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Mechanism and Profile Resistance of Neiserria Gonorrhoea to Antimicrobial


Travel medicine is a medical discipline that focuses attention on issues related to health conditions in relation to a process of travel (traveling). This development is in line with the modern human mobility that was very high. Two special cases are the basis for the travel medicine is health promotion and disease prevention. There are some that must be considered in particular the introduction of diseases that exist in the target area, education on disease prevention, behavior change, imunoprofilaksis, and chemoprophylaxis. Another special case of concern is malaria (and other tropical diseases), infections, HIV / AIDS and sexually transmitted diseases, diarrhea, hepatitis, respiratory disorders, and accidents. Bali is one of the destinations of tourism in the world. Bali famous and became like that because their unique custom. Besides presenting it, natural panorama is one of the attractions for tourists. But not only that, many tourists also enjoyed the dark side of tourism in Bali. The one that called the dark side tourism was sex tourism or sex traveling. This habit can cause many trouble like mentioned above. Thats why travel medicine was considered to be important. One of such many diseases was gonorrhea, caused by bacteria called Neisseria Gonorrhoeae (N. Gonorrhoeae). N. gonorrhoeae is a Gram-negative diplococcus and is known to infect humans only. It is transmitted from contact human-to-human and persists badly outside the human body. N. gonorrhoeae can adapt to host defenses, live without severely damaging the host, and be transmitted to and infect other hosts. Among the treatable sexually transmitted diseases (STDs), N. gonorrhoeae is considered to be most important because of emerging antibiotic resistant strains that compromise the effectiveness of treatment of the disease - gonorrhoea. N. gonorrhoeae has developed resistance not only to less expensive antimicrobials such as sulphonamide, penicillin and tetracycline but also to fluoroquinolone. Among the antimicrobials available so far, only the third-generation cephalosporin could be safely recommended1. Mechanism of drug resistance Originally, N. gonorrhoeae is highly susceptible to antibiotics. But it can adapt to adverse conditions. Mechanisms of antibiotic resistance in gonococcal may be conveniently

grouped as those that involve reduced access of the antibiotic to the target site and those that involve change of the target site itself. Access of antibiotics to the target site may be limited by reduced permeability of the cell envelope caused by changes in porin proteins; active export of antibiotics from the cell by means of efflux pumps; and destruction of the antibiotic before it can interact with the target. Change or deletion of the target site of the antibiotic results in a reduction of its affinity for the antibiotic1. In N. gonorrhoea, the process of genetic transformation is known to be responsible for acquiring drug resistance. Other than that, plasmid mediated resistance also know responsible for the resistant, but at present it limited to penicillin and tetracycline. It is transmitted by means of conjugation. In N. gonorrhoeae, plasmid mediated resistance spreads more rapidly than chromosomally mediated resistance1. (i) Resistant to penicillin : The penicillin were used for the treatment of gonorrhea for many years (and still are in some regions). Later on decreased in vitro susceptibility towards penicillin appeared and it was thought to be associated with treatment failure. Increasing the recommended dose of penicillin temporarily decreased the clinical problems, but levels of resistance increased and large numbers of treatment failures again occurred. This was an example of stepwise chromosomal changes over a period of many years. Changes in PBP-2 and PBP-1 decreased their affinity for the penicillin, and the susceptibility of the organism. PBP-2 is encoded by the penA locus. Changes in other loci such as mtr and penB produce additive effects. The mtr locus mediates resistance to a wide range of antibiotics, detergents and dyes through an active efflux system. Mutations in the penB locus, which affect a porin, result in reduced permeability of the cell envelope to hydrophilic antibiotics and other compounds. The combined effect of penA mutations and increased expression of mtr is shown to increase the N. gonorrhoeae resistance toward penicillin. Other than that, resistance to penicillin is also mediated by a plasmid-bome, inducible TEM-1 type -lactamase. lactamase is known to hydrolyze the -lactam ring of penicillin, which can inactivate them1. (ii) Resistance to quinolones : Quinolone antibiotics most widely used for the treatment of gonorrhea are 'second generation' agents such as ciprofloxacin and ofloxacin. Resistance to these antibiotics has gradually developed over a number of years and multiple chromosomal changes are involved. The targets of the quinolones are topoisomerases, including DNA gyrase. High-level clinically resistance is mediated by alteration of the target sites, initially via mutation in the gyrA gene. Multiple mutations also occur in the parC gene which codes for the production of topoisomerase IV, a secondary target for quinolones in gonococcal, but found in association with high level resistance. Changes in parC gene seem

