The use of fluoroquinolones in gonorrhoea: the increasing problem of resistance

The recent re-emergence of gonorrhoea in developed countries has been accompanied by the rise and spread of gonococcal resistance to the fluoroquinolones. In the 1980s fluoroquinolones were considered an important addition to the arsenal of agents used to treat gonorrhoea. They proved to be excellent drugs for this indication, including infections caused by penicillinase-producing and tetracycline-resistant strains of Neisseria gonorrhoeae. However, as gonococci have a well-recognised potential to develop resistance to antibiotics, the first reports of reduced susceptibility to fluoroquinolones appeared a few years after their introduction. Gonococcal resistance to fluoroquinolones is now well-established in the Far East, from where it has spread to Australia, Hawaii, California and Europe. In Africa and Latin America, gonococci continue to be susceptible to fluoroquinolones.     

Fluoroquinolone antibiotics. Microbiology, pharmacokinetics and clinical use

The newer fluoroquinolones are a major advance in antimicrobial chemotherapy. They inhibit the supercoiling activity of the DNA gyrase enzyme, thus exerting their antibacterial action on DNA and RNA synthesis, resulting in a biphasic response and killing of susceptible organisms. The newer fluoroquinolones have an extended antimicrobial spectrum compared to their older congeners, and are highly active against most Gram-negative pathogens including the Enterobacteriaceae and Pseudomonas aeruginosa. While Staphylococcus aureus and coagulase-negative staphylococci are usually susceptible to the fluoroquinolones, streptococci are generally more resistant and enterococci are resistant. All of the newer fluoroquinolones may be administered orally and most of them have been administered parenterally. They are widely distributed in the body, attaining therapeutic concentrations in most tissues. All of the fluoroquinolones have long half-lives and may be administered once or twice daily. The fluoroquinolones have proved effective in many infections, including uncomplicated or complicated urinary tract infections, respiratory tract infections, gonorrhoea, bacterial gastroenteritis, and soft tissue infections due to Gram-negative organisms. In general, success has been notable in the management of Gram-negative infections but less so with Gram-positive infections. Resistance has occurred and is proving a problem with P. aeruginosa in some cystic fibrosis patients, but as yet no plasmid-mediated resistance has developed. Cross-resistance occurs between the quinolones but only rarely with other classes of antibacterial drugs. The fluoroquinolones have an excellent safety record and their adverse effects, which include hypersensitivity reactions, dizziness, headache, gastrointestinal disturbance and minor haematological abnormalities are usually mild and transient. However, the fluoroquinolones have been found to damage juvenile weight-bearing joints in animals and are therefore only to be used with caution in children; transient arthralgia has been reported in a cystic fibrotic teenager on long term ciprofloxacin therapy. All of the fluoroquinolones except ofloxacin are associated with a variable increase in the serum concentration of theophylline, warfarin and caffeine. Thus, the fluoroquinolones are an attractive option in the management of many infections. Cost and possible resistance, however, should counsel caution in their use, and may limit them to situations where a cheaper antimicrobial of equivalent efficacy is not available.     

Current concepts in the management of gonorrhoea

The incidence of gonorrhoea is again rising in developed countries and a high disease rate has been maintained in less developed regions for a number of years. The need not only for treatment of the individual but also for control of gonorrhoea at a community level has increased significantly following recognition of its role in the amplification of human immunodeficiency virus (HIV) transmission. A sustainable decrease in the incidence of gonorrhoea and other sexually transmitted diseases (STDs) requires an integrated approach combining improved prevention, better diagnosis and optimal treatment. Effective antibiotic treatment is an essential element of this approach. However, antibiotic treatment of gonorrhoea has been severely hampered by the development of antibiotic resistance in Neisseria gonorrhoeae, to the extent that many therapies are no longer effective. Those treatments that retain acceptable efficacy are often unaffordable where they are most needed. Penicillins and tetracyclines should no longer be used in gonococcal disease, there are limitations on the effectiveness of newer macrolides and spectinomycin and in many parts of the world quinolones have been withdrawn from schedules for the treatment of gonorrhoea. Of all the current agents used to treat all forms of gonococcal disease, only the third generation cephalosporins (most notably ceftriaxone) have retained their efficacy; however, decreased susceptibility to these antibiotics has also appeared. Continuing reliance on antibiotic treatment for controlling gonorrhoea in the absence of other necessary approaches will see a further deterioration in the situation. In these circumstances the possibility that gonorrhoea will be untreatable becomes more real.     

