Rifamycin resistance

Rifabutin, a semi-synthetic derivative of rifamy-cin S, is a bactericidal antibiotic primarily used in the treatment of tuberculosis. Its effect is based on blocking the DNA-dependend RNA-polymerase of the bacteria. Rifabutin is used in the treatment of infections with Mycobacterium avium intracellulare. Rifabutin is well tolerated in patients with HIV-related tuberculosis, but patients with low CD4 cell counts have a high risk of treatment failure or relapse due to acquired rifamycin resistance. 

The antibiotic rifamycin (Box 28-A) appears to interfere with initiation by competing for the binding of the initial purine nucleoside 5 -triphosphate. The same bacterial RNAP that synthesizes mRNA also transcribes both rRNA and the tRNAs. Thus, the synthesis of all forms of RNA is inhibited by rifamycin. When a population of bacteria is subjected to this antibiotic, a few individuals survive. These rifamycin-resistant mutants are no longer sensitive to the antibiotic. Among them are some mutants that produce an... 

RNAP with an altered (3 subunit. Since the mutant polymerases do not bind rifamycin, it was concluded that rifamycin binds to the (3 subunit and that the rifamycin-resistance gene rpoB or rif (which maps at 89 min) is the gene for the (3 subunits of RNA polymerase. 

Antimicrobial resistance to rifamycins develops rapidly both in vitro and in vivo [65,85,86], As a consequence, all the three members of the family (i.e. rifampicin, rifabutin and rifapentine) are used clinically as components of combination therapies [65,87], Being structurally related, rifaximin could share this potential. And indeed resistance rates, recorded in fecal strains of Enterobacteriaceae, Enterococcus, Bacteroides, Clostridium and anaerobic cocci, ranged between 30 and 90% after short-term (5 days) antibiotic (800 mg daily) treatment [82], A similar pattern was observed in 10 patients with hepatic encephalopathy after treatment with rifaximin 1,200 mg/day for 5 days [80]. 

Since rifamycins are important drugs for the treatment of M. tuberculosis infection [36, 86, 87] the activity of rifaximin on and interference with this bacterium have been carefully studied. Indeed, a potential problem of the treatment with this antibiotic is represented by the possibility that even very low blood levels achieved by oral administration might be able to select mutants, cross-resistant to rifamycins [85], in patients treated for GI infections and harboring M. tuberculosis. 

Mycobacteria are also killed in vitro, as expected from an antibiotic sharing the properties of the rifamycin family [24], In a study by Soro et al. [25], the MIC of rifaximin was determined for five Mycobacterium tuberculosis isolates from patients with tuberculosis. MIC concentrations were studied at 6, 20, 90 and 270 pg/ml, respectively. No resistant organisms were found. Growing M. tuberculosis in the presence of varying doses of rifaximin did not induce the occurrence of rifampicin-resistant strains [25]. In addition to this, experimental tubercular infection in the guinea pig was found not to be affected by an oral treatment course with rifaximin, therefore confirming the lack of absorption of the molecule after oral administration [26],... 

Rifaximin, a nonabsorbable derivative of rifamycin, has shown promising bactericidal action against both aerobes and anaerobes, such as bacterioides, lactobacilli and clostridia [33, 34], The development of resistance to this antibiotic can occur, but resistant strains rapidly disappear from the intestine thus allowing cyclic administration of rifaximin. Controlled clinical trials showed efficacy of rifaximin in adult and pediatric patients with infectious diarrhea [36,37], hepatic encephalopathy [38], post-surgical complications [39] and colonic diverticulosis [40], Only recently was the efficacy of rifaximin in the treatment of SIBO demonstrated [41-43]. 

The prospects, including questions still unresolved, have recently been reviewed [435]. It is to be hoped that the usefulness of this effective, almost non-toxic addition to the antitubercular range of drugs will not be jeopardized by injudicious use of other rifamycins since cross-resistance exists between all known members of this group—at least so far as mycobacteria are concerned. 

