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Infectious disease 2000: drug resistance and new drugs
Infectious disease 2000
Infectious disease 2000: drug resistance and new drugs Nafsika H. Georgopapadakou DuPont Pharmaceuticals Research Labs,Wilmington, Delaware, USA
Abstract 40th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) was held in Toronto on 17–20 September 2000. It attracted thousands of delegates from industry and academia and covered, in over 2300 oral and poster presentations, topics ranging from microbial pathogenesis to infection control, vaccines, antibiotic resistance and new antimicrobial agents. Summarized here are highlights on microbial resistance and agents in clinical and preclinical development.
BACTERIAL RESISTANCE Drug efflux eith Poole, in a State-of-the-Art Mini-lecture, reviewed the efflux pumps in Pseudomonas aeruginosa and their contribution to antimicrobial resistance.1 They are chromosomally encoded and consist of three parts: an inner membrane drug-proton antiporter, an outer membrane channel-forming protein, and an inner-membrane-linked periplasmic protein connecting the other two.Two of these efflux systems, encoded by the mexAB-oprM and mexXYoprM genes are expressed constitutively and provide intrinsic resistance to fluoroquinolones, β-lactams, macrolides, tetracycline, chloramphenicol, trimethoprim and sulfonamides (MexAB-OprM) and aminoglycosides (MexXY-OprM). Mutational overexpression of these and two additional systems, encoded by the mexCD-oprJ and mexEF-oprN operons, is also responsible for the multidrug resistance of resistant strains of P. aeruginosa. Recent data suggest that these systems may also contribute to pathogenesis: pumpdeficient strains have reduced virulence in animal models of infection. Intriguingly, the MDR efflux systems of P. aeruginosa are coordinately regulated, with increases in the levels of one system matched by decreases in others.
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Efflux inhibitors for resistance? MC-207,110 (Microcide) is a dipeptide amide identified by high-throughput screening as an inhibitor of the RND family of multidrug resistance pumps in P. aeruginosa, E. coli and other gram-negative bacteria.2 It had marginal antibacterial activity (MIC=256 µg/ml), but potentiated the activity of levofloxacin against P. aeruginosa 8-fold at 10 µg/ml. Although MC-207,110 was a substrate of the pumps, it did not compete with any of the known substrates tested, such as nalidixic acid, chloramphenicol, erythromycin and tetracycline.
MC-02595 is another lead compound which potentiates levofloxacin by up to 8-fold against P. aeruginosa at concentrations ranging from 0.6–20 ug/ml3. The compound is also effective with levofloxacin in mouse Pseudomonas infection models. MC-04124, on the other hand, potentiates the macrolides azithromycin and clarithromycin against several gram-negative bacteria4. β-Lactamases David Livermore (CPHL, London, UK) reviewed the impact of β-lactamases in gram-negative resistance in the past twenty years.5,6 In Enterobacteria, the most prominent mechanisms are: 1.
2.
overproduction of AmpC chromosomal β-lactamases in Enterobacter spp., Citrobacter freundii and Serratia spp. Escape of the genes for AmpC enzymes to plasmids and spread into new hosts, notably Klebsiella spp. dissemination of ‘extended spectrum’ variants of TEM and SHV β-lactamases, especially in Klebsiella spp. Combinations of β-lactams with β-lactamase inhibitors can select inhibitor-resistant TEM mutants, though these remain rarer than ESBLs.
There is increased occurrence of bacteria with acquired carbapenemases: IMP-1 has been established in P. aeruginosa and in Serratia and IMP-2 and -3 have been reported in Acinetobacter. Other acquired metallo-β-lactamases, the VIM, have emerged in P. aeruginosa in Europe, Middle East, and East Asia, while Class D β-lactamase (OXA-23 to -27) with weak carbapenem-hydrolyzing activity are emerging worldwide in Acinetobacter. In a poster session, metalloβ-lactamase inhibitors were reported from SmithKline Beecham7 and Merck.8 Macrolide-ketolide-lincosamine-streptogramin (MKLS) resistance Joyce Sutcliffe (Pfizer) discussed the mechanism of action and resistance of macrolides, ketolides, lincosamides and streptogramins.9 These compounds bind to overlapping sites within the peptidyltransferase region of 23S RNA, thereby blocking movement of the growing peptide in the protein channel (14- and 15-membered macrolides and telithromycin) or inhibiting peptide bond formation directly (16-membered macrolides, lincosamides, streptogramin A and streptogramin B). Macrolides and ketolides also inhibit 50 S subunit assembly. Resistance to MLSK antibiotics can be mediated by target modification, inactivation of the drug, and efflux.Target modification includes mutations in 23S RNA, mutations in conserved regions of ribosomal proteins L4 and L22 and methylation of A2058, a key residue which interacts with the MKLS antibiotics. Due to overlapping binding sites, some of these mutations or rRNA methylation are sufficient to confer resistance to more than one of the MKLS antibiotics. Inactivation is usually more specific to an antibiotic class and includes a wide range of phosphotransferases, glycosylases, acetyltransferases, nucleotidyltrasferases, deacylases, formyl reductases, hydrolases and esterases. Efflux can be mediated by a pump of narrow specificity such as MsrA, or by a pump of broad specificity such as MexAB-OprM. 2000 Harcourt Publishers Ltd Drug Resistance Updates (2000) 3, 265–269 doi: 10.1054/drup.2000.0168, available online at http://www.idealibrary.com on