Current concepts in the management of gonorrhoea

The incidence of gonorrhoea is again rising in developed countries and a high disease rate has been maintained in less developed regions for a number of years. The need not only for treatment of the individual but also for control of gonorrhoea at a community level has increased significantly following recognition of its role in the amplification of human immunodeficiency virus (HIV) transmission. A sustainable decrease in the incidence of gonorrhoea and other sexually transmitted diseases (STDs) requires an integrated approach combining improved prevention, better diagnosis and optimal treatment. Effective antibiotic treatment is an essential element of this approach. However, antibiotic treatment of gonorrhoea has been severely hampered by the development of antibiotic resistance in Neisseria gonorrhoeae, to the extent that many therapies are no longer effective. Those treatments that retain acceptable efficacy are often unaffordable where they are most needed. Penicillins and tetracyclines should no longer be used in gonococcal disease, there are limitations on the effectiveness of newer macrolides and spectinomycin and in many parts of the world quinolones have been withdrawn from schedules for the treatment of gonorrhoea. Of all the current agents used to treat all forms of gonococcal disease, only the third generation cephalosporins (most notably ceftriaxone) have retained their efficacy; however, decreased susceptibility to these antibiotics has also appeared. Continuing reliance on antibiotic treatment for controlling gonorrhoea in the absence of other necessary approaches will see a further deterioration in the situation. In these circumstances the possibility that gonorrhoea will be untreatable becomes more real.     

Of stewardship,motherhood and apple pie

Antibiotic stewardship is universally agreed to be desirable, but optimal models for stewardship remain uncertain. UK stewardship targets the particular antibiotic families—cephalosporins and fluoroquinolones—blamed for the selection of Clostridium-difficile-associated disease. To balance this there have been dramatic increases in the use of penicillin–β-lactamase inhibitor combinations. By channelling selection pressure in this way, we hazard destroying the utility of these antibiotic classes in turn, as happened with gonorrhoea where penicillins, fluoroquinolones and cefixime were sequentially lost as therapies. Strikingly, in context, almost all carbapenemase-producers are highly resistant to penicillin–β-lactamase inhibitor combinations, which may select for them. There is an urgent need to explore an alternative stewardship model, seeking to limit total antibiotic use but to maintain heterogeneity in what is used, avoiding concentrated selection pressure. There is also a great need to improve and accelerate diagnostics for infection and resistance, reducing or removing the need for protracted empirical treatment with broad-spectrum agents.     

Fourteen years in resistance

Resistance trends have changed greatly over the 14 years (1997-2011) whilst I was Director of the UK Antibiotic Resistance Monitoring and Reference Laboratory (ARMRL). Meticillin-resistant Staphylococcus aureus (MRSA) first rose, then fell with improved infection control, although with the decline of one major clone beginning before these improvements. Resistant pneumococci too have declined following conjugate vaccine deployment. If the situation against Gram-positive pathogens has improved, that against Gram-negatives has worsened, with the spread of (i) quinolone- and cephalosporin-resistant Enterobacteriaceae, (ii) Acinetobacter with OXA carbapenemases, (iii) Enterobacteriaceae with biochemically diverse carbapenemases and (iv) gonococci resistant to fluoroquinolones and, latterly, cefixime. Laboratory, clinical and commercial aspects have also changed. Susceptibility testing is more standardised, with pharmacodynamic breakpoints. Treatments regimens are more driven by guidelines. The industry has fewer big profitable companies and more small companies without sales income. There is good and bad here. The quality of routine susceptibility testing has improved, but its speed has not. Pharmacodynamics adds science, but over-optimism has led to poor dose selection in several trials. Guidelines discourage poor therapy but concentrate selection onto a diminishing range of antibiotics, threatening their utility. Small companies are more nimble, but less resilient. Last, more than anything, the world has changed, with the rise of India and China, which account for 33% of the world's population and increasingly provide sophisticated health care, but also have huge resistance problems. These shifts present huge challenges for the future of chemotherapy and for the edifice of modern medicine that depends upon it.     

