mother was treated with oral azithromycin experienced no adverse effects and the amount of drug in the breast milk was not clinically significant. The following breast milk concentrations were reported: 1.3 mcg/mL one hour after the first 500-mg dose; 2.8 mcg/mL 30 hours after the third 500-mg dose; 0.64 mcg/mL 48 hours after the first 1-g dose. Assuming a consumption of 150 mL/kg/day of breast milk, it was estimated that the infant would have received a maximum of 482 mcg/day of azithromycin (Kelsey et al, 1994).

a) In a rat study, no adverse effects were noted in the feeding pups exposed to clarithromycin through milk consumption while the lactating mother received clarithromycin 150 mg/kg/day, despite finding higher drug levels in the milk than in maternal plasma (Prod Info BIAXIN(R) Filmtab(R) oral tablets, 2014; Prod Info BIAXIN(R) XL Filmtab(R) oral extended-release tablets, 2014; Prod Info BIAXIN(R) Granules oral suspension, 2014).

a) In animal studies, there was no evidence of impaired fertility with azithromycin use (Prod Info ZMAX(R) oral extended release suspension, 2015).

a) In a rat fertility study, male and female rats given 160 mg/kg/day (equal to 1.3-fold the maximum recommended human dose based on mg/m2 and 2-fold the human serum levels) showed no adverse effects on the estrous cycle, fertility, parturition, or the number and viability of offspring (Prod Info BIAXIN(R) Filmtab(R) oral tablets, 2014; Prod Info BIAXIN(R) XL Filmtab(R) oral extended-release tablets, 2014; Prod Info BIAXIN(R) Granules oral suspension, 2014).

a) RATS: In rat studies, there was no evidence of adverse effects on fertility in male and female rats that received erythromycin base up to 0.25% of their diet (Prod Info PCE(R) Dispertab(R) oral tablets, 2008).

a) RATS: The fertility of male and female rats was not affected after receiving IV fidaxomicin at a dose of 6.3 mg/kg (approximately 100 times the human exposure; AUC(0 to t)) (Prod Info DIFICID(TM) oral tablets, 2011).

a) Long-term animal studies have not been performed to evaluate the carcinogenic potential of azithromycin (Prod Info Zmax(R) oral extended release powder for suspension, 2012).

a) Long-term animal studies have not been performed to evaluate the carcinogenic potential of clarithromycin (Prod Info BIAXIN(R) Filmtab(R) oral tablets, 2011).

a) Long-term animal studies have not been performed to evaluate the carcinogenic potential of erythromycin lactobionate (Prod Info Erythrocin(R) Lactobionate-IV intravenous injection, 2011).

a) Long-term animal studies have not been performed to evaluate the carcinogenic potential of fidaxomicin (Prod Info DIFICID(TM) oral tablets, 2011).

a) No evidence of tumorigenicity was noted in long-term oral dietary studies conducted in rats administered erythromycin stearate doses up to 400 mg/kg/day and in mice at doses up to 500 mg/kg/day (approximately 1 to 2 times the maximum human dose on a mg/m(2) basis) (Prod Info ERY-PED(R) oral suspension, 2012) or with erythromycin ethylsuccinate and erythromycin base in long-term oral studies in rats (Prod Info Erythrocin(R) Lactobionate-IV intravenous injection, 2011).

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.

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).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

a) Toxicity following an acute overdose is uncommon. Treatment is symptomatic and supportive. Treat significant vomiting and diarrhea with IV fluids; administer antiemetics, as needed. Manage mild hypotension with IV fluids.

a) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Dysrhythmias should be treated with standard antiarrhythmic drugs, if necessary. SEIZURES: Administer IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. HYPERSENSITIVITY REACTION: Administer antihistamines, with or without inhaled beta agonists, corticosteroids or epinephrine.

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.

a) ALBUTEROL

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).

a) DIPHENHYDRAMINE

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).

a) EPINEPHRINE

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).

a) CARDIAC MONITOR: All complicated cases.
b) IV ACCESS: Routine in all complicated cases.

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.

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).
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).

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.

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).

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

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).

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).

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).

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).

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).
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).

a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).

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.

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

a) OPHTHALMIC SOLUTION: One drop twice daily (8 to 12 hours apart) for 2 days, then 1 drop once daily for 5 days (Prod Info AZASITE(TM) ophthalmic solution, 2007).
b) ORAL EXTENDED-RELEASE SUSPENSION: The recommended dosage is 2 g as a single dose (Prod Info ZMAX(R) extended release oral suspension, 2008).
c) ORAL TABLET: Dosing varies by indication; range, 250 to 500 mg daily. A single dose of 1 to 2 g may also be used (Prod Info ZITHROMAX(R) oral suspension, oral tablets, 2009).

a) ORAL EXTENDED-RELEASE TABLET: The recommended dosage is two 500-mg tablets (1000 mg) every 24 hours for between 7 and 14 days (Prod Info BIAXIN(R) Filmtab(R), BIAXIN(R) XL Filmtab(R), BIAXIN(R) extended-release oral tablets, oral suspension, oral tablets, 2009).
b) ORAL TABLET: The recommended dosage is 250 to 500 mg every 12 hours for between 7 and 14 days (Prod Info BIAXIN(R) Filmtab(R), BIAXIN(R) XL Filmtab(R), BIAXIN(R) extended-release oral tablets, oral suspension, oral tablets, 2009).