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Georgopapadakou ANTIBACTERIAL AGENTS IN DEVELOPMENT β-Lactams Cephems Cefditoren pivoxil (Spectracef, ME 1207, ME 1206A: TAP (Takeda/Abbott Pharmaceuticals), licensed from Meiji Seika) is a broad-spectrum,10 orally active cephalosporin awaiting FDA approval for the empirical treatment of respiratory tract infections. BMS 247243 (BristolMeyers Squibb) is active against most MRSA strains.11–13 It binds to penicillin-binding protein (PBP) 2a with an IC50 of 0.6 µg/ml and is preclinical development. RWJ-333441/MC-04,546 (Johnson and Johnson/Microcide; RWJ-333442/MC-04,699 is the aspartate prodrug form) is also active against MRSA and binds to PBP2a with and IC50 of 0.8 µg/ml. It is also in preclinical development.14–15 Carbapenems MK-0826 (L 749345, ZD 4433; Merck, licensed from AstraZeneca) is broad-spectrum, long-acting, injectable 1βmethyl carbapenem in phase III.14 E-1010 (Eisai) is a broad-spectrum, long-acting 1β-methyl carbapenem in phase II.15 Faropenem (Farom, SUN 5555; Suntory, licensed to Bayer) is an oral penem in phase II for respiratory infections.16 R-11568 (Sankyo) is a parenteral 1β-carbapenem with a half life in humans (2.3 h) more than twice that of meropenem and imipenem.17 Glycopeptides, lipopeptides BI 397 (V-glycopeptide; Biosearch Italia/Versicor) is a longacting semisynthetic glycopeptide currently in phase I. It has in vitro activity superior to vancomycin and in vivo activity superior to both vancomycin and teicoplanin. In a phase I study, patients dosed with 360 mg of B I 397 had serum bactericidal activity at 8-fold dilutions 24 h after dosing, consistent with a low clearance rate for the compound. Single and multiple doses were well tolerated and there were no infusion-related events.18 Daptomycin (Dapcin, LY 146032, A 21978C; Cubist, licensed from Lilly) is a lipopeptide active against gram-positive bacteria.19 It was developed by Lilly in the 1980s, but its development stopped in phase III because of toxicity concerns. Development has resumed by Cubist and is now again in phase III. Past toxicities have been attributed to the dosing regimen used (4 mg/kg, bid). Pharmacokinetics and efficacy studies with daptomycin suggest once-daily dosing, which may reduce toxicity.The compound is rapidly cidal and there is little evidence of resistance. Quinolones Moxifloxacin (Avelox, BAY 12–8039; Bayer) and gatifloxacin (Tequin,AM1155; BristolMeyer Squibb) have been launched. They are both oral, broad-spectrum, once daily drugs. Interestingly, they both target DNA gyrase, not topoisomerase IV, in S. pneumoniae and perhaps other gram-positive bacteria20. Gemifloxacin (Factive, SB 265805, LB 20304; SmithKline Beecham, licensed from LG Chem (South Korea) is a
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broad-spectrum drug, with particularly good activity against gram-positive and anaerobic bacteria. Phase III studies have been completed and an NDA has been submitted in the US for RTIs. BMS 284756 (T 3811; Bristol-Myers Squibb licensed from Toyama) is a des-F-(6)-quinolone curently in Phase II. Phase I studies showed that single oral doses of up to 800 mg were safe and well tolerated and that BMS 284756 could be given once daily.21,22 Sitafloxacin (DU 6859a; Daiichi Seiyaku) is in late clinical development. Interestingly, it inhibits both DNA gyrase and topoisomerase IV at comparable concentrations suggesting low target-associated resistance frequency.24 Quinolones in preclinical development include D 61113 (Daiichi) and WQ 2944 (Wakunaga). The latter has in vitro activity against gram-positive bacteria superior to trovafloxacin and activity against gram-negative bacteria similar or better than ciprofloxacin.24 Ketolides Telithromycin (Ketek; HMR 3647; RU 66647) (Aventis), an oral, once daily ketolide, has been submitted to FDA for regulatory approval for the treatment of community-acquired pneumonia, acute sinusitis, acute exacerbations of chronic bronchitis and tonsillitis/pharyngitis. Its clinical and preclinical development was covered in several presentations. ABT-773 (Abbott), currently in late phase II, was highly active against respiratory pathogens and gram-positive bacteria, including those resistant to macrolides, and had a long post-antibiotic effect.Although its half life in humans ranged between 3.6 and 6.7 h, animal pharmacodynamic studies suggest that the 24 h area under the curve (AUC):MIC ratio is the best predictor of in vivo activity of ABT-773, supporting a once-daily dosing of the drug.25 Other The glycylcycline GAR 936 (Wyeth Ayerst/American Home Products) is in Phase II. No oxazolidinone is in clinical development, although several companies (Pharmacia, Bayer, AstraZeneca, Johnson and Johnson), have efforts in that area. A new semisynthetic pleuromutilin, SB 264128 (SmithKline Beecham) had strong in vitro activity against respiratory pathogens (MICs, <0.06 µg/ml) and good efficacy in vivo. Peptide deformylase inhibitors are being examined by Versicor and British Biotech as broad-spectrum antibiotics.