NCCLS perspectives in changing susceptibility breakpoints for antimicrobial drugs

The spread of resistance to many antimicrobial agents in various microbial species has been highlighted by the World Health Organisation and many government agencies around the world. The reasons for this increase and spread are complex and are discussed. A number of surveillance studies has monitored the increase in resistance among isolates of Streptococcus pneumoniae to various important classes of antimicrobials. These results are discussed with particular reference to penicillins, macrolides and fluoroquinolones. Although there is evidence that in vitro resistance to macrolides and more recently to fluoroquinolones may be associated with a reduced clinical efficacy, there is no such clear association with resistance to beta-lactams and lack of clinical efficacy in non-meningeal infections. Resistance or susceptibility to an antimicrobial agent is based on breakpoints and these are set in the US by the National Committee of Clinical and Laboratory Standards. In response to these recent clinical studies showing that non-meningeal pneumococcal infections with strains classified as resistant in vitro still responded well to treatment with various beta-lactams, new breakpoints have been set. Results are presented showing that using these breakpoints, the levels of resistance to the third generation cephalosporins, ceftriaxone and cefotaxime against a range of non-meningeal pneumococcal isolates were lower than those obtained using the previous breakpoints. The excellent pharmacokinetic and pharmacodynamic properties of these agents are believed to contribute to their good activity in the clinic.     

Antimicrobial activity of BMS 284756 (T-3811) against Neisseria gonorrhoeae tested by three methods.

The potency of BMS 284756, a novel des-F(6)-quinolone, was tested against 137 clinical isolates of Neisseria gonorrhoeae including 50 strains observed to be resistant to ciprofloxacin and other newer quinolones. The gonococci were tested using NCCLS methods (agar dilution, disk diffusion) and Etest. BMS 284756 potency versus N. gonorrhoeae was generally two- to four-fold greater than ciprofloxacin. Penicillin resistance in the absence of ciprofloxacin resistance did not affect BMS 284756 activity. However, elevated ciprofloxacin MICs were associated with higher BMS 284756 MIC results as follows (BMS 284756 MIC(50)/MIC range in mg/l): ciprofloxacin-susceptible strains (0.016 or 0.03/0.004-0.06), ciprofloxacin-intermediate strains (0.06 or 0.12/0.008-0.25) and ciprofloxacin-resistant strains (0.12 or 0.5/0.12-1). Etest MICs were routinely lower than those produced by the reference agar dilution method, but the correlation coefficient remained acceptable (r = 0.87). Similarly acceptable correlation was achieved with 5 microg disk zone diameters (r = 0.78), where all zones were > or = 28 mm (MIC < or = 1 mg/l). In conclusion, BMS 284756 was very active against N. gonorrhoeae (MIC(50) 0.03 mg/l overall) including ciprofloxacin-resistant strains and could be considered as a single-dose therapeutic option for gonorrhoea.     

Alterations within the quinolone resistance-determining regions of GyrA and ParC of Neisseria gonorrhoeae isolated in the Far East and the United States.

The genetic mutations within the quinolone resistance-determining regions (QRDRs) of gyrA and parC of 234 Neisseria gonorrhoeae strains isolated in the Far East and the United States, which exhibited either clinically significant ciprofloxacin resistance (CipR) or intermediate ciprofloxacin resistance (CipI) were characterized. A number of GyrA/ParC amino acid alteration patterns were identified, the most prevalent alteration pattern among CipR isolates being GyrA-91,95/ParC-Asp-86->Asn (91,95/Asp-86->Asn). Isolates containing 91,95/Asp-86->Asn belonged to a number of A/S classes, penicillin/tetracycline resistance phenotypes, and plasmid profiles. These results strongly suggest that the continuing emergence of ciprofloxacin-resistant gonococci is not due to the spread of a single or a few strains but to numerous factors such as spread of existing strains, importation of new strains and, possibly, de novo development of ciprofloxacin resistance in previously susceptible strains.     

In vitro method for prediction of the phototoxic potentials of fluoroquinolones

The phototoxic potential of eight fluoroquinolones (norfloxacin, ofloxacin, enoxacin, ciprofloxacin, lomefloxacin, tosufloxacin, sparfloxacin and gatifloxacin) was evaluated by using three in vitro methods of cytotoxicity against mammalian cells, erythrocyte lysis and DNA strand breakage. All fluoroquinolones tested with the exception of gatifloxacin, an 8-methoxy quinolone, showed DNA strand breaking activities under UV-A irradiation. Their cytotoxicity against HeLa cells was also enhanced by UV-A irradiation. In particular, the phototoxic potential of sparfloxacin, enoxacin and lomefloxacin was high in both methods. Ofloxacin is very photocytotoxic against HeLa cells, while it has low potential to cause DNA strand breakage. Norfloxacin, ciprofloxacin and enoxacin were very photohemolytic, but sparfloxacin was not, indicating that the in vivo phototoxic potencies of fluoroquinolones might not be predictable by the photohemolysis study. Gatifloxacin, a non-phototoxic quinolone, showed no phototoxic potential in any of these three in vitro tests. These results suggest that determination of DNA strand breaking activity, combined with cytotoxicity against mammalian cells, is available to predict the phototoxic potential of fluoroquinolones without laboratory animals.     

