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In vitro activity of ketolides telithromycin and HMR 3004 against italian isolates of Streptococcus pyogenes and Streptococcus pneumoniae with different erythromycin susceptibility.

Two ketolides, telithromycin and HMR 3004, were evaluated for their in vitro activity against erythromycin-susceptible and -resistant strains of Streptococcus pyogenes and Streptococcus pneumoniae. On the basis of their resistance to macrolide, lincosamide and streptogramin (MLS) antibiotics, erythromycin-resistant test strains were assigned to the constitutive resistance (cMLS) phenotype, the inducible resistance (iMLS) phenotype or the M phenotype. iMLS S. pyogenes strains were further subdivided into the three recently described subtypes iMLS-A, -B and -C. Telithromycin and HMR 3004 were uniformly and highly active against pneumococci (regardless of their susceptibility or resistance to erythromycin and/or penicillin), erythromycin-susceptible S. pyogenes and erythromycin-resistant S. pyogenes strains of the M phenotype (in which resistance is mediated by an efflux system) or iMLS-B or -C phenotype (in which resistance is mediated by a methylase encoded by the ermTR gene). Both ketolides were less active against erythromycin-resistant S. pyogenes strains with the cMLS phenotype or the iMLS-A subtype (where resistance is mediated by a methylase encoded by the ermAM gene), these strains ranging in phenotype from the upper limits of susceptibility to low-level resistant.

Anti-Bacterial Agents↗

HMR 3647 human-like treatment of experimental pneumonia due to penicillin-resistant and erythromycin-resistant Streptococcus pneumoniae.

An experimental Streptococcus pneumoniae pneumonia model in rabbits was used to assess the efficacy of amoxycillin, erythromycin and a new ketolide, telithromycin (HMR 3647). The MICs of amoxycillin, erythromycin and HMR 3647 for the three clinical S. pneumoniae strains used were, respectively, (mg/L): 0.01, 16 and 0.02 (strain 195); 2, 0.25 and 0.02 (strain 16089); 8, >64 and 0.02 (strain 11724). Antibiotic therapy reproduced human serum pharmacokinetics (amoxycillin 1 g iv tds or erythromycin 500 mg qds or HMR 3647 800 mg bd). Forty-eight hours of therapy with HMR 3647 and amoxycillin resulted in significant bacterial clearance in the lungs and spleen of rabbits infected by S. pneumoniae strain 195 and strain 16089 (at least 3 log(10) cfu/g decrease, P < 0.001). Erythromycin was active against only the erythromycinsusceptible strain (3 log(10) cfu/g decrease at 48 h, P < 0.001). None of the antibiotics showed significant efficacy with strain 11724. All agents produced significant bacterial clearance when time above MBC was >33%, and microbiological failure when it was <25%, whereas MIC was not correlated with microbiological outcome with HMR 3647. Our findings suggest that pharmacodynamic data integrating MBC may be predictive of microbiological success or failure with greater accuracy than with MIC. HMR 3647 produced significant bacterial clearance in both penicillin- and erythromycin-resistant pneumonia, but was less effective against the highly erythromycin-resistant S. pneumoniae strain.

Amoxicillin↗

The activity of 14-hydroxy clarithromycin, alone and in combination with clarithromycin, against penicillin- and erythromycin-resistant Streptococcus pneumoniae.