FUNGAL RESISTANCE Drug efflux Drug efflux is a significant factor in fluconazole resistance in Candida and may be the source of the intrinsic drug resistance in Aspergillus. Efflux inhibitors for resistance? MC-510,027 is a natural product lacking significant antifungal activity. It potentiates fluconazole activity against C. albicans.26
Infectious disease 2000 ANTIFUNGAL AGENTS IN DEVELOPMENT Triazoles Clinical development Voriconazole (UK 109, 496; Pfizer) is a broad-spectrum, lipophilic triazole derived from fluconazole currently in phase III. It is active against Candida and Aspergillus species as well as emerging pathogens such as Fusarium. In clinical trials, it showed a long half life, good oral bioavailability, penetration into CSF and efficacy.27 Posaconazole (SCH 56592; Schering Plough) is an broadspectrum, orally active, metabolically stable derivative of itraconazole currently in phase III. It has a long half life (15–25 h) though poor penetration into CSF. SCH 59884 is a watersoluble prodrug of SCH 56592 for intravenous formulation.28 The triazole ravuconazole (BMS 207147, ER30346; BristolMyers Squibb, licensed from Eisai) is currently in phase II. Its antifungal spectrum includes Aspergillus. Results from phase I studies were presented. The compound had a 50% oral bioavailability a half life of 3.5–7.5 days, was well tolerated up to 400–800 mg, and inhibited CYP3A less potently than itraconazole.29,30 Preclinical development R-120758 (Sankyo) is an orally active triazole with in vitro activity against Aspergillus superior to itraconazole. It is also active in mouse infection models of candidiasis, aspergillosis and cryptococcosis.11 SS750 (SS Seiyaku) is an orally active triazole (76% oral bioavailability in rats), with a long half life (3 days in rats), in vitro activity against Candida and Aspergillus species superior to fluconazole and in vivo activity against systemic candidiasis 4 and 16 times greater than fluconazole and itraconazole respectively.32 TAK 457 (Takeda) is an injectable, water-soluble prodrug of the oral triazole TAK456 (itself not sufficiently water soluble for liquid formulation) whose antifungal spectrum includes Aspergillus and fluconazole-resistant Candida strains. At 10 mg/kg, TAK 457 was as effective as 1 mg/kg amphotericin B in a mouse model of pulmonary aspergillosis (Abstr. 1086). At 1 mg/kg, TAK 456 was effective in mouse model of systemic candidiasis while itraconazole and voriconazle were ineffective at the same dose.33 Glucan synthase inhibitors: echinocandins The three echinocandins currently in clinical trials was the subject of an excellent presentation by John Graybill.34 His conclusion was that they have cidal activity and great efficacy for candidiasis, but only static activity against aspergillosis.The three echinocandins, listed belw, have similar in vitro and in vivo activity. • • •
Caspofungin (Cansidas, MK-991, L-743872; Merck) is an injectable antifungal in late phase III. Micafungin (FK-463; Fujisawa) is a water-soluble, semisynthetic echinocandin in phase III. Anidulafungin (LY 303366; Lilly, licensed to Versicor) is in phase II and is the least water soluble of the three glucan synthetase inhibitors.
