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Enhanced anti-Shigella activity of erythromycin supplemented with sulfadiazine.

Sulfadiazine enhanced the anti-Shigella activity of erythromycin. Erythromycin passes through the type III secretion apparatus and suppresses the growth of invasive Shigella organisms. Sulfadiazine enhanced this effect at the concentration under minimum inhibitory concentration and it came from not only the folate-inhibiting activity but also from a new function. It has proved that sulfadiazine stimulated type III secretion in Shigella as determined from the secretion of the pathogenic protein IpaB. As Congo red induced secretion of Ipa proteins and uptake of erythromycin through the type III secretion gate, sulfadiazine which is similar to Congo red in chemical structure may induce the uptake in the same way.

Animals↗

Molecular characterization of the erythromycin resistance plasmid pPV142 from Staphylococcus simulans.

The 2.5-kb erythromycin resistance (EmR) plasmid pPV142 of Staphylococcus simulans 13044 was isolated and characterized. Sequence analysis identified ORF1 and ORF2 encoding a 158-residue replication protein (Rep142) and a 244-residue erythromycin resistance protein (Erm, rRNA adenine N-6-methyltransferase), respectively. Structural analysis and Southern hybridization showed that the rep and ermM genes in pPV142 shared homology with the EmR plasmid pPV141 (2.4 kb) of S. chromogenes 3688 and other EmR plasmids known to exist in staphylococci and bacilli. Based on the presence of a 61-bp repeat upstream of the ermM gene, pPV142 is apparently a unique member of the pSN2 family of EmR plasmid able to express erythromycin resistance constitutively.

Amino Acid Sequence↗

23S rRNA point mutation associated with erythromycin resistance in Treponema denticola.

Mechanisms and occurrence of macrolide resistance in the periodontal pathogen Treponema denticola have received little attention. In this study, erythromycin resistance due to mutations in the genes encoding T. denticola 23S rRNA was investigated. The T. denticola genome was shown to contain two copies of 23S rDNA. 23S rRNA genes of nine erythromycin-resistant isolates derived from T. denticola were amplified and sequences were analyzed. All the erythromycin-resistant strains had at least one A-->G transition mutation at the 23S rRNA gene sequence cognate to position A2058 in Escherichia coli 23S rDNA. This suggests that antibiotic pressure is sufficient to select for point mutations that confer resistance in this organism.

Anti-Bacterial Agents↗

Acute hepatocellular effects of erythromycin, gentamicin, and trospectomycin in the perfused rat liver: lack of correlation between lamellar body induction potency and cytotoxicity.

The formation of multilamellar inclusion bodies in cytoplasm is a generalized cellular response to treatment with a variety of chemical agents. The present study was conducted to determine if a correlation exists between acute lamellar body induction potency and cytotoxicity in the perfused rat liver. Livers were perfused for 3 hrs with various concentrations of erythromycin, gentamicin, sulfate, or trospectomycin sulfate, all of which are known to produce lamellar bodies in the rat in vivo. At the end of the experiments, the livers were perfusion fixed for transmission electron microscopy. Based on the bile flow rate, perfusion rate at constant pressure, and cytoplasmic enzyme release, neither gentamicin nor trospectomycin was hepatotoxic at concentrations up to 1.8 mM, whereas erythromycin was toxic at 0.1 mM. Gentamicin caused no ultrastructural changes compared to controls, but trospectomycin caused the dose-dependent formation of lamellar bodies in hepatocytes without other cytoplasmic alterations. Erythromycin caused cellular degeneration accompanied by an increase in the number of secondary lysosomes, but these lacked lamellated inclusions. It is concluded that hepatic lamellar bodies can be induced in acute ex vivo experiments, but that their formation does not appear to be linked with acute cytotoxicity.

Animals↗

Influence of carbon-dioxide tension and medium buffer concentration on medium pH and MIC values of erythromycin for Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 25923 in a micro-aerobic atmosphere.