There are no data regarding the activity of clarithromycin's active metabolite, 14-hydroxy clarithromycin, against penicillin-intermediate, penicillin-resistant or erythromycin-resistant Streptococcus pneumoniae. Agar dilution MICs were determined for clarithromycin, 14-hydroxy clarithromycin (henceforth called 'metabolite'), azithromycin, erythromycin and clarithromycin/metabolite (2:1 and 1:1 ratio) against 24 penicillin-intermediate and 14 penicillin-resistant strains, including 13 erythromycin-resistant clinical strains and one ATCC strain of S. pneumoniae. The interaction between clarithromycin and its metabolite was determined using an agar chequerboard assay against all isolates, and time-kill tests were performed against five penicillin-intermediate (macrolide-susceptible) and five penicillin-resistant (two macrolide-resistant) strains of S. pneumoniae using all antibiotics alone at simulated peak serum concentrations, and clarithromycin/metabolite in a 2:1 ratio (physiological). MICs were as follows: clarithromycin, 0.008-->64 mg/L; metabolite, 0.015-->64 mg/L; erythromycin, 0.015-->64 mg/L; azithromycin, 0.125-->64 mg/L; clarithromycin/metabolite (1:1 and 2:1 combinations), 0.001-->64 mg/L. The MIC of the clarithromycin/metabolite combination was one or more tube dilution lower than the MIC of clarithromycin in 28 of the isolates tested. In chequerboard testing, 13 strains (seven erythromycin susceptible and six erythromycin resistant) demonstrated synergy, 18 additivity and seven indifference. In time-kill testing, bacterial eradication below detection limits occurred with clarithromycin and metabolite in seven of 10 organisms. The combination of parent and metabolite was more rapidly bactericidal than clarithromycin alone in six of the seven isolates (P = 0.026). The metabolite has potent activity against S. pneumoniae and enhances the activity of the parent compound against this organism. The metabolite's activity must be considered in evaluating clarithromycin in vitro to avoid underestimation of clarithromycin's activity against the pneumococcus.

Anti-Bacterial Agents↗

Emergence of invasive erythromycin-resistant Streptococcus pneumoniae strains in Portugal: contribution and phylogenetic relatedness of serotype 14.

OBJECTIVES: To study the phenotype and phylogenetic relatedness of invasive Streptococcus pneumoniae strains isolated in Portugal. METHODS: A total of 614 invasive S. pneumoniae strains, isolated in Portugal from 1999 to the first 6 months of 2002, were characterized using serotyping and antimicrobial susceptibility testing. National outpatient sale data for macrolides were compared with erythromycin resistance. We investigated the main clonal lineages from erythromycin-resistant strains of serotype 14 by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). RESULTS: The emergence of erythromycin-resistant strains correlated well with the usage of azithromycin in Portugal during the period of the study (r=0.900, P=0.001). Serotype 14 made the largest contribution to this emergence. We found two clonal complexes (CC) among erythromycin-resistant strains: CC1 was formed by three sequence types (ST), ST156, ST143 and ST1042, and CC2 by ST15 and ST9. All STs described, except ST1042, are putative founders of clonal groups or subgroups from serotype 14 as defined in the pneumococcal MLST database. CONCLUSIONS: This study suggests that macrolides usage is an important factor enhancing the spread of invasive erythromycin-resistant S. pneumoniae clones in Portugal. The study also makes a contribution to the understanding of spread of erythromycin-resistant clones in an international context.

Anti-Bacterial Agents↗

Evolution of erythromycin resistance in Streptococcus pneumoniae in Italy.

OBJECTIVES: To evaluate erythromycin resistance in recent invasive isolates of Streptococcus pneumoniae in Italy, to study the phenotypic and genotypic characteristics of the isolates, and to compare data with those obtained in a previous survey. METHODS: Invasive pneumococcal isolates were obtained from 56 laboratories throughout the country, in 2001-2003. Isolates were serotyped and antimicrobial susceptibilities determined by Sensititre panels and Etest. A new PCR was performed to detect erythromycin resistance genes. Typing methods for selected erythromycin-resistant isolates included PFGE and multilocus sequence typing (MLST). RESULTS: One hundred and fifty-five isolates out of 444 (34.9%) were resistant to erythromycin: 95 isolates (21.4%) carried erm(B), 56 (12.6%) carried mef(A) and three carried both genes. One isolate, carrying neither erm(B) nor mef(A), showed a point mutation in domain V of the 23S rRNA genes. The mef(A)-positive isolates carried subtype mef(A) (47 isolates), subtype mef(E) (nine isolates), and both subtype mef(E) and erm(B) (three isolates). All subtype mef(A) strains, except two, belonged to serotype 14, appeared to be clonally related by PFGE and related to the England14-9 clone by MLST. The two isolates belonging to other serotypes showed different genetic backgrounds. CONCLUSIONS: Erythromycin resistance in S. pneumoniae has increased in the last few years in Italy. erm(B) is still the predominant resistance determinant; however, the increase in erythromycin resistance (34.9% versus 28.8% of the previous years) is mainly due to an increase in the proportion of isolates carrying the efflux pump mef(A), whereas the proportion of isolates carrying erm(B) has not changed.