Polyenes SPK-843 (Kaken) is a polyene antibiotic in preclinical development that has efficacy in mouse models of candidiasis and aspergillosis superior to amphotericin B.35 ANTIVIRAL AGENTS IN DEVELOPMENT HIV NNRTIs R-165335 (Janssen) is in preclinical development. It is more potent than either delavirdine of efavirenz, being active at low nanomolar concentrations, even against NNRTI-resistant strains. In studies with over 2000 clinical isolates, R-165335TMC-125 inhibited 98% of the strains with IC50 values below 100 nM.At least three mutations in the RT gene are required for resistance to develop. Chemokine receptor antagonists AMD-8664 is a CXCR4 antagonist, inhibiting HIV replication with IC50s of 10 to 30 ng/ml in MT-4 cells and PBMCs, while remaining non-toxic to MT-4 cells at concentrations greater than 100 ug/ml. In rabbits,AMD-8664 had oral bioavailability greater than 50% and a half-life of 6.4 h. Similar results were obtained in rats. In both species, it was well tolerated when administered as a single dose In a late breaker session, high concentrations of the CXCR4 antagonists T-134 and T-140 Kyoto University) increased the levels of CCR5 expression and R5 HIV-1 infectivity.The T-134-resistant X4 HIV showed several mutations in the V1-V4 domains of gp120. It was postulated that amino acid substitutions in the envelope glycoprotein of X4 HIV-1 may confer resistance to T-134. Herpes viruses The 4-hydroxyquinolone PNU-145185 (Chiron/Pharmacia) is a selective, non-nucleoside inhibitor of herpes virus polymerase. It did not inhibit human polymerase or the polymerases of other viruses but had good activity against HSV-1, HSV-2, CMV,VZV. PD-0084430 (Pfizer) is a potent non-nucleoside inhibitor of cytomegalovirus (CMV). It had EC50 values against CMV comparable to ganciclovir, but was active against ganciclovirresistant strains. Respiratory viruses T-705 (Toyama) is a highly selective replication inhibitor of influenza virus. It showed potent virucidal activity against influenza A, B and C. In mouse models, oral T-705 was superior to the neuraminidase inhibitor oseltamivir; it completely prevented death when given up to 25 h after infection. It also reduced symptoms and virus titers in ferrets. Pleconaril (Sanofi-Synthelabo/ViroPharma) inhibits viral uncoating of picornaviruses, such as the human rhinoviruses (HRVs) which cause over 50% of the colds. In patients suffering from rhinorrhea, the compound (400 mg tid) reduced both symptoms and illness duration by 2 days. AG7088 (Agouron) is a rhinovirus 3C protease inhibitor with broad-spectrum activity against all HRV serotypes and related picornaviruses. Comparison of over 30 HRVs and 18
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Georgopapadakou enteroviruses revealed strong conservation of the catalytic and RNA-binding regions of the viral 3C protease, consistent with the observed activity of AG 7088 against all these serotypes. These observations support the atractiveness of AG7088 as a clinical candidate and the 3C protease as an antiviral target. SUMMARY As with last year’s ICAAC, the new compounds presented this year were largely members of known classes. In the antibacterial area new quinolones, β-lactams and ketolides are progressing in clinical development, while in antifungals several new azoles and echinocandins are in late clinical development. In antivirals, NNRTIs and chemoreceptor antagonists for HIV, DNA polymerase inhibitors for herpes viruses and inhibitors of viral uncoating and 3C protease are being developed. New technologies, both in molecular diagnostics and drug discovery or refinement are coming of age and may impact therapy and therapeutics.Although drug resistance is clearly increasing in bacteria, fungi and viruses, available drugs are also increasing (antivirals) or improving (quinolones, azoles). It is an exciting time for infectious diseases, full of challenges and opportunities.
Received 2 October 2000; Accepted 5 October 2000 Correspondence to: Nafsika H. Georgopapadakou PhD, DuPont Pharmaceuticals, Experimental Station, E400/3456A, PO Box 80400, DE 19880–0400, USA.Tel: +302 695 8525; Fax: +1 302 695 7407; E-mail: [email protected]
References 1. Poole RK.Antimicrobial resistance and multidrug effux pumps in Pseudomonas aeruginosa.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:73 (# 436). 2. Warren MS, Lee JC, Lee A, Hoshino K, Ishida H, Lomovskaya O.An inhibitor of the Mex pumps from Pseudomonas aeruginosa is also a substrate of these pumps.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:207 (# 1495). 3. Griffith D, Lomovskaya O, Lee VJ, Dudley M. Potentiation of levofloxacin by MC-02,595, a broad-spectrum efflux pump inhibitor in mouse models of infection due to Pseudomonas aeruginosa with combinations of different Mex pump expression and a gyrA mutation.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:207 (# 1496). 4. Cho D, Lofland D, Blais J, et al.An efflux pump inhibitor, MC-04, 124, enhances the activity of macrolides against gram-negative bacteria.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:208 (# 1497). 5. Livermore DM. β-Lactamases and pumps in gram-negative bacilli. Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:519 (# 4). 6. Rice LB, Bonomo RA. β-Lactamases: which ones are clinically important? Drug Resist Updates 2000;32:178–189.