The effect of an elevated carbon-dioxide tension on medium pH and MIC determination with erythromycin for Staphylococcus aureus (ATCC 25923) and Escherichia coli (ATCC 25922) was investigated in a micro-aerobic atmosphere, using an agar dilution method. During 30 h of incubation in an atmosphere containing approximately 6% CO2, 5% O2 and 89% N2, pH of uninoculated, as well as of seeded, blood agar plates decreased from 7.4 to 6.8. MIC values of erythromycin were two dilution steps higher after micro-aerobic incubation than after aerobic incubation. A decrease in agar pH during micro-aerobic incubation was eliminated by increasing the phosphate buffer concentration in the medium. However, MIC values of erythromycin remained high.

Aerobiosis↗

Postantibiotic effect and postantibiotic sub-mic effect of dirithromycin and erythromycin against respiratory tract pathogenic bacteria.

The postantibiotic effect (PAE) of dirithromycin and erythromycin against strains Streptococcus pyogenes group A M12, NCTC P1800, Streptococcus pneumoniae 23, Staphylococcus aureus Oxford strain 209, Moraxella catarrhalis 15616 and Haemophilus influenzae 5590 was investigated in vitro and in vivo by use of the tissue cage model in rabbits. By exposing strains to 2.5-5 x MIC levels for 6 h or 12 h, both compounds induced in vitro PAEs of 1-9 h, and in two cases >20 h. Cultures in the PAE-phase were then re-exposed to subinhibitory concentrations (0.25 x MIC and 0.5 x MIC) of antibiotic and prolonged suppression of regrowth was obtained for 2->20 h. Following i.v. antibiotic treatment of rabbits (10 mg/kg or 20 mg/kg dirithromycin and 20 mg/kg or 40 mg/kg erythromycin) and bacterial infection of the implanted tissue cages in the same rabbit, the tissue cage fluid (TCF) was sampled 6 h after infection and regrowth was monitored by sampling from new tissue cages in untreated rabbits. These i.v. single doses of both antibiotics induced in vivo PAEs of >6 h, but <20 h against S. pyogenes. Suppression of regrowth in TCF was also obtained for > or = 20 h on infection with exposed S. pyogenes in the PAE-phase in newly implanted tissue cages in rabbits that had been treated with low doses of antibiotic to produce subinhibitory concentrations in the TCE Dirithromycin was in general as active as erythromycin in inducing PAE and in prolonging suppression of bacterial regrowth in the PAE phase.

Animals↗

Treatment of concomitant eye and genital chlamydial infection with erythromycin and roxithromycin.

A single blind study of 10 days' randomly allocated treatment with erythromycin (1000 mg/day) and roxithromycin (300 mg/day) in 14 (group A) and 13 (group B) adults, respectively, all with culture-proven chlamydial conjunctivitis was performed. For comparison, 14 days' treatment with 1 g erythromycin daily given to 35 adults (Group C) with chlamydial conjunctivitis was also evaluated. Follow-up was made approximately one month after start of therapy. Only 2 of the 37 men and 1 of the 25 women studied, all of whom had signs of conjunctivitis, had noticed concomitant symptoms of infection from the genital tract. Nasopharyngeal cultures were chlamydia-positive in 7 (50%), 7 (54%) and 20 (57%) of the patients in Group A, B and C, respectively, while for genital cultures the corresponding figures were 9 (64%), 8 (62%) and 23 (66%), respectively. The course with erythromycin in group C cured the conjunctivitis in 34 (97%) of the patients both clinically and microbiologically. Ten days' treatment with the same dose (Group A) did not eradicate chlamydiae from the eye in one, from the nasopharynx in 5 and from the genital tract in still another patient. The roxithromycin treatment (Group B) resulted in negative chlamydial cultures from the eyes in all 13 cases, while the nasopharyngeal and genital cultures were still positive in one patient each. The study showed that in spite of the eye being cured by macrolide therapy, other sites like the nasopharynx and the genital tract may still be colonized, why sampling for C. trachomatis from these sites should be made in tests for cure in chlamydial conjunctivitis cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

[Effect of erythromycin on anti staphylococcal activity and dye production of Pseudomonas aeruginosa isolated from clinical materials].