The use of cephalosporins for gonorrhea: the impending problem of resistance

Gonorrhea remains an important clinical and public health problem throughout the world. Gonococcal infections have historically been diagnosed by Gram stain and culture but are increasingly diagnosed through nucleic acid tests, thereby eliminating the opportunity for antimicrobial susceptibility testing. Gonococcal infections are typically treated with single-dose therapy with an agent found to cure > 95% of cases. Unfortunately, the gonococcus has repeatedly developed resistance to antimicrobials including sulfonamides, penicillin, tetracyclines and fluoroquinolones. This has now left third-generation cephalosporins as the lone class of antimicrobials recommended as first-line therapy for gonorrhea in some regions. However, resistance to oral third-generation cephalosporins has emerged and spread in Asia, Australia and elsewhere. The mechanism of this resistance seems to be associated with a mosaic penicillin binding protein (penA) in addition to other chromosomal mutations previously found to confer resistance to β-lactam antimicrobials (ponA, mtrR, penB, pilQ). Few good options exist or are in development for treating cephalosporin-resistant isolates, as most have had multidrug resistance. Preventing the spread of resistant isolates will depend on ambitious antimicrobial management programs, strengthening and expanding surveillance networks, and through effective sexually transmitted disease control and prevention.     

Activities of antimicrobial agents against 8,474 clinical isolates obtained from 37 medical institutions during 2000 in Japan

A survey was conducted to determine the antimicrobial activity of fluoroquinolones and other antimicrobial agents against 8,474 clinical isolates obtained from 37 Japanese medical institutions in 2000. A total of 25 antimicrobial agents were used, comprising 4 fluoroquinolones, 13 beta-lactams, minocycline, chloramphenicol, clarithromycin, azithromycin, gentamicin, amikacin, sulfamethoxazole-trimethoprim, and vancomycin. A high resistance rate of over 85% against fluoroquinolones was exhibited by methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecium. Isolates showing resistance to fluoroquinolones among methicillin-resistant coagulase-negative Staphylococci, Enterococcus faecalis, and Pseudomonas aeruginosa from UTI accounted for 30-60%. However, many of the common pathogens were still susceptible to fluoroquinolones, such as Streptococcus pneumoniae (including penicillin-resistant isolates), Streptococcus pyogenes, methicillin-susceptible S. aureus (MSSA), methicillin-susceptible coagulase-negative Staphylococci, Moraxella catarrhalis, the Enterobacteriaceae family, and Haemophilus influenzae (including ampicillin-resistant isolates). About 85% of P. aeruginosa isolated from RTI were susceptible to fluoroquinolones. In conclusion, this survey of sensitivity to antimicrobial agents clearly indicated trend for increasing resistance to fluoroquinolones among MRSA, Enterococci, and P. aeruginosa isolated from UTI, although fluoroquinolones are still effective against other organisms and P. aeruginosa from RTI as has been demonstrated in previous studies.     

北京地区志贺菌8年来耐药趋势

为探讨北京地区志贺菌耐药趋势，对1994－2001年327株志贺菌对30种抗生素做药敏实验，结果8年来耐氟喹诺酮类菌株逐渐增多，1997－1998耐诺氟沙星菌株达11．6％，耐环丙沙星菌株达16．3％，均比1994显著增加（P＜0．001），3从1994－1998志贺菌对氟喹诺酮类中敏菌株也渐增加，且1999－2001增加迅速，是否预示今后几年氟喹诺酮类耐药株会迅速增加，应引起注意，氟喹诺酮类存在部分交叉耐药，耐5种氟喹诺酮类药物的菌株从1995逐渐上升，1999－2001耐药率达8．5％，8年来志贺菌对一代头孢，氨基糖甙类耐药相对稳定，仍可首选治疗急性菌痢，但丁胺卡那和几乎所有头孢类中敏菌株急剧增加，应引起重视。     

Alterations within the quinolone resistance-determining regions of GyrA and ParC of Neisseria gonorrhoeae isolated in the Far East and the United States

The genetic mutations within the quinolone resistance-determining regions (QRDRs) of gyrA and parC of 234 Neisseria gonorrhoeae strains isolated in the Far East and the United States, which exhibited either clinically significant ciprofloxacin resistance (CipR) or intermediate ciprofloxacin resistance (CipI) were characterized. A number of GyrA/ParC amino acid alteration patterns were identified, the most prevalent alteration pattern among CipR isolates being GyrA-91,95/ParC-Asp-86->Asn (91,95/Asp-86->Asn). Isolates containing 91,95/Asp-86->Asn belonged to a number of A/S classes, penicillin/tetracycline resistance phenotypes, and plasmid profiles. These results strongly suggest that the continuing emergence of ciprofloxacin-resistant gonococci is not due to the spread of a single or a few strains but to numerous factors such as spread of existing strains, importation of new strains and, possibly, de novo development of ciprofloxacin resistance in previously susceptible strains.     