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7. Gilpin M, Cheever C, Pearson S, et al. SAR and selectivity analysis of a series of thiazolidine and proline mercaptocarboxylate metallo-β-lactamase inhibitors.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:203 (# 1225). 8. Huber JL,Young K, Painter RE, Rosen H, Silver LL. Inhibition of IMP1 metallo-b-lactamase in clinical isolates by two succinic acid derivatives.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:203 (# 1226). 9. Sutcliffe J. Resistance to macrolides and functionally related drugs. Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:545 (# 1923). 10. Dubois J, St-Pierre C. Superior inhibitory and bactiricidal activity of cefditoren agains respiratory tract pathogens.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:161 (# 370). 11. Kim O, Zhang Y,Wichtowski J, et al. Discovery, synthesis and SAR of BMS-247243, a novel cephalosporin active against methicillinresistant Staphylococcus aureus (MRSA) and susceptible Staphylococcus aureus (MSSA).Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:193 (# 1062). 12. Fung-Tomc J, Minassian B, Pucci M, et al.Anti-staphylococcal activity of a novel MRSA (methicillin-resistant Staphylococcus aureus cephem BMS-247243.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:193 (# 1063). 13. Hucsko E, Minassian B, Gradelski E, et al.Antibacterial spectrum of a novel MRSA (methicillin-resistant Staphylococcus aureus cephem BMS-247243.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:194 (# 1064). 14. Majumdar AK, Birk KL, Neway W et al. Single-dose pharmacokinetics and dose-proportionality of MK-0826, a oncedaily carbapenem antibiotic in healthy male and female volunteers. Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:15 (# 491). 15. Hirasawa T, Okereke C,Wheeler J, et al. Pharmacokinetics, safety and tolerability of E1010, a new parenteral long half-life carbapenem, in healthy volunteers.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:15 (# 492). 16. Schuehly U,Voith B,Voigt U, et al. Safety, tolerability and pharmacokinetics following multiple oral doses of faropenem daloxate and impact on fecal and oral flora.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:15 (# 494). 17. Ohya S, Fukuoka T, Kawada H, et al. R-115685, a novel parenteral carbapenem: in vivo antibacterial activity.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:205 (# 1232). 18. White RJ, Brown GL, Cavelero M.V-glycopeptide: phase 1 single and multiple-dose placebo controlled intravenous safety, pharmacokinetic and pharmacodynamic study in healthy subjects. Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:233 (# 2196). 19. Golstein WJC, Citron DM. In vitro activity of daptomycin, quinopristin/dalfopristin, and linezolid against 275 gram-positive aerobic and anaerobic organisms.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:183 (# 2293). 20. Kilburn L, Downar J,Tong B, et al. Moxifloxacin and gatifloxacin preferentially target GyrA in Streptococcus pneumoniae.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:79 (# 743). 21. Gajjar D, Grasela D, Bello A, Ge Z, Christopher L. Safety, tolerability and pharmacokinetics of BMS-284756, a novel des-F(6)quinolone antibiotic, following single oral doses in healthy adult subjects.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:36 (# 2259).
Infectious disease 2000 22. Grasela D, Gajjar D,A Bello, Ge Z, Christopher L. Safety, tolerability and pharmacokinetics of BMS-284756, a novel des-F(6)quinolone antibiotic, following 14-day oral doses in healthy adult subjects.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:36 (# 2260). 23. Okuda J, Onodera Y,Tanaka M, Sato K. Dual inhibitory activity of sitafloxacin against DNA gyrase and topoisomerase IV of Enterococcus faecalis and Streptococcus pneumoniae.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:81 (# 750). 24. Kuramoto Y, Ohshita Y,Amano H, et al. Structure-activity relationships of novel acidic, 7-amino or 7-alkylamino-1-(5-amino2, 4-difluorophenyl)-8-methylquinolones.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:209 (# 1504). 25. Pradhan RS, Gustavson LE, Londo DD, et al. Single oral dose pharmacokinetics and safety of ABT-773 in healthy subjects.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:30 (# 2135). 26. Sorensen K, Corcoran E, Clark D, et al. In vivo potentiation of fluconazole by the fungal pump inhibitor MC-510,011 in a mouse model of pyelonephritis due to fluconazole-susceptible and resistant Candida albicans.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:209 (# 1502). 27. DuPont B,Ally R, Burke J, et al.A double-blind, randomized, multicenter trial of voriconazole vs. fluconazole for the treatment of esophageal candidiasisin immunocompromised adults.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:365 (# 706). 28. Hachem RY, Raad II,Afif CM, et al.An open, non-comparative multicenter study to to evaluate efficacy and safety of
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posaconazole (SCH 56592) in the treatment of invasive fungal infections refractory or intolerant to standard therapy. Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:372 (# 1109). Olsen SJ, Mummaneni V, Rolan P, Norton J, Grasela DM. Ravuconazole single ascending oral dose study in healthy subjects. Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:22 (# 838). Grasela DM, Olsen SJ, Mummaneni V, et al. Ravuconazole: multiple ascending oral dose study in healthy subjects.Abstr. 40th Intersci Conf Antimicrob Agents Chmother 2000:22 (# 839). Kamai Y, Harasaki T, Fukuoka T, et al. R-120758, a novel triazole antifungal agent: in vivo antifungal activity.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:201 (# 1091). Yokoyama K,Wang L, Kaji H, et al. In vivo antifungal activity of SS750, a new triazole agent, against systemic and pulmonary candidosis in mice.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:199 (# 1084). Iizawa Y, Hayashi R, Kitamoto N, et al.TAK-456 and the watersoluble prodrug TAK-457, new antifungal triazoles; in vitro and in vivo antifungal activity.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:199 (# 1086). Graybill JR.Will the promise of candins be realized? Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000 (addendum):8 (# 640). Senda H, Maejima T, Konishi Y. SPK-843, a new polyene antibiotic with potent in vitro activity and a strong fungicidal effect.Abstr. 40th Intersci Conf Antimicrob Agents Chemother 2000:201 (# 1093).