Drug Resistance, Bacterial↗

The effect of erythromycin, fluvoxamine, and their combination on the pharmacokinetics of ropivacaine.

UNLABELLED: We studied the effect of fluvoxamine and erythromycin on the pharmacokinetics of ropivacaine in a double-blinded, randomized, four-way cross-over study. Eight healthy volunteers ingested daily 1500 mg erythromycin for 6 days, 100 mg fluvoxamine for 5 days (Days 2-6), both erythromycin and fluvoxamine, or placebo. On Day 6, each subject received a single dose of 0.6 mg/kg ropivacaine IV over 30 min. Ropivacaine, 3-hydroxyropivacaine, and 2',6'-pipecoloxylidide in venous plasma and urine samples were measured for up to 12 h and 24 h, respectively. Fluvoxamine increased the area under the drug plasma concentration-time curve (AUC) of ropivacaine 3.7-fold (P: < 0.001), prolonged the elimination half-life (t(1/2)) from 2.3 to 7.4 h (P: < 0.01), and decreased the clearance by 77% (P: < 0.001). Erythromycin alone had only a minor effect on the pharmacokinetics of ropivacaine. However, when compared with fluvoxamine alone, the combination of fluvoxamine and erythromycin further increased the area under the drug plasma concentration-time curve and t(1/2) of ropivacaine by 50% (P: < 0.01). We conclude that inhibition of CYP1A2 by fluvoxamine considerably reduces elimination of ropivacaine. Concomitant use of fluvoxamine and CYP3A4 inhibitor erythromycin further increases plasma ropivacaine concentration by decreasing its clearance. IMPLICATIONS: Clinicians should be aware of the possibility of increased toxicity of ropivacaine when used together with inhibitors of CYP1A2. Concomitant use of CYP1A2 and CYP3A4 inhibitors further increases ropivacaine concentration.

Adult↗

Ionic basis of the differential effects of intravenous anesthetics on erythromycin-induced prolongation of ventricular repolarization in the guinea pig heart.

BACKGROUND: Dysrhythmias and death occur in patients with acquired long QT syndrome (LQTS). Little information exists regarding interactions between anesthetics and drugs that prolong ventricular repolarization. Therefore the effects of three commonly used intravenous anesthetics on ventricular repolarization were investigated in the setting of drug-induced, long QT syndrome. METHODS: The effects of increasing concentrations (0, 10, 25, and 50 microM) of propofol, ketamine, and thiopental on ventricular repolarization were evaluated by measuring the monophasic action potential duration at 90% repolarization (MAPD90) in guinea pig Langendorff-perfused hearts in the absence or presence of erythromycin (100 microM). If an anesthetic enhanced erythromycin-induced prolongation of MAPD90, its effects on the delayed rectifier (I[K]) and inward rectifier (I[Kl]) potassium currents were measured using the whole-cell patch-clamp technique. RESULTS: At clinically relevant concentrations, only thiopental significantly modulated erythromycin's effect on MAPD90. Thiopental at 10, 25, and 50 microM prolonged MAPD90 from a control of 163 +/- 6 ms by 18 +/- 4, 30 +/- 3, and 31 +/- 4 ms, respectively. In a separate group, erythromycin prolonged MAPD90 from 155 +/- 2 ms to 171 +/- 2 ms (n = 21, P < 0.001). In the presence of erythromycin, thiopental at 10, 25, and 50 microM caused significantly greater prolongation from a control of 171 +/- 2 ms by 39 +/- 2, 58 +/- 3, and 72 +/- 6 ms, respectively. Whole-cell patch-clamp experiments indicated that thiopental inhibited I(K) and I(Kl). CONCLUSIONS: Intravenous anesthetics caused markedly different effects on ventricular repolarization. Thiopental, unlike propofol and ketamine, potentiated the effects of erythromycin on ventricular repolarization by inhibiting I(K) and I(Kl).