Anti staphylococcal activity by Pseudomonas aeruginosa was investigated through the use of the reversed agar plate and the filter paper stamp methods. Investigation was also conducted on the dye production of different clinical isolates of Pseudomonas aeruginosa, the relationship between drug susceptibility and anti staphylococcal activity, and the influence of erythromycin on anti staphylococcal activity. Seventy four strains of Pseudomonas aeruginosa were prepared which included 20 strains from pus, 34 strains from sputum and 20 strains from urine. These were then inoculated with methicillin resistant Staphylococcus aureus (MRSA). They were then cultured for 48 hours by using the reversed agar plate and the filter paper stamp methods. Anti staphylococcal activity was observed in 16 strains from pus (80%), 19 strains from sputum (55.9%) and 8 strains from urine (40%). The Pseudomonas aeruginosa strains which have no pigment tended to show poor anti staphylococcal activity. Drug susceptibility was tested using PIPC, AMK, IPM, CFS and OFLX. The strains which showed resistance to OFLX tended to show poor anti staphylococcal activity. Erythromycin inhibited the dye production of Pseudomonas aeruginosa but exhibited no effect on anti staphylococcal activity. Consequently, these results suggest erythromycin has exhibited a previously unknown pharmacological effect, furthermore, anti staphylococcal activity was not caused by pigmentation only.

Erythromycin↗

[Suppression of the Pseudomonas aeruginosa-induced biofilm formation on human epithelial cells by erythromycin].

In the present study, were examined the inhibitory effect of erythromycin on the biofilm formation by a temperature-sensitive mutant (Ts25) of Pseudomonas aeruginosa N-42 on the surface of Ishikawa cells which can produce a mucin-like glycoprotein physicochemically similar to mucoproteins produced in the human airway. Usually, 38-45 microcolonies (biofilms) were formed after 10 days of incubation in cultures of Ishikawa cells and P. aeruginosa Ts25. Erythromcin suppressed the adhesion to Ishikawsa cells of P. aeruginosa and its subsequent biofilm formation at doses as low as 0.2 microgram/ml. Erythromycin also exhibited the suppressive effect on the production of glycoproteins by Ishikawa cells at doses higher than 1 microgram/ml and the production of elastase and exoenxyme A from P. aeruginosa at doses higher than 2 micrograms/ml. These results suggest that erythromycin can inhibit the biofilm formation in culture of human epithelial cells and P. aeruginosa and the in-vivo bacterial biofilm formation may be attributed to host cell-derived factors rather than bacterial products.

Biofilms↗

[Efficacy of erythromycin inhalation in chronic respiratory infection caused by Pseudomonas aeruginosa].

The prognosis of chronic respiratory tract infection with Pseudomonas aeruginosad considered to be poor. However, low-dose and long-term 14 membered macrolide, such as erythromycin or clarithromycin, treatment has been reported as effective clinically in chronic lower respiratory tract disease. There was no report to investigate the effect of macrolide on chronic biofilm related Pseudomonas aeruginosa respiratory tract infection in vivo. In a newly established murine model of chronic Pseudomonas aeruginosa respiratory infection mimicking diffuse panbronchiolitis (DPB), we investigated the effect of erythromcin inhalation on viable bacteria in the lungs. Infection was produced by placement of a plastic tube in the bronchus with inoculating. Pseudomonas aeruginosa suspended in saline was also inoculated in bronchus after intubation of the tube. Viable bacteria were constantly isolated at 10(4) 10(6) cfu-specimen from the lungs for more than 30 days. Treatment with erythromycin inhalation for four days reduced the number of viable bacteria in the lungs with statistically significant. Our result indicated that our new model of chronic respiratory tract infection is simple and provides a useful tool to study the pathogenic process and treatment of such infection. Our results also suggest that the erythromycin inhalation is effective on chronic Pseudomons aeruginosa respiratory infection.