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Infectious disease 2000: drug resistance and new drugs Nafsika H. Georgopapadakou DuPont Pharmaceuticals Research Labs,Wilmington, Delaware, USA
Abstract 40th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) was held in Toronto on 17–20 September 2000. It attracted thousands of delegates from industry and academia and covered, in over 2300 oral and poster presentations, topics ranging from microbial pathogenesis to infection control, vaccines, antibiotic resistance and new antimicrobial agents. Summarized here are highlights on microbial resistance and agents in clinical and preclinical development.
BACTERIAL RESISTANCE Drug efflux eith Poole, in a State-of-the-Art Mini-lecture, reviewed the efflux pumps in Pseudomonas aeruginosa and their contribution to antimicrobial resistance.1 They are chromosomally encoded and consist of three parts: an inner membrane drug-proton antiporter, an outer membrane channel-forming protein, and an inner-membrane-linked periplasmic protein connecting the other two.Two of these efflux systems, encoded by the mexAB-oprM and mexXYoprM genes are expressed constitutively and provide intrinsic resistance to fluoroquinolones, β-lactams, macrolides, tetracycline, chloramphenicol, trimethoprim and sulfonamides (MexAB-OprM) and aminoglycosides (MexXY-OprM). Mutational overexpression of these and two additional systems, encoded by the mexCD-oprJ and mexEF-oprN operons, is also responsible for the multidrug resistance of resistant strains of P. aeruginosa. Recent data suggest that these systems may also contribute to pathogenesis: pumpdeficient strains have reduced virulence in animal models of infection. Intriguingly, the MDR efflux systems of P. aeruginosa are coordinately regulated, with increases in the levels of one system matched by decreases in others.
K
Efflux inhibitors for resistance? MC-207,110 (Microcide) is a dipeptide amide identified by high-throughput screening as an inhibitor of the RND family of multidrug resistance pumps in P. aeruginosa, E. coli and other gram-negative bacteria.2 It had marginal antibacterial activity (MIC=256 µg/ml), but potentiated the activity of levofloxacin against P. aeruginosa 8-fold at 10 µg/ml. Although MC-207,110 was a substrate of the pumps, it did not compete with any of the known substrates tested, such as nalidixic acid, chloramphenicol, erythromycin and tetracycline.
MC-02595 is another lead compound which potentiates levofloxacin by up to 8-fold against P. aeruginosa at concentrations ranging from 0.6–20 ug/ml3. The compound is also effective with levofloxacin in mouse Pseudomonas infection models. MC-04124, on the other hand, potentiates the macrolides azithromycin and clarithromycin against several gram-negative bacteria4. β-Lactamases David Livermore (CPHL, London, UK) reviewed the impact of β-lactamases in gram-negative resistance in the past twenty years.5,6 In Enterobacteria, the most prominent mechanisms are: 1.
2.
overproduction of AmpC chromosomal β-lactamases in Enterobacter spp., Citrobacter freundii and Serratia spp. Escape of the genes for AmpC enzymes to plasmids and spread into new hosts, notably Klebsiella spp. dissemination of ‘extended spectrum’ variants of TEM and SHV β-lactamases, especially in Klebsiella spp. Combinations of β-lactams with β-lactamase inhibitors can select inhibitor-resistant TEM mutants, though these remain rarer than ESBLs.