Action Potentials↗

Intravenous erythromycin facilitates bedside placement of postpyloric feeding tubes in critically ill adults: a double-blind, randomized, placebo-controlled study.

UNLABELLED: OBJECTIVE To evaluate the efficacy of intravenous erythromycin as a method to facilitate feeding tube placement into the small intestine in critically ill patients. DESIGN Double blind, randomized, controlled trial. SETTING Medical and surgical intensive care units in an academic medical center. PATIENTS Prospective cohort of 36 consecutive adults requiring intensive care unit care and enteral tube feeding for nutritional support. INTERVENTION Infusion of a single dose of intravenous erythromycin (500 mg) or saline before placement of 10-Fr feeding tubes using a standardized active bedside protocol. MEASUREMENTS AND MAIN RESULTS We determined the success rate of feeding tube placement into or beyond the second portion of the duodenum and the time required for this procedure by experienced nurses. The feeding tube was considered to be postpyloric when the tip was in the second portion of the duodenum or beyond. The predictive value of a serial step-up in gastrointestinal aspirate pH from < or = 5.0 to > or = 6.0 was also determined. Use of intravenous erythromycin significantly improved the rate of feeding tube placement into the duodenum or jejunum (erythromycin group, 13 of 14 patients or 93% vs. the control group, 12 of 22 patients or 55%; p < .03). Erythromycin administration also significantly decreased the procedure time from 25 +/- 3 to 15 +/- 2 mins (p < .04). Feeding tube placement into either duodenum or jejunum was confirmed in all 18 patients with a pH step-up from < or = 5.0 to > or = 6.0. CONCLUSION: A single bolus dose of intravenous erythromycin facilitates active bedside placement of postpyloric feeding tubes in critically ill adult patients.

Critical Illness↗

Effect of erythromycin on gastroduodenal contractile activity in developing neonates.

BACKGROUND: The occurrence of phase III of migrating motor complexes in neonates is inversely related to gestational age, and it can be triggered in some infants by the motilin receptor agonist erythromycin. After intragastric erythromycin, the authors determined 1) the occurrence and characteristics of phase III of migrating motor complexes, 2) the antral and duodenal motor responses, and 3) the dose-response relation among preterm and full-term infants. METHODS: Using an unbalanced, repeated measures design, 25 preterm and term infants were given two of three doses of intragastric erythromycin: 0.75, 1.5, and 3.0 mg/kg. Motor activity was recorded 3 hours before and 2 hours after each dose using a continuous water perfusion manometry system. RESULTS: Erythromycin failed to induce phase III of migrating motor complexes in infants younger than 31 weeks' gestation; however, it induced phase III in a dose-dependent manner among infants whose gestational ages were 32 weeks and older ( P < 0.05). Erythromycin significantly increased the amplitude and frequency of antral contractions in term infants and significantly increased the duodenal contraction amplitude in older preterm and term infants, but these effects were absent in younger preterm infants. CONCLUSIONS: The ontogenic emergence of the motilin receptor-mediated induction of phase III occurs by 32 weeks' gestation, whereas the non-motilin-mediated response of increased antroduodenal motor activity is not observed until term. Therefore, early use of erythromycin as a prokinetic agent may not be useful in very preterm infants, partially useful in older preterm infants, and useful in full-term infants.

Aging↗

Erythromycin as a prokinetic agent in preterm infants.

