Resistance

Summary:

Bacterial resistance is not a targeted process, but occurs by chance when selective pressure on the bacterial flora is present. Selection of resistant organisms is a side effect of any therapy with antiinfectives. Resistance to quinolones occurs slowly and is primarily caused by:

• decreased binding affinity to bacterial topoisomerase II or IV,
• alterations in bacterial cell wall penetration,
• activation of the energy dependent efflux pump mechanism of the cell (13), (14), (15), (16), (17).

In general, resistant organisms have less hybrid vigor than the "wild" type and in many cases they are outcompeted by the normal flora after discontinuation of antimicrobial therapy (15).

Transfer of resistance plasmids, the most common cause of resistance build-up in non-quinolone antibiotics, has not been confirmed for quinolones to date (15).

Detailed information:

Bacterial resistance is not a targeted process, but occurs by chance and is only of relevance when selective pressure on the bacteria is present. Therefore, selection of resistant organisms is a potential side effect of any therapy with antiinfectives.

Resistance to quinolones primarily occurs through decreased binding affinity of these drugs to bacterial topoisomerase II or IV (a.), alterations in bacterial cell wall penetration (b.), or through an activation of the efflux pump mechanisms of the cell (c.), resulting in decreased intracellular drug concentrations (13).

(a.) A change in binding affinity of quinolones to topoisomerase II or IV is caused by chromosomal mutation (single step type). Usually a point mutation in the gene coding for this enzyme (exchange of a single amino acid) is responsible for this phenomenon (14). Single-step chromosomal mutations causing fluoroquinolone resistance occur as infrequently as every 10⁹ cell divisions, which is a factor of 10 ³ smaller than for mostof the other antibiotics (14). This kind of mutation may increase the MIC of the bacterium by a factor of 8-30. The new MIC, however, can still be within the susceptibility range of the drug. In this case, the change in susceptibility is clinically irrelevant. High-level resistance in general occurs through multistep type mutations, usually caused by a change in drug binding affinity to topoisomerase II or IV, combined with a decreased penetration ability across cell membranes. Development of multistep type mutational resistance is relatively rare in fluoroquinolones, as it occurs only at a rate of 10¹⁷ cell divisions (15).

(b.) For Gram-negative bacteria, such as E. coli, Klebsiella, Salmonella, as well as Pseudomonas, it has been shown that uptake-deficient mutants have only a reduced number of porin proteins in their outer cell membrane. This makes them less suscep tible to quinolones and antiinfectives of other classes (16).

(c.) Little is known about the role of efflux pump mechanisms in quinolone resistance, about the interaction of these drugs with the inner cell membrane of Gram-negative, and the single-layer cell membrane of Gram-positive bacteria (17).

Resistant bacteria can become a problem in individual patients undergoing antibiotic treatment. Transfer of resistant organisms to other individuals, however, does not occur to a great extent. Beyond that, resistant organisms have less hybrid vigor than the "wild" type. Their selection advantage in most cases only is maintained as long as the antiinfective is administered. When therapy is stopped they are outcompeted by the normal flora, which will return in the short term after discontinuation of treatment (15).

Plasmid-mediated resistance, the most common cause of resistance in non-quinolone antibiotics, has not been confirmed for fluoroquinolones. Plasmids are spread in the bacterial population quickly by transfection or conjugation, where they cause high-level resistance with MICs up to 100 times the initial value (15). Quinolones, in contrast, have been reported to experimentally eliminate plasmids from bacterial populations as so-called plasmid curing agents (16).

As development of bacterial resistance to fluoroquinolones is slow and not plasmid-mediated they today play an important role in the battle against bacteria, which have become resistant to members of the conventional antibiotic families.

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