There is increased occurrence of bacteria with acquired carbapenemases: IMP-1 has been established in P. aeruginosa and in Serratia and IMP-2 and -3 have been reported in Acinetobacter. Other acquired metallo-β-lactamases, the VIM, have emerged in P. aeruginosa in Europe, Middle East, and East Asia, while Class D β-lactamase (OXA-23 to -27) with weak carbapenem-hydrolyzing activity are emerging worldwide in Acinetobacter. In a poster session, metalloβ-lactamase inhibitors were reported from SmithKline Beecham7 and Merck.8 Macrolide-ketolide-lincosamine-streptogramin (MKLS) resistance Joyce Sutcliffe (Pfizer) discussed the mechanism of action and resistance of macrolides, ketolides, lincosamides and streptogramins.9 These compounds bind to overlapping sites within the peptidyltransferase region of 23S RNA, thereby blocking movement of the growing peptide in the protein channel (14- and 15-membered macrolides and telithromycin) or inhibiting peptide bond formation directly (16-membered macrolides, lincosamides, streptogramin A and streptogramin B). Macrolides and ketolides also inhibit 50 S subunit assembly. Resistance to MLSK antibiotics can be mediated by target modification, inactivation of the drug, and efflux.Target modification includes mutations in 23S RNA, mutations in conserved regions of ribosomal proteins L4 and L22 and methylation of A2058, a key residue which interacts with the MKLS antibiotics. Due to overlapping binding sites, some of these mutations or rRNA methylation are sufficient to confer resistance to more than one of the MKLS antibiotics. Inactivation is usually more specific to an antibiotic class and includes a wide range of phosphotransferases, glycosylases, acetyltransferases, nucleotidyltrasferases, deacylases, formyl reductases, hydrolases and esterases. Efflux can be mediated by a pump of narrow specificity such as MsrA, or by a pump of broad specificity such as MexAB-OprM. 2000 Harcourt Publishers Ltd Drug Resistance Updates (2000) 3, 265–269 doi: 10.1054/drup.2000.0168, available online at http://www.idealibrary.com on
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Georgopapadakou ANTIBACTERIAL AGENTS IN DEVELOPMENT β-Lactams Cephems Cefditoren pivoxil (Spectracef, ME 1207, ME 1206A: TAP (Takeda/Abbott Pharmaceuticals), licensed from Meiji Seika) is a broad-spectrum,10 orally active cephalosporin awaiting FDA approval for the empirical treatment of respiratory tract infections. BMS 247243 (BristolMeyers Squibb) is active against most MRSA strains.11–13 It binds to penicillin-binding protein (PBP) 2a with an IC50 of 0.6 µg/ml and is preclinical development. RWJ-333441/MC-04,546 (Johnson and Johnson/Microcide; RWJ-333442/MC-04,699 is the aspartate prodrug form) is also active against MRSA and binds to PBP2a with and IC50 of 0.8 µg/ml. It is also in preclinical development.14–15 Carbapenems MK-0826 (L 749345, ZD 4433; Merck, licensed from AstraZeneca) is broad-spectrum, long-acting, injectable 1βmethyl carbapenem in phase III.14 E-1010 (Eisai) is a broad-spectrum, long-acting 1β-methyl carbapenem in phase II.15 Faropenem (Farom, SUN 5555; Suntory, licensed to Bayer) is an oral penem in phase II for respiratory infections.16 R-11568 (Sankyo) is a parenteral 1β-carbapenem with a half life in humans (2.3 h) more than twice that of meropenem and imipenem.17 Glycopeptides, lipopeptides BI 397 (V-glycopeptide; Biosearch Italia/Versicor) is a longacting semisynthetic glycopeptide currently in phase I. It has in vitro activity superior to vancomycin and in vivo activity superior to both vancomycin and teicoplanin. In a phase I study, patients dosed with 360 mg of B I 397 had serum bactericidal activity at 8-fold dilutions 24 h after dosing, consistent with a low clearance rate for the compound. Single and multiple doses were well tolerated and there were no infusion-related events.18 Daptomycin (Dapcin, LY 146032, A 21978C; Cubist, licensed from Lilly) is a lipopeptide active against gram-positive bacteria.19 It was developed by Lilly in the 1980s, but its development stopped in phase III because of toxicity concerns. Development has resumed by Cubist and is now again in phase III. Past toxicities have been attributed to the dosing regimen used (4 mg/kg, bid). Pharmacokinetics and efficacy studies with daptomycin suggest once-daily dosing, which may reduce toxicity.The compound is rapidly cidal and there is little evidence of resistance. Quinolones Moxifloxacin (Avelox, BAY 12–8039; Bayer) and gatifloxacin (Tequin,AM1155; BristolMeyer Squibb) have been launched. They are both oral, broad-spectrum, once daily drugs. Interestingly, they both target DNA gyrase, not topoisomerase IV, in S. pneumoniae and perhaps other gram-positive bacteria20. Gemifloxacin (Factive, SB 265805, LB 20304; SmithKline Beecham, licensed from LG Chem (South Korea) is a
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broad-spectrum drug, with particularly good activity against gram-positive and anaerobic bacteria. Phase III studies have been completed and an NDA has been submitted in the US for RTIs. BMS 284756 (T 3811; Bristol-Myers Squibb licensed from Toyama) is a des-F-(6)-quinolone curently in Phase II. Phase I studies showed that single oral doses of up to 800 mg were safe and well tolerated and that BMS 284756 could be given once daily.21,22 Sitafloxacin (DU 6859a; Daiichi Seiyaku) is in late clinical development. Interestingly, it inhibits both DNA gyrase and topoisomerase IV at comparable concentrations suggesting low target-associated resistance frequency.24 Quinolones in preclinical development include D 61113 (Daiichi) and WQ 2944 (Wakunaga). The latter has in vitro activity against gram-positive bacteria superior to trovafloxacin and activity against gram-negative bacteria similar or better than ciprofloxacin.24 Ketolides Telithromycin (Ketek; HMR 3647; RU 66647) (Aventis), an oral, once daily ketolide, has been submitted to FDA for regulatory approval for the treatment of community-acquired pneumonia, acute sinusitis, acute exacerbations of chronic bronchitis and tonsillitis/pharyngitis. Its clinical and preclinical development was covered in several presentations. ABT-773 (Abbott), currently in late phase II, was highly active against respiratory pathogens and gram-positive bacteria, including those resistant to macrolides, and had a long post-antibiotic effect.Although its half life in humans ranged between 3.6 and 6.7 h, animal pharmacodynamic studies suggest that the 24 h area under the curve (AUC):MIC ratio is the best predictor of in vivo activity of ABT-773, supporting a once-daily dosing of the drug.25 Other The glycylcycline GAR 936 (Wyeth Ayerst/American Home Products) is in Phase II. No oxazolidinone is in clinical development, although several companies (Pharmacia, Bayer, AstraZeneca, Johnson and Johnson), have efforts in that area. A new semisynthetic pleuromutilin, SB 264128 (SmithKline Beecham) had strong in vitro activity against respiratory pathogens (MICs, <0.06 µg/ml) and good efficacy in vivo. Peptide deformylase inhibitors are being examined by Versicor and British Biotech as broad-spectrum antibiotics.