BACKGROUND: The macrolide antibiotic erythromycin is a prokinetic agent that stimulates gastrointestinal motility. The aim of the study was to determine the effect of erythromycin on the gastrointestinal motility of preterm infants. METHODS: Erythromycin 10 mg/kg, 8 hourly or a placebo, was given orally for 7 days in a double-blind randomized, crossover study of 20 preterm infants with a median gestational age of 32 weeks (range, 26-34 weeks). Antral contractility was determined by using ultrasonography to measure the decrease in the gastric antral cross-sectional area after a feed. The whole gut transit time was assessed by timing the transit of carmine red through the gut. RESULTS: Antral contractility lasted for a shorter period of time during erythromycin treatment than during placebo treatment (mean [standard deviation], 31 minutes [9.9 minutes] vs. 70 minutes [13 minutes]; P < 0.01). Whole gut transit time was also shorter during erythromycin treatment (mean, 23.1 hours [12.9 hours] vs. 49.3 hours [29 hours]; P < 0.01). All infants tolerated the drug well. CONCLUSIONS: Oral erythromycin in food-intolerant preterm infants enhances both antral contractility and whole gut transit time.

Administration, Oral↗

Erythromycin fails to improve feeding outcome in feeding-intolerant preterm infants.

OBJECTIVE: Approximately half of extremely low birth weight infants have feeding intolerance, which delays their achievement of full enteral feedings. Erythromycin, a motilin receptor agonist, triggers migrating motor complexes and accelerates gastric emptying in adults with feeding intolerance. Few studies have assessed the efficacy of this drug in preterm infants with established feeding intolerance. This study was designed to assess the efficacy of erythromycin in feeding-intolerant infants, as measured by gastric emptying, maturation of gastrointestinal motor patterns, and time to achieve full enteral feedings. METHODS: Subjects were 27 preterm infants who were admitted to the neonatal intensive care unit and who did not achieve full enteral feeding volumes (150 mL/kg/day) within 8 days of the initiation of feedings. In a controlled, randomized, double-blinded clinical trial, infants received intragastric erythromycin or placebo for 8 days without crossover. At study entry, the authors recorded motor activity in the antrum and the duodenum during fasting, in response to intragastric erythromycin (1.5 mg/kg) or placebo, and in response to feeding. Gastric emptying at 20 minutes and transit time from duodenum to anus were determined. Each infant then received erythromycin or placebo for 8 days, and feeding characteristics were prospectively tracked. RESULTS: Gastric emptying and characteristics of antroduodenal motor contractions were similar in the two groups, as were the transit times from duodenum to anus. Feeding outcomes were comparable in the two groups. CONCLUSION: Intragastric erythromycin does not improve feeding tolerance in preterm infants with established feeding intolerance because it fails to improve gastrointestinal function in the short or long term.

Administration, Oral↗

Outbreak of erythromycin-resistant staphylococcal conjunctivitis in a newborn nursery.

We investigated an outbreak of erythromycin-resistant Staphylococcus aureus conjunctivitis in a hospital newborn nursery that used erythromycin eye ointment to prevent ophthalmia neonatorum. Cases occurred in 2 clusters; 20 (14%) of 146 infants in the nursery developed conjunctivitis from July through October, 1987; and 5 (7%) of 69 infants in the nursery developed conjunctivitis during April and May, 1988. A case-control study of the first cluster demonstrated that culture-confirmed cases were more likely than controls to have received prophylactic erythromycin eye ointment or their initial bath from one nurse (odds ratio, 9.0; P = 0.01) or to have been delivered by one physician (odds ratio, 12.7; P = 0.03). The nurse was the only staff person to have a nasopharyngeal culture which yielded erythromycin-resistant S. aureus. Control measures, instituted in October, 1987, included using silver nitrate drops instead of erythromycin eye ointment for prophylaxis; however, in January, 1988, the hospital resumed use of erythromycin eye ointment. No additional cases were identified until mid-April, 1988, when the second cluster of cases occurred. At that time the hospital reinstituted the use of silver nitrate and no additional cases were identified. This investigation illustrates the potential for conjunctival infection with an antimicrobial-resistant pathogen when antimicrobials are used to prevent ophthalmia neonatorum.