淋病流行株耐药基因的定位研究

为了对淋病流行株的耐药基因作定位研究 ,对 1998～ 1999年间从广东省湛江地区分离出的 98株淋病流行株 ,采用 K- B法测定了其对 10种抗生素的敏感性 ;应用碱裂解法提取了相应菌株的质粒 ;并筛选其中的 NG4 、NG31 、NG4 3、NG70 4株菌作质粒的转化、接合及消除试验 ,对耐药基因进行定位。结果显示 ,98株淋病流行株对环丙沙星、四环素、氯霉素高度耐药 ,耐药率分别为 82 .6 5 %、6 9.39%、5 0 % ;检出 4 2 .5、39.5、7.4、4 .2 kb质粒分别占 11.2 2 %、4 1.82 %、5 9.16 %和 6 7.32 %。 NG4 3能通过接合、转化将对四环素和氯霉素的耐药性传递给受体菌淋病奈瑟氏敏感菌和大肠埃希氏菌 C6 0 0 ,NG31 通过接合传递实验 ,将对氯霉素的耐药性传递给淋病奈瑟氏标准敏感菌 ,通过质粒消除 ,上述菌株又恢复对抗生素的敏感性 ,而环丙沙星的耐药性通过接合、转化及消除均未见改变。从而提示湛江地区淋病流行株耐药形势严峻 ,淋球菌对四环素和氯霉素的耐药由质粒介导 ,对环丙沙星的耐药则有可能由染色体介导。     

Fluoroquinolones in the treatment of acute uncomplicated urinary tract infections in adult women

Urinary tract infections (UTIs) are among the most commonly encountered bacterial infections. Acute uncomplicated UTIs in adults include episodes of cystitis and pyelonephritis. The main uropathogens causing uncomplicated UTIs have, in the past, been fairly predictable and they have generally been susceptible to several commonly used oral antimicrobials. There has been a trend, however, towards increasing antimicrobial resistance among uropathogens over the past few years, especially to beta-lactams and trimethoprim-sulfamethoxazole (TMP-SMX). The current standard of therapy for the empiric treatment of acute uncomplicated cystitis is TMP-SMX for 3 days. Since the prevalence of resistance to TMP-SMX among uropathogens is increasing, however, fluoroquinolones, with their low side effect profile, convenient pharmacokinetics and effectiveness, are increasingly being used first-line for the management of cystitis. Treatment of acute pyelonephritis is less controversial and fluoroquinolones are recommended as first-line agents in the empiric treatment of community-acquired pyelonephritis. Of concern, the increased use of fluoroquinolones for the treatment of UTIs and other infectious processes has resulted in an increasing prevalence of fluoroquinolone-resistant uropathogens worldwide. In light of these changing resistance patterns, prudent use of fluoroquinolones for the treatment of UTIs is warranted.     

Fluoroquinolones in the treatment of acute uncomplicated urinary tract infections in adult women

Urinary tract infections (UTIs) are among the most commonly encountered bacterial infections. Acute uncomplicated UTIs in adults include episodes of cystitis and pyelonephritis. The main uropathogens causing uncomplicated UTIs have, in the past, been fairly predictable and they have generally been susceptible to several commonly used oral antimicrobials. There has been a trend, however, towards increasing antimicrobial resistance among uropathogens over the past few years, especially to beta-lactams and trimethoprim-sulfamethoxazole (TMP-SMX). The current standard of therapy for the empiric treatment of acute uncomplicated cystitis is TMP-SMX for 3 days. Since the prevalence of resistance to TMP-SMX among uropathogens is increasing, however, fluoroquinolones, with their low side effect profile, convenient pharmacokinetics and effectiveness, are increasingly being used first-line for the management of cystitis. Treatment of acute pyelonephritis is less controversial and fluoroquinolones are recommended as first-line agents in the empiric treatment of community-acquired pyelonephritis. Of concern, the increased use of fluoroquinolones for the treatment of UTIs and other infectious processes has resulted in an increasing prevalence of fluoroquinolone-resistant uropathogens worldwide. In light of these changing resistance patterns, prudent use of fluoroquinolones for the treatment of UTIs is warranted.     