Administration, Inhalation↗

Erythromycin, roxithromycin, and clarithromycin: use of slow-binding kinetics to compare their in vitro interaction with a bacterial ribosomal complex active in peptide bond formation.

In a cell-free system derived from Escherichia coli, it is shown that clarithromycin and roxithromycin, like their parent compound erythromycin, do not inhibit the puromycin reaction (i.e., the peptide bond formation between puromycin and AcPhe-tRNA bound at the P-site of 70S ribosomes programmed with heteropolymeric mRNA). Nevertheless, all three antibiotics compete for binding on the ribosome with tylosin, a 16-membered ring macrolide that behaves as a slow-binding, slowly reversible inhibitor of peptidyltransferase. The mutually exclusive binding of these macrolides to ribosomes is also corroborated by the fact that they protect overlapping sites in domain V of 23S rRNA from chemical modification by dimethyl sulfate. From this competition effect, detailed kinetic analysis revealed that roxithromycin or clarithromycin (A), like erythromycin, reacts rapidly with AcPhe-tRNA.MF-mRNA x 70S ribosomal complex (C) to form the encounter complex CA which is then slowly isomerized to a more tight complex, termed C*A. The value of the overall dissociation constant, K, encompassing both steps of macrolide interaction with complex C, is 36 nM for erythromycin, 20 nM for roxithromycin, and 8 nM for clarithromycin. Because the off-rate constant of C*A complex does not significantly differ among the three macrolides, the superiority of clarithromycin as an inhibitor of translation in E. coli cells and many Gram-positive bacteria may be correlated with its greater rate of association with ribosomes.

Anti-Bacterial Agents↗

Resistance of group A beta-hemolytic streptococci to lincomycin and erythromycin.

Ten (0.05%) of 18,628 strains of Streptococcus pyogenes isolated from clinical specimens in the 3 years 1968 to 1970 were resistant to lincomycin and erythromycin. All 10 strains were highly resistant to lincomycin, having minimal inhibitory concentration (MIC) values of 200 mug/ml. There were two degrees of resistance to erythromycin: four strains were highly resistant, having MIC values of 200 mug or more/ml; and six strains showed slight resistance, MIC values being 0.78 to 1.56 mug/ml. There was no known epidemiological relationship between any of the patients infected with the resistant strains, which belonged to a variety of T serotypes. A zonal pattern of resistance to lincomycin occurred in four strains, all of which were only slightly resistant to erythromycin. After incubation for 24 hr in a twofold dilution series of lincomycin in broth, the strains grew in 0.05 mug or less/ml and in 50 and 100 mug/ml, but not in intermediate concentrations. Tests in agar indicated that the bacterial population of one strain, but not of the other three, was homogeneous in respect to its ability to grow readily in low and high, but not in intermediate, concentrations. The zone phenomenon is of significance in the clinical laboratory, since unawareness of it might result in a highly resistant strain being regarded as susceptible to lincomycin in tube or plate MIC tests that do not include sufficiently high concentrations of lincomycin.

Drug Resistance, Microbial↗

Comparison of clindamycin, erythromycin, and methicillin in streptococcal infections in monkeys.

Intravenous inoculation of a group A hemolytic streptococcus caused lethal infections in all of eight untreated monkeys. Intramuscular injections of clindamycin-2-phosphate in a daily dose of 25 mg/kg given in equal morning and afternoon doses for 10 days resulted in survival of all of eight monkeys. Similar results were observed with the same dose schedule of clindamycin hydrochloride given intragastrically; no fatalities occurred among eight monkeys. In monkeys receiving erythromycin stearate intragastrically or methicillin intramuscularly, three of eight and four of eight monkeys, respectively, died. Duration of both illness and positive blood cultures was greater in the erythromycin- and methicillin-treated survivors than in the clindamycin-treated monkeys. The differences in results between clindamycin and erythromycin could not be correlated with serum antibacterial activity levels, which were similar, or with minimal inhibitory concentrations, which were 0.02 mug/ml with both antibiotics. With methicillin, however, the minimal inhibitory concentration was 0.16 mug/ml and serum antibacterial activity varied from titers of less than 1:2 to 1:8. As in previous studies of staphylococcal infections in monkeys with the same antibiotics, in vitro susceptibility data and serum antibacterial activity did not completely correlate with in vivo results.