to arise in the presence of mutations affecting gyrA gene. The fourth generation quinolones are more active against strains with altered parC, but are less effective against gyrA mutants1. (iii) Resistance to cephalosporin: gonococcal susceptibility to cephalosporin antibiotics is chromosomally mediated and is due to the same changes that account for decreased penicillin susceptibility. There is cross-resistance between penicillin and early generation cephalosporin such as cefuroxime. But, this is not the case for the later generation cephalosporin such as ceftriaxone and cefixime. In the past five years, gonococcal with decreased susceptibility to ceftriaxone has been reported. Recent data also suggest that the emergence and spreading of cephalosporin resistance gonococcal is quite similar to the data showing the emergence of quinolone-resistance strains1. Profile resistance of Neiserria gonorrhoeae N. gonorrhoeae has started developing resistance against most of the antimicrobials1. Also in the recent time the gonococcal with reduced susceptibility to the currently recommended antibiotics for gonorrhea therapy, including flouroquinolones and some cephalosporin was found2. But this incident does not happen in all places. In another area such as Australia, gonorrhea has some unique feature. In urban population the options for the treatment decrease because of increasing AMR. But in non-urban area the older treatment like penicillin, still effective against gonorrhoeae3. This make surveillance of the antimicrobial resistance becomes very important in monitoring the emergence and spread of resistance and in planning appropriate treatment1. In discuss this profile resistance of N. gonorrhoeae will be divided into pre-quinolone, quinolone and post quinolone era. Pre-quinolone era Sulphanilamide was introduced as an antimicrobial for N. gonorrhoeae in 1937. Before it, Alexander Fleming also documented the ability of penicillin to inhibit the growth of N. gonorrhoeae in 1929. In 1943, Penicillin became the choice for the treatment of gonorrhea. Susceptibility N. gonorrhoeae against penicillin was monitored, and in vitro resistance to penicillin was expressed in terms of minimum inhibitory concentration (MIC). During the initial year treatment of gonorrhea with penicillin had an MIC of < 0,0125 mg/l and considered to be sensitive to the treatment. But the MIC value of the isolates N. gonorrhoeae gradually increase to >0,12 mg/l and gradually all stains became resistant to penicillin (MIC >0,5). This penicillin resistant was proved to be additive effect of multiple chromosomal mutations. Plasmid mediated resistant isolates of N. gonorrhoeae were also observe. This isolates were termed as penicilinase producing N. gonorrhoeae (PPNG) and it has a gene of -lactamase. The isolates that had -lactamase in its plasmid know to be

resistance to penicillin. Due to this, in 1989 penicillin was no longer considered effective treatment for gonorrhoeae1. Coincident with the development of resistance to penicillin, Gonococcal also developed resistance to several other antibiotics, including tetracycline, chloramphenicol, streptomycin and erythromycin. Tetracycline was also considered as another important antimicrobial during the pre-quinolone era. It is because tetracycline was not very expensive and thus was a widely used antimicrobial. Same was the case with azithromycin, even though it was considered to be a more expensive alternative. Gradually through constant use of tetracycline to treat such co-infections, N. gonorrhoeae acquired low-level resistance towards this antimicrobial1. Quinolone era In 1989 Center for Disease Control recommended the use of board spectrum cephalosporin or flouroquinolones for primary treatment of uncomplicated gonorrhea. Quinolones treatments of gonorrhoeae are second generation antimicrobials such as ciprofloxacin, norfloxacin, ofloxacin. Ciprofloxacin was recommended as the first line therapy to treat gonorrhea in 19931. Initially most of the isolates of gonococcal were found to be extremely susceptible to quinolones and more importantly, fluoroquinolones. It was evident for the resistance towards flouroquinolones, the initial isolates shows susceptibility towards ciprofloxacin. The MIC value found was 0, 06 mg/l, which gradually increase to 1 mg/l and later to 16 mg/l. Strains with MIC value >4 mg/l were considered as high level resistance. Patient infected with this isolates showing intermediate resistance to ciprofloxacin. Ciprofloxacin resistant spread very quickly; it was thought that the emergence of ciprofloxacin resistance was accelerated mainly because of its use for the treatment of other diseases. In response to the increase in ciprofloxacin resistant isolates from throughout the world, the use of this antimicrobial to treat gonorrhea was discontinued in early 2000s from most of the countries1. Post-quinolone era Consequent to the increase in the resistance profile of N. gonorrhoeae towards quinolones, third-generation cephalosporin, both injectable (ceftriaxone) and oral (cefixime and cefdinir), were the only available treatment recommended by the CDC and other national organizations. But some surveillance report from India, Bangladesh, Nepal and Sri Lanka during 1999-2001, documented significant increase in the isolates with decreased susceptibility to ceftriaxone1.

Spectinomycin can also be considered as a therapeutic option. But, it would probably remain as an alternative treatment rather than a recommended one, because high levels of resistance developed when this antimicrobial was widely used in the mid-1980s. Azithromycin, 2 g, taken orally has been shown to be effective against uncomplicated gonococcal infection and could be thought as an option for persons who are allergic to cephalosporins1. From all above we can conclude that the N. gonorrhoeae was characterized by high rates of resistance and intermediate susceptibility to penicillin, tetracycline, erythromycin and fluoroquinolones. None of these agents is currently used as first-line therapy for gonorrhea. Nevertheless, third-generation cephalosporin must be considered as first-choice drugs for the treatment of gonorrhoea2. Besides that, there is need for better control of gonococcal disease including enhanced global surveillance resistance and improved treatment1.


1. Neiserria gonorrhoeae resistant mechanism can divide into two, chromosomally and plasmid mediated resistance. 2. In recent year Neiserria gonorrhoeae has build resistant toward almost kind of antimicrobial like penicillin, tetracycline, sulphanilamide, and ciprofloxacin and etc. Now, just the third generation cephalosporin ceftriaxone and cefixime considered effective against the bacterium. 3. There is need for better control of gonococcal disease including enhanced global surveillance resistance and improved treatment