Administration, Topical↗

Evaluation of oral erythromycin and local isoniazid instillation therapy in infants with Bacillus Calmette-Guérin lymphadenitis and abscesses.

A randomized placebo-controlled prospective trial was conducted to evaluate the efficacy of erythromycin therapy in 69 patients affected with Bacillus Calmette-Guérin lymphadenitis. When patients who developed subsequent regional abscesses were excluded, erythromycin caused significantly earlier resolution of lymphadenitis (5.1 months vs. 5.7 months for placebo; P < 0.01) compared with placebo. There was no significant difference in the proportion of patients who developed subsequent regional abscesses between the 2 groups (47% for erythromycin, 60% for placebo, P = 0.14). When the entire group of 69 patients was evaluated for "duration to heal" (regardless of subsequent abscess formation), erythromycin therapy (4.1 +/- 1.5 SD months) did not differ significantly from the placebo group (3.5 +/- 1.3 months, P = not significant). Patients who developed subsequent abscess (n = 36) along with those with B. Calmette-Guérin regional abscesses at presentation (n = 27) were further studied to compare oral erythromycin therapy with that of single dose 50-mg intranodal isoniazid instillation. Local isoniazid therapy caused significantly earlier resolution of the abscesses (3.9 months) compared with erythromycin therapy (5.2 months; P < 0.001).

Abscess↗

Erythromycin resistance of Streptococcus pyogenes in Madrid.

BACKGROUND: Erythromycin is considered to be an adequate alternative to penicillin for patients who are allergic to penicillin. Erythromycin-resistant Streptococcus pyogenes strains have been reported in some parts of the world. METHOD: The in vitro activity of erythromycin and other antimicrobial agents was determined in a total of 1310 clinical Streptococcus pyogenes isolates collected in the city of Madrid from January, 1993, through December, 1996. RESULTS: All strains showed susceptibility to penicillin, rifampin, vancomycin and chloramphenicol. Tetracycline resistance was 8.5%. In 36 of the strains (2.7%) MIC was 4 microg/ml for ofloxacin. Clindamycin resistance was observed in only 18 strains (1.4%); this resistance was constitutive in 15 and inducible in 3 strains. Resistance to erythromycin was observed in 14.3% of the strains, showing an increase during the study period (2.0% in 1993 vs. 22.4% in 1996; chi square for linear trend 68.8, P < 0,0001); >90% of them showed the novel resistance phenotype described by Seppälä et al. and 32 of 32 of these strains showed by PCR the 1.4-kb fragment of the mefA gene recently described as the novel macrolide efflux resistance determinant. The erythromycin-resistant strains were isolated more often in pediatric patients (144 of 872) than in adults (44 of 438) (chi square 9.9, P = 0.0016). CONCLUSION: The study emphasizes the need to screen for resistance to macrolides in S. pyogenes and indicates that resistance to erythromycin in S. pyogenes has increased significantly in Madrid.

Adolescent↗

High prevalence of erythromycin resistance of Streptococcus pyogenes in Greek children.

