Antibiotic resi5tance. Cephalo.1porins- in STD Rational approach to treatment INCREASING RESISTANCE TO SOME ANTIBIOTICS. USE OF CEPHALOSPORINS. M. V. Budihna SUMMARY Resistance to chemotherapeutic agents is the adaptation of bacteria to changes in their environment. The introduction of a novel antibacterial agent will inevitably lead to the emergence of resistant organisms. In the present short review the ways of transferring of antibiotic resistance in bacteria are described as well as the most important molecular and biochemical mechanisms responsible for the development of antibiotic resistance. Due to changed circumstances many cephalosporins have got an important role in the treatment of some STDs e.g. gonorrhoea or chancroid. A short overview of the use of cephalosporins is given. KEY WORDS antibiotic resistance, molecular mechanisms, biochemical mechanisms, cephalosporins in STD INTRODUCTION Bacterial and some fungal STDs have been successfully treated in the last four decades due to antibacterial and antifungal drugs. However many of these drngs lost their effectiveness because many of microorganisms developed resistance to them. Unchanged sensitivity of Treponema pallidum to pencillin is rather an exception (1 ). Resistance to chemotherapeutics can seriously constrain the options available for the medical treatment of many bacterial infections (2). Resistance to chemotherapeutic agents can develop to particular drug or group of drugs. Particular bacterial genera or environments develop particular mechanisms of resistance. In most cases the resistance is apparently acquired acta dermatovenerologica A.P A. Vol 4, 95, No 3 rather than intrinsic. The rapidity with which resistance often appears after introducing of a new drug is astonishing (3) . GENETIC DETERMINANTS OF ANTIBIOTIC RESISTANCE Chromosomal determinants: mutations Although spontaneous mutation is an important mechanism for the evolution of resistance it is not of great clinical relevance, possibly because mutants often have reduced pathogenecity (2,3). It is important in mycobacterial infections, particularly tuberculosis (and leprosy) (2) . 109 Mobile genetic elements: plasmids and transposons Plasmids are extrachromosomal genetic elements that can replicate on their own and can cany genes coding for resistance to antibiotics (r genes) from one bacterium to another (2,3). The main method of transfer of r genes from one bacterium to another is conjugation. Conjugative plasmids can cause the bacterium to make a connecting tube between bacteria, through which the plasmid -itself (and other plasmids) can pass (2). A less common method of transfer is by trans- duction. This is the transmission of a r-gene-carrying plasmid into a bacterium by a bacterial virus (phage) (2). The third way of transfer, clinically not very important, is transformation. The bacterium incor- porates naked DNA - coming from a cell belonging to the same strain or a strain very closely related to the bost bacterium - into its genome by the normal cross-over mechanism (2) . Transposons are stretches of DNA that can be transposed from one plasmid to another, and also from plasmid to chromosome and vice versa. They are not able to replicate on their own. Transposition is a continuous process in bacterial population and is a powerful mechanism for generation and dissemination of resistance determinants (2,3). BIOCHEMICAL MECHANISMS OF RESISTANCE TO ANTIBIOTICS Production of enzymes that inactivate the drug Some microorganisms e.g. staphylococci, and some Gram-negative organisms produce 13-lactamases, which inactivate 13-lactam antibiotics ( e.g. penicillins, ceph- alosporins, semisynthetic broad-spectrum 13-lactam antibiotics) by cleaving their 13-lactam ring (2,4 ). Resistant strains of both Gram-positive and Gram- negative organisms produce acetyltrasferases, which inactivate chloramphenicol (2,5). Enzymes for phosphorylation, adenylation or acetylation which inactivate aminoglycosides have been found in both Gram-negative and Gram-positive organisms (2,6). Alteration of drug-sensitive site or drug-binding site · These mechanisms may provoke the resistance to aminoglycosides, erythromycin, rifampicin, penicillins (2,3). 110 Decreased drug accumulation in the bacterium Energy dependent efflux ( due to inducible "resi- stance" proteins) of tetracyclines in both Gram- positive and Gram-negative bacteria results in a common type of resistance. Resistance to some hydrophylic antibiotics and to ampicillin is based on altered permeability of the outer membrane of bacteria. The accumulation of aminoglycosides, 13-lactams, chloramphenicol, peptide antibiotics and tetracyclines is changed by mutations affecting envelope components of bacteria (2). The development of an alternative pathway that bypasses the reaction inhibited by the antibiotic Some strains of staphylococci have developed alternative pathways to bypass the reactions inhibited by the antibiotics, and have become multiple resistant to virtually all current antibiotics: methicillin, stre- ptomycin, aminoglycosides, trimethoprim, sulpho- namides, rifampicin, fusidic acid. This resistance is transferred by transposons and/or plasmids (2) . Due to mentioned and other mechanisms the antibiotic therapy of many STDs bas changed. Azithromycin, roxythromycin, cephalosporins, cepha- mycins as well as quinolones and fluoroquinolones are frequently used in the treatment of some STD. Fortunately, resistance to the newer macrolides, cephalosporins, fluoroquinolons remains uncommon in most settings, although fluoroquinolone resistance of Neisserria gonorrhoeae in some geographic areas represents a growing problem (7). In the present work we wish to elucidate the use of cephalosporins and cephamycins in some STDs. BASIC PHARMACOLOGY OF CEPHA- LOSPORINS AND THEIR USE IN SOME STDs Cephalosporins and cephamycins are chemically and pharmacologically closely related to each other. Both agents are bactericidal antibiotics, inhibiting bacterial cell-wall synthesis similarly as does penicillin: they interfere with peptidoglycan synthesis after binding to the 13-lactam antibiotic binding proteins (2,8). Resistance: As with penicillins, resistance occurs if an organism generates enzymes that cleave the 13-lactam ring ( although penicillinase-producing staphylococci may be susceptible to ce'phalosporins) or if it has an outer membrane that prevents penetration of the acta dermatovenerologica A.P A. Vol 4, 95, No 3 drug. The cephalosporins and cephamycins are not readily attacked by the plasmid-encoded B-lactamases, but there are reports of resistance due to mutations involving the binding-site proteins (9). Classification Development of new cephalosporins during past decade led to different classifications. The well- accepted system of classification by "generations" is based on general features of antimicrobial activity (8): The first-generation cephalosporins ( e.g. cephalotin and cefazolin) have good activity against Gram- positive bacteria and relative modest activity against Gram-negative microorganisms. The second-generation cephalosporins ( e.g. cephamandole, cefuroxime) have somewhat increased activity against Gram-negative microorganisms but are much less active than the third-generation agents. Third-generation cephalosporins ( e.g. cefotaxime, cefmenoxime, ceftriaxone, cefixime) are generally less active than first-generation agents against Gram-positive cocci, but they are more active against Enterobacteriaceae, including ~-lactamase- producing strains. The newer cephalosporins cefepime and cefpirome have been described by some as forth-generation because of their broad spectrum of activity ( 8). The semisynthetic cephamycins ( e.g. cefoxitin, cefmetazole, cefotetan, cefbuperazone, cefminox) are generally classified with the second-generation cephalosporins, but are more active against some anaerobic bacteria (8). Use of cephalosporins in gonorrhoea Combined results of severa! studies showed that following cephalosporins can cure anogenital infections with N. gonorrhoeae: - 2nd generation: cefuroxime (1 g, single oral