Animals↗

Comparative pharmacology of josamycin and erythromycin stearate.

Two macrolide antibiotics, josamycin and erythromycin stearate, were administered orally to healthy, adult male volunteers for a comparative study of their pharmacological properties. In comparable doses, josamycin and erythromycin produced similar plasma concentrations, with similar half-lives and elimination constants. An initial loading dose of 1.5 g of josamycin produced greater peak concentrations of antibiotic throughout a 10-day period with a regimen of every 6 h. In addition, josamycin tended to reach higher peak and trough concentrations after regimens of every 6 or 8 h were maintained for 2 days. Josamycin penetrated into saliva, sweat, and tears, and it was better tolerated in fasting subjects than was erythromycin stearate.

Adult↗

Mechanism of penicillin-erythromycin synergy on antibiotic-resistant Staphylococcus aureus.

Clinically isolated strains of Staphylococcus aureus that are inducibly resistant to both erythromycin and penicillin were susceptible to a combination of the two antibiotics. The synergistic effect of the combination results from an inhibition of penicillinase induction by erythromycin, sparing penicillin and allowing this drug to inhibit growth. When resistance to erythromycin is constitutive rather than inducible, the combination is no longer synergistic.

Drug Synergism↗

In vitro antagonism by erythromycin of the bactericidal action of antimicrobial agents against common respiratory pathogens.

Ten strains each of Staphylococcus aureus, Haemophilus influenzae, Enterobacter spp., Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Streptococcus pneumoniae were tested in vitro against erythromycin combined with ampicillin, cefamandole, or gentamicin. Antagonism by erythromycin occurred with 47% of the combinations involving strains of S. aureus and to a lesser degree with H. influenzae. Synergy occurred most commonly with H. influenzae (27%). The high frequency of antagonism and synergy with these organisms was associated with a broad range of bacteriostatic action by erythromycin against these same bacteria. The implications for the treatment of pneumonia are discussed.

Ampicillin↗

Susceptibility of group A beta-hemolytic Streptococcus isolates to penicillin and erythromycin.

We have reevaluated the antibiotic susceptibilities of group A beta-hemolytic streptococci in view of recent reports of a high prevalence of erythromycin resistance in Japan and of an increase in penicillin treatment failures in the United States. A total of 474 isolates recovered during a 2- to 3-month period in 1980 were tested. All were susceptible by microtiter broth dilution to a penicillin concentration of less than or equal to 0.03 micrograms/ml (minimal inhibitory concentration), and 473 were killed by less than or equal to 0.06 micrograms/ml (minimal inhibitory concentration). Erythromycin minimal inhibitory concentrations showed a bimodal distribution: 95% were less than or equal to 0.06 micrograms/ml, and 5% were greater than or equal to 1 microgram/ml. Of the minimal bactericidal concentrations, 21% were greater than or equal to 1 microgram/ml and 3% were greater than or equal to 16 micrograms/ml. Group A beta-hemolytic streptococci remain susceptible to the inhibitory and bactericidal actions of penicillin, thus providing no in vitro explanation for the bacteriological relapses reported in some clinical studies. Unlike the Japanese experience, only 5% of our isolates were resistant to erythromycin (minimal inhibitory concentration, greater than or equal to 1 microgram/ml); however, 22% were tolerant (ratio of minimal inhibitory/bactericidal concentrations, greater than or equal to 32).

Erythromycin↗