Fluoroquinolones resistance mechanisms

Chen FJ, Lo HJ. Molecular mechanisms of fluoroquinolone resistance. J Microbiol Immunol Infect. 2003 36 1-9. 

LJ Piddock. Mechanisms of fluoroquinolone resistance an update 1994-1998. Drugs 58 Suppl 2 11-18, 1999. 

The resistance mechanisms that cause the inactivation of penicillins, cephalosporins, aminoglycosides, macrolides and tetracyclines do not apply to fluoroquinolones, and there is therefore no cross-resistance between quinolones and other antibiotics. 

The inducible mar locus specifies a novel antibacterial mechanism that could well play an important role in the clinical emergence of fluoroquinolone-resistant E. coli isolates [274]. The mar regulon is one of several Mdr systems present in members of the Enterobacteriaceae [71]. Other Mdr systems include ... 

Zhang, Q. Lin, J. Pereira, S. Fluoroquinolone-resistant Campylobacter in animal reservoirs dynamics of development, resistance mechanisms and ecological fitness. Anim. Health Res. Rev. 2003, 4,... 

Fluoroquinolones must penetrate bacteria to reach their target, DNA gyrase. The second mechanism of fluoroquinolone resistance is decreased cell wall permeability. The fluoroquinolones diffuse through porin channels in the outer membrane of Gram-negative bacteria. Mutation results in a decrease in porin channel proteins, resulting in decreased uptake of the fluoroquinolones into bacterial cells. Alterations in a wide range of outer membrane proteins in Pseudomonas spp. result in resistance. From these mutations, the increase in MIC of the fluoroquinolones is relatively low (2-to 32-fold). Flowever, there is cross-resistance with unrelated antibiotics, most frequently cefoxitin, chloramphenicol, trimethoprim and tetracycline. 

No quinolone-inactivating mechanisms have been identified. Resistance has increased, especially in Pseudomonas and staphylococci. Fluoroquinolone resistance also is increasing in C. jejuni, Salmonella, Neisseria gonorrhoeae, and S. pneumoniae. 

Two mechanisms of resistance have been discovered with respect to fluoroquinolones a change in subunits A of DNA-gyrase, and reduced permeability of the outer membrane of the bacteria. Resistance is mediated by chromosomes, and not plasmids in the bacteria. The development of resistance while using the drugs is very rarely observed. 

Mechanism of Action A fluoroquinolone that inhibits two enzymes, topoisomerase 11 and IV, in susceptible microorganisms. Therapeutic Effect Interferes with bacterial DNA replication. Prevents or delays emergence of resistant organisms. Bactericidal. Pharmacokinetics Well absorbed from the GI tract after PO administration. Protein binding 50%. Widely distributed throughout body with tissue concentration often exceeding plasma concentration. Metabolized in liver. Primarily excreted in urine with a lesser amount in feces. Haif-iife 10.7-13.3 hr. 

When the fluoroquinolones were first introduced, there was optimism that resistance would not develop. Although no plasmid-mediated resistance has been reported, resistance of MRSA, pseudomonas, coagulase-negative staphylococci and enterococci has unfortunately emerged due to chromosomal mutations. Crossresistance exists among the quinolones. The mechanisms responsible for this resistance include ... 

In the treatment of tuberculosis, resistant strains of M. tuberculosis (multidrug-resistant tuberculosis, MDRTB) present a growing problem, so that new antituber-culotic agents are required which act according to a different mechanism to that of standard agents such as isoniazid, rifampicin, pyrazinamide, and ethambutol. The more modern fluoroquinolones are of particular interest, and in particular moxifloxacin, which has powerful in vitro and in vivo activity and, in contrast to sparfloxacin and clinafloxacin, is not photo toxic [191]. 

Everett MJ, Piddock LJV. Mechanisms of resistance to fluoroquinolones. In Quinolone Antibacterials. Kuhlmann J, DalhoffA, Zeiler H-J (Eds.) Springer Berlin, Heidelberg, New York, Barcelona, Budapest, Hong Kong, London, Milan, Paris, Santa Clara, Singapore, Tokyo, 1998, pp. 259-296. 

Some streptococci have developed a different mechanism of acquired resistance to penicillin drugs. These bacteria have altered transpeptidases (also known as penicillin-binding proteins) that no longer bind penicillin, and thus peptidoglycan synthesis is not disrupted. This mechanism of resistance is found in Streptococcus pneumoniae. Estimates of penicillin-resistant S. pneumoniae in the United States range from 25% to 66%, including strains recovered from ocular and periocular infections. Many isolates of penicillin-resistant S.pneumoniae also are resistant to the cephalosporins, macrolides, and the older fluoroquinolones. Use of alternative antibiotics such as vancomycin is necessary for infections caused by penicillin-resistant isolates. 

Bacteria have developed resistance to the fluoroquinolones by two main mechanisms. The first involves modifying the enzyme(s) targeted by the drug either DNA gyrase or topoisomerase IV or both. The second involves rednction of flnoroqninolone access to its target enzyme either by efflux pumps that remove the fluoroquinolone from the cell or by the cell s membrane acquiring reduced permeability to the fluoroquinolone. 

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. 

Ando, T., Kusuhara, H., Merino, G., Alvarez, A.I., Schinkel, A.H. and Sugiyama, Y. (2007) Involvement of breast cancer resistance protein (ABCG2) in the biliary excretion mechanism of fluoroquinolones. Drug Metabolism and Disposition The Biological Fate of Chemicals, 35, 1873-1879. 

Hooper, D.C. (2000) Mechanisms of action and resistance of older and newer fluoroquinolones. Clinical Infectious Diseases, 31 (Suppl 2), S24-S28. 

Answer A- Microbial resistance to fluoroquinolones is increasing, and some strains of Streptococcus pneumoniae are now resistant to ciprofloxacin. The mechanism can involve changes in the structure of topoisomerase IV, one of the targets of fluoroquinolones, which inhibit nucleic acid synthesis. Pneumococcal resistance to penicillins is also increasing via changes in penicillin-binding proteins (PBPs). The other mechanisms listed underlie microbial resistance to other antibiotics as follows sulfonamides (choice B), macrolides (choice C), extended-spectrum penicillins (choice D), and beta-lactams (choice E). 

---