Pharmacology Rifampin inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase, but does not inhibit the mammalian enzyme. Cross-resistance has only been shown with other rifamycins. Rifampin at therapeutic levels has demonstrated bactericidal activity against intracellular and extracellular Mycobacterium tuberculosis organisms. Pharmacokinetics ... 

Resistance M. tubercuiosis organisms resistant to other rifamycins are likely to be resistant to rifapentine. Cross-resistance does not appear between rifapentine and non-rifamycin antimycobacterial agents such as isoniazid and streptomycin. 

The rifamycins induce CYP450 and may substantially decrease blood levels of the antiretroviral drugs resulting in the potential development of resistance to these agents. The potential benefit of the... 

Rifampin is a semisynthetic derivative of rifamycin, an antibiotic produced by Streptomyces mediterranei. It is active in vitro against gram-positive and gram-negative cocci, some enteric bacteria, mycobacteria, and chlamydia. Susceptible organisms are inhibited by less than 1 mcg/mL. Resistant mutants are present in all microbial populations at... 

Rifabutin is derived from rifamycin and is related to rifampin. It has significant activity against M tuberculosis, M avium-intracellulare, and M fortuitum (see below). Its activity is similar to that of rifampin, and cross-resistance with rifampin is virtually complete. Some rifampin-resistant strains may appear susceptible to rifabutin in vitro, but a clinical response is unlikely because the molecular basis of resistance, rpoB mutation, is the same. Rifabutin is both substrate and inducer of cytochrome P450 enzymes. Because it is a less potent inducer, rifabutin is indicated in place of rifampin for treatment of tuberculosis in HIV-infected patients who are receiving concurrent antiretroviral therapy with a protease inhibitor or nonnucleoside reverse transcriptase inhibitor (eg, efavirenz)—drugs that also are cytochrome P450 substrates. 

Rifapentine is an analog of rifampin. It is active against both M tuberculosis and Mavium. As with all rifamycins, it is a bacterial RNA polymerase inhibitor, and cross-resistance between rifampin and rifapentine is complete. Like rifampin, rifapentine is a potent inducer of cytochrome P450 enzymes, and it has the same drug interaction profile. Toxicity is similar to that of rifampin. Rifapentine and its microbiologically active metabolite, 25-desacetylrifapentine, have an elimination half-life of 13 hours. Rifapentine is indicated for treatment of tuberculosis caused by rifampin-susceptible strains. The dose is 600 mg once or twice weekly. Whether rifapentine is as effective as rifampin has not been established, and rifampin therefore remains the rifamycin of choice for treatment of tuberculosis. 

As would be expected from their similar mechanisms of action, resistance to streptovaricins and tolypomycins develops in a way analogous to that found with the rifamycins, and cross-resistance is observed between all three groups of antibiotics78 79). 

Wehrli, W., Kniisel, F. Staehelin, M. Action of rifamycin on RNA polymerase from sensitive and resistant bacteria. Biochim. Biophys. Res. Commun. 32, 284 (1968)... 

One of the most straightforward mechanisms of antibiotic resistance is mutation of the target to a form that has less affinity for the antibiotic. Spontaneous mutations that provide some benefit to the organism occur roughly 2 x 10 per replication (reviewed in Reference 73). Exposure to certain classes of antibiotics such as the rifamycins and fluoroquinolones can induce mutation, increasing the opportunity of developing resistance (74). Point mutations are associated with resistance to virtually all antibiotics, but this form of resistance is particularly important in the clinic for the fluoroquinolones, rifamycins such as rifampin, trimethroprim, and the sulfonamides. 

The mechanism of action of rifamycins involves primarily a strong, but noncovalent, interaction with DNA-dependent RNA polymerase enzyme in sensitive bacterial cells. The mammalian enzyme is not affected, which explains the selective toxicity neither is it mutated to resistant organisms. RNA polymerase has two components. The core enzyme contains polypeptide subunits a, J3, and i and a c factor, which are needed for recognition of RNA synthesis initiation sites. The drug binds to the J subunit of the complete enzyme only. The result is effective inhibition of RNA synthesis. It is of interest that many rifampinlike hydrazine derivatives were also found to be potent inhibitors of reverse transcriptase and shown to have antiviral properties. 

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