a) The recommended dose is lansoprazole 30 mg combined with amoxicillin 1 g and clarithromycin 500 mg orally twice daily for 10 to 14 days (Prod Info PREVPAC(TM) oral delayed-release capsules, oral capsules, oral tablets, 2014).

a) The recommended dose is omeprazole 20 mg combined with amoxicillin 1 g and clarithromycin 500 mg orally twice daily for 10 days (Prod Info Omeclamox-Pak(TM) oral kit, 2015).

a) DELAYED-RELEASE CAPSULES: The recommended dosage is 250 to 2000 mg/day, in equally divided doses, given one hour before meals; may increase dose up to 4 g/day. Do not use twice-daily dosing for doses greater than 1 g/day. Doses of 40 to 50 mg/kg/day have been used in clinical studies (Prod Info ERYC(R) oral capsules, 2007).
b) OPHTHALMIC OINTMENT: Apply a 1-cm ribbon to the affected area up to 6 times per day (Prod Info erythromycin ophthalmic ointment, USP, 1999).
c) PARTICLES IN TABLETS: The recommended dosage is 500 to 2000 mg/day in divided doses; may increase dose up to 4 g/day. Do not use twice-daily dosing for doses greater than 1 g/day. Doses of 40 to 50 mg/kg/day have been used in clinical studies (Prod Info PCE(R) Dispertab(R) oral tablets, 2008).
d) TOPICAL GEL: Apply a thin film to affected area once or twice a day (Prod Info erythromycin 2% topical gel, 2007).
e) TOPICAL PADS: Rub over affected area in morning and evening (Prod Info Ery Pads topical pads, 2007).

a) ORAL SUSPENSION AND TABLETS: The recommended dosage is 800 to 2400 mg/day in divided doses; may increase dose up to 4 g per day. Doses of 40 to 50 mg/kg/day have been used in clinical studies (Prod Info E.E.S.(R) oral liquid, granules, filmtab, 2008; Prod Info ERYPED(R) oral suspension, chewable oral tablets, 2003).

a) INTRAVENOUS INJECTION: The recommended dosage is 500 mg IV every 6 hours for 3 days (Prod Info PCE(R) Dispertab(R) oral tablets, 2008) OR 15 to 20 mg/kg/day followed by oral therapy; may increase dose up to 4 g/day. Administer in a continuous or intermittent intravenous infusion only; IV push is NOT recommended (Prod Info ERYTHROCIN(R) LACTOBIONATE IV injection, powder, lyophilized, for solution, 2008).

a) ORAL TABLETS: 200 mg orally twice daily with or without food for 10 days (Prod Info DIFICID(TM) oral tablets, 2011)

a) OPHTHALMIC SOLUTION
b) ORAL EXTENDED-RELEASE SUSPENSION
c) ORAL SUSPENSION

a) GRANULES FOR ORAL SUSPENSION

a) Safety and effectiveness have not been established in pediatric patients (Prod Info PREVPAC(TM) oral delayed-release capsules, oral capsules, oral tablets, 2014).

a) Safety and effectiveness have not been established in pediatric patients (Prod Info Omeclamox-Pak(TM) oral kit, 2015).

a) DELAYED-RELEASE CAPSULES: The recommended dose is 30 to 100 mg/kg/day in divided doses (Prod Info ERYC(R) oral capsules, 2007).
b) OPHTHALMIC OINTMENT: Apply a 1-cm ribbon to the affected area up to 6 times per day (Prod Info erythromycin ophthalmic ointment, USP, 1999).
c) PARTICLES IN TABLETS: The recommended dose is 30 to 50 mg/kg/day, in equally divided doses. MAXIMUM dose: 4 g per day (Prod Info PCE(R) Dispertab(R) oral tablets, 2008).
d) TOPICAL GEL AND PADS: Safety and efficacy have not been established (Prod Info erythromycin 2% topical gel, 2007; Prod Info Ery Pads topical pads, 2007).

a) ORAL SUSPENSION AND TABLETS: The recommended dosage is 30 to 100 mg/kg/day in equally divided doses (Prod Info E.E.S.(R) oral liquid, granules, filmtab, 2008; Prod Info ERYPED(R) oral suspension, chewable oral tablets, 2003).

a) INTRAVENOUS INJECTION: The recommended dose is 15 to 20 mg/kg/day followed by oral therapy. May increase dose up to 4 g/day. Administer in a continuous or intermittent intravenous infusion only (Prod Info ERYTHROCIN(R) LACTOBIONATE IV injection, powder, lyophilized, for solution, 2008).

a) Safety and effectiveness have not been studied in patients younger than 18 years of age (Prod Info DIFICID(TM) oral tablets, 2011).

a) 1.3 g/kg
b) 1.2 g/kg