Erythromycins accumulation

EM-susceptible or resistance-uninduced cells of S. aureus strains, on the other hand, is 12 to 15 times greater than the same extracellular level. The addition of CCCP to the culture of these strains increases erythromycin accumulation from 34 X 10 to 37 X 10 M. The increase in the bacterial cells in the presence of CCCP is estimated to be 25 to 27 times higher than the extracellular concentration. The amounts that accumulate in the presence of an uncoupler (0.1 mM) are only about twice the level of that in the absence of an inhibitor [197,198]. In addition, ribosome has a high affinity for erythromycin (K 1 x 10 to 3 x 10 A0, regardless of whether it is sensitive or resistant S. aureus ribosome [199]. 

Certain drugs are excreted in urine only in small amounts but appear in high concentrations in the bile for example, erythromycin, novobiocin, tetracycline, phenolphthalein etc. The abnormality or any disease related to liver may impair bile secretion which can lead to the accumulation of certain drugs like probenecid, digoxin etc. This can also lead to decreased drug metabolism and decreased rates of secretion of drugs into bile. 

Health hazards from drug residues in food depend on the frequency and degree of human exposure. Increase in the degree of human exposure occurs when injection sites are accidentally consumed. Continuous exposure is more probable when a side or quarter of a contaminated food animal is purchased by a consumer for deep-freeze use. Basic antibiotics such as chloramphenicol, erythromycin, tylosin, and oleandomycin, are more likely to accumulate in tissue at a higher concentration than in plasma due both to ion trapping, which results from a pH difference between blood and tissue, and to the innate lipid solubility of the compounds (1). A factor with the potential to reduce the drug residues intake is that most animal tissues are cooked before eating, which may decrease 269... 

Distribution Erythromycin distributes well to all body fluids except the cerebrospinal fluid (CSF). It is one of the few antibiotics that diffuses into prostatic fluid and has the unique characteristic of accumulating in macrophages. It concentrates in the liver. Inflammation allows for greater tissue penetration. Similarly, clarithromycin and azithromycin are widely distributed in tissues. Serum levels of azithromycin are low the drug is concentrated in neutrophils, macrophages, and fibroblasts. 

Contraindications Patients with hepatic dysfunction should not be treated with erythromycin, since the drug accumulates in the liver. 

Interactions Erythromycin and clarithromycin inhibit the hepatic metabolism of theophylline, warfarin, terfenadine, astemizole, carbamazepine and cyclosporine which can lead to toxic accumulations of these drugs. An interaction with digoxin may occur in some patients. In this case, the antibiotic eliminates a species of intestinal flora that ordinarily inactivates digoxin, thus leading to greater reabsorption of digoxin from the enterohepatic circulation. 

Mibefradil inhibits CYP3A4 (2). Other drugs that are metabolized by this pathway accumulate as a result. Drugs that were commonly affected included amiodarone, astemizole, ciclosporin, cisapride, erythromycin, imi-pramine, lovastatin, propafenone, quinidine, simvastatin (9), tacrohmus (10), tamoxifen, terfenadine, thioridazine, and drugs that impair sinoatrial node function (for example beta-blockers) (6). 

Accumulation of the parent drug and resultant QT prolongation may occur following a overdose, a drug interaction that limits metabolism of terfenadine (e.g., concomitant administration with erythromycin or other macrolide antibiotic or with the azole derivatives ketoconazole or itraconazole), or significant hepatic dysfunction that limits metabolism of terfenadine. Patients with preexisting cardiac disease or those with electrolyte abnormalities are also at increased risk for cardiac toxicity. 

The accumulation of novel erythromycin-derivatives has been reported after replacing the loading domains (AT and ACP) of module 1 of DEBS with the loading domains from the avermectin producer. As expected, and again due to the broad substrate specificity of AT and ACP from S. avermitils, the hybrid enzyme was producing a number of new antibiotics (72-80)) [53] (Fig. 12.14). 

Figure 5.42. The 2D C, H COSY NMR spectrum of erythromycin in CDCIj as a contour plot beneath the corresponding ID C spin-echo NMR spectrum. The spin-echo spectrum (pulse sequence 90°-(r-I80°-x) -data acquisition) was acquired with broadband proton decoupling during the second period and data accumulation. With x = 8 ms CH2 and C resonances are inverted relative to CHj and CH resonances. The small triangles (A) indicate the two outer lines of the solvent triplet. The contour plot levels are higher than the cross-peaks due to methylene moieties.

It has been found that macrolide-susceptible bacteria such as Bacillus subtilis and S. aureus accumulate about 10 times more erythromycin than do resistant bacteria, namely, clinically isolated S. aureus [6], spontaneously mutated B. subtilis [7], and intrinsically resistant . coli [8]. 

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