The epidemiology of antibiotic resistance in Streptococcus pneumoniae and the clinical relevance of resistance to cephalosporins, macrolides and quinolones

Invasive non-meningeal pneumococcal infections remain a major cause of morbidity and mortality worldwide. The factors affecting the epidemiology and mortality of pneumococcal infections are discussed. The increase and spread of resistance to antimicrobial agents among pneumococci is a cause of concern to the clinician. There are links between the usage of antibacterial agents and the development of resistance. Resistance to penicillin and other beta-lactams has become widespread but this does not appear to have decreased the efficacy of some of these agents against non-meningeal infections. There is evidence that the good pharmacokinetic and pharmacodynamic features of the third generation cephalosporins (cefotaxime and ceftriaxone) contribute to their efficacy in vivo. New breakpoints for cefotaxime and ceftriaxone against non-meningeal pneumococcal isolates were proposed by the National Committee for Clinical Laboratory Standard (NCCLS, US), based on the clinical evidence of the efficacy of these drugs. In contrast there is increasing evidence that resistance to macrolides can lead to a poor clinical response. Fluoroquinolones have been widely used to treat respiratory tract infections among others, and pneumococcal resistance to these agents in vitro, although currently low, is increasing. There are reports that resistance to fluoroquinolones can develop during treatment and may be reflected in a lack of clinical response. Several clinical and epidemiological variables (e.g. prior antibiotic use) can be useful to identify patients at risk from infections with antibiotic-resistant pneumococci. These patients would be those who would benefit the most from a pneumococcal vaccination programme.     

Multi-drug resistance in Salmonella enterica: efflux mechanisms and their relationships with the development of chromosomal resistance gene clusters

Bacterial drug resistance represents one of the most crucial problems in present day antibacterial chemotherapy. Of particular concern to public health is the continuing worldwide epidemic spread of Salmonella enterica serovar Typhimurium phage type DT104 harbouring a genomic island called Salmonella genomic island I (SGI-1). This island contains an antibiotic gene cluster conferring resistance to ampicillin, chloramphenicol, florfenicol, streptomycin, sulfonamides and tetracyclines. These resistance genes are assembled in a mosaic pattern, indicative of several independent recombinational events. The mobility of SGI-1 coupled with the ability of various antibiotic resistance genes to be integrated and lost from the chromosomal resistance locus allows for the transfer of stable antibiotic resistance to most of the commonly used antibiotics and adaptation to new antibiotic challenges. This, coupled with the incidence of increasing fluoroquinolone resistance in these strains increases the risk of therapeutic failure in cases of life-threatening salmonellosis. Fluoroquinolone resistance has largely been attributed to mutations occurring in the genes coding for intracellular targets of these drugs. However, efflux by the AcrAB-TolC multi-drug efflux pump has recently been shown to directly contribute to fluoroquinolone resistance. Furthermore, the resistance to chloramphenicol-florfenicol and tetracyclines in DT104 isolates, is due to interaction between specific transporters for these antibiotics encoded by genes mapping to the SGI-1 and the AcrAB-TolC tripartite efflux pump. The potential for the use of efflux pump inhibitors to restore therapeutic efficacy to fluoroquinolones and other antibiotics offers an exciting developmental area for drug discovery.     

The use of fluoroquinolones in the treatment of skin infections

Fluoroquinolones have been studied for both uncomplicated and complicated skin and skin structure infections. Their broad spectrum, rapid bactericidal activity, extensive tissue penetration, excellent bioavailability and ease of administration have made these drugs a common choice for many infectious diseases, including skin infections. Extensive research has shown the fluoroquinolones to be as effective as beta-lactam antibiotics in managing a spectrum of diseases including erysipelas, cellulitis, impetigo, surgical wounds and diabetic foot infections. However, resistance to the fluoroquinolones has increased among the staphylococci, streptococci, Enterobacteriaceae and other important Gram-negative bacilli. Resistance has been linked directly to the widespread use of these compounds. Despite their appeal in the treatment of both uncomplicated and complicated skin infections, the fluoroquinolones should be reserved as alternatives to beta-lactams and other antibiotics or as empirical therapy in complicated infections until pathogens have been identified and drug regimens can be focused.