BACKGROUND: Macrolide resistance among Streptococcus pyogenes strains is increasing in many European countries. Greece was not considered a country with high prevalence of macrolide-resistant S. pyogenes strains, and until now the genetic mechanism of resistance was unknown. METHODS: During the 25-month period from December, 1998, to December, 2000, pharyngeal cultures for S. pyogenes were performed on 743 Greek children with the clinical diagnosis of pharyngitis. The children were 1 to 16 years old (median age, 7 years) and were living in Central and Southern Greece. S. pyogenes isolates were tested for their susceptibility to erythromycin, clarithromycin, azithromycin, clindamycin, penicillin G, amoxicillin/clavulanate and cefprozil. The erythromycin-resistant isolates were further studied for their genetic mechanism of resistance by means of PCR. RESULTS: Of a total of 275 S. pyogenes isolates recovered, 105 (38%) were erythromycin-resistant (MIC > or = 1 microgram/ml) [corrected], with 54, 45 and 1% of them carrying mef(A), erm(A) [subclass erm(TR)] and erm(B) gene, respectively. The prevalence of erythromycin-resistant strains was 29 and 42% during the time periods December, 1998, to December, 1999, and January, 2000, to December, 2000, respectively. All erythromycin-resistant isolates were also resistant to clarithromycin and azithromycin. The isolates carrying the erm(A) gene were inducibly resistant to clindamycin. The 275 S. pyogenes isolates had ceprozil MICs < or = 0.032 microgram/ml. CONCLUSIONS: The current high (38%) prevalence of erythromycin-resistant S. pyogenes in Central and Southern Greece requires continuous surveillance and careful antibiotic policy.

Adolescent↗

A clinical isolate of Neisseria gonorrhoeae with in vitro resistance to erythromycin and decreased susceptibility to azithromycin.

BACKGROUND AND OBJECTIVES: Erythromycin is a recommended treatment for penicillin-allergic pregnant women with gonorrhea, and azithromycin has been suggested as therapy for coexisting gonococcal and chlamydial infections. Although gonococcal resistance to erythromycin is not uncommon, decreased resistance to azithromycin is rare. A clinical isolate of Neisseria gonorrhoeae with in vitro resistance to erythromycin and decreased susceptibility to azithromycin is reported. STUDY DESIGN: This is a case report. RESULTS: Antimicrobial susceptibility testing of a clinical isolate of N. gonorrhoeae revealed a minimal inhibitory concentration (MIC) of 2 micrograms/ml to azithromycin and 32 micrograms/ml to erythromycin. Five hundred other urethral isolates were tested, resulting in an MIC for erythromycin ranging from 0.015 to 2 micrograms/ml. The range for azithromycin was 0.015 to 0.5 micrograms/ml. There was a strong correlation between erythromycin and azithromycin MICs (r = 0.73; P < 0.0001). CONCLUSIONS: Continued national monitoring is needed to detect the appearance and early dissemination of new types of gonococcal resistance.

Adult↗

Carbamazepine--erythromycin interaction leading to carbamazepine toxicity in four epileptic children.

We report four cases of carbamazepine toxicity in children associated with the concurrent administration of erythromycin. They all developed clinical toxicity (ataxia, dizziness, nausea, and vomiting) when erythromycin administration was begun; symptoms disappeared after erythromycin was discontinued. Serum carbamazepine levels were measured before, during, and, in most cases, after the toxic episodes. In all cases, there was a sharp increase in carbamazepine concentration after erythromycin therapy was begun and a rapid fall once erythromycin was discontinued. Our data support the previous suggestion that erythromycin interferes with the liver microsomal metabolism of carbamazepine with a subsequent increase in blood levels of the drug.

Carbamazepine↗

Lack of interaction of erythromycin with temazepam.

Erythromycin is a strong inhibitor of cytochrome P450 [CYP3A4] and has a potentially dangerous interaction with midazolam and triazolam. The possible interaction between erythromycin and a short-acting benzodiazepine, temazepam, was investigated in a double-blind, randomized crossover study. Ten healthy volunteers received 500 mg erythromycin or placebo orally three times a day for 6 days followed by a challenge dose of 20 mg temazepam. Plasma samples were collected for the determination of temazepam, oxazepam, and erythromycin, and psychomotor effects were measured during the 24 h after intake of temazepam. Erythromycin did not change the pharmacokinetics or pharmacodynamics of temazepam to a statistically significant degree. The metabolic fate of temazepam and its almost complete bioavailability explain the lack of interaction. Temazepam, unlike midazolam or triazolam, can thus be prescribed in the usual doses for patients receiving erythromycin.

Administration, Oral↗