FUNGAL RESISTANCE Drug efflux Drug efflux is a significant factor in fluconazole resistance in Candida and may be the source of the intrinsic drug resistance in Aspergillus. Efflux inhibitors for resistance? MC-510,027 is a natural product lacking significant antifungal activity. It potentiates fluconazole activity against C. albicans.26
Infectious disease 2000 ANTIFUNGAL AGENTS IN DEVELOPMENT Triazoles Clinical development Voriconazole (UK 109, 496; Pfizer) is a broad-spectrum, lipophilic triazole derived from fluconazole currently in phase III. It is active against Candida and Aspergillus species as well as emerging pathogens such as Fusarium. In clinical trials, it showed a long half life, good oral bioavailability, penetration into CSF and efficacy.27 Posaconazole (SCH 56592; Schering Plough) is an broadspectrum, orally active, metabolically stable derivative of itraconazole currently in phase III. It has a long half life (15–25 h) though poor penetration into CSF. SCH 59884 is a watersoluble prodrug of SCH 56592 for intravenous formulation.28 The triazole ravuconazole (BMS 207147, ER30346; BristolMyers Squibb, licensed from Eisai) is currently in phase II. Its antifungal spectrum includes Aspergillus. Results from phase I studies were presented. The compound had a 50% oral bioavailability a half life of 3.5–7.5 days, was well tolerated up to 400–800 mg, and inhibited CYP3A less potently than itraconazole.29,30 Preclinical development R-120758 (Sankyo) is an orally active triazole with in vitro activity against Aspergillus superior to itraconazole. It is also active in mouse infection models of candidiasis, aspergillosis and cryptococcosis.11 SS750 (SS Seiyaku) is an orally active triazole (76% oral bioavailability in rats), with a long half life (3 days in rats), in vitro activity against Candida and Aspergillus species superior to fluconazole and in vivo activity against systemic candidiasis 4 and 16 times greater than fluconazole and itraconazole respectively.32 TAK 457 (Takeda) is an injectable, water-soluble prodrug of the oral triazole TAK456 (itself not sufficiently water soluble for liquid formulation) whose antifungal spectrum includes Aspergillus and fluconazole-resistant Candida strains. At 10 mg/kg, TAK 457 was as effective as 1 mg/kg amphotericin B in a mouse model of pulmonary aspergillosis (Abstr. 1086). At 1 mg/kg, TAK 456 was effective in mouse model of systemic candidiasis while itraconazole and voriconazle were ineffective at the same dose.33 Glucan synthase inhibitors: echinocandins The three echinocandins currently in clinical trials was the subject of an excellent presentation by John Graybill.34 His conclusion was that they have cidal activity and great efficacy for candidiasis, but only static activity against aspergillosis.The three echinocandins, listed belw, have similar in vitro and in vivo activity. • • •
Caspofungin (Cansidas, MK-991, L-743872; Merck) is an injectable antifungal in late phase III. Micafungin (FK-463; Fujisawa) is a water-soluble, semisynthetic echinocandin in phase III. Anidulafungin (LY 303366; Lilly, licensed to Versicor) is in phase II and is the least water soluble of the three glucan synthetase inhibitors.
Polyenes SPK-843 (Kaken) is a polyene antibiotic in preclinical development that has efficacy in mouse models of candidiasis and aspergillosis superior to amphotericin B.35 ANTIVIRAL AGENTS IN DEVELOPMENT HIV NNRTIs R-165335 (Janssen) is in preclinical development. It is more potent than either delavirdine of efavirenz, being active at low nanomolar concentrations, even against NNRTI-resistant strains. In studies with over 2000 clinical isolates, R-165335TMC-125 inhibited 98% of the strains with IC50 values below 100 nM.At least three mutations in the RT gene are required for resistance to develop. Chemokine receptor antagonists AMD-8664 is a CXCR4 antagonist, inhibiting HIV replication with IC50s of 10 to 30 ng/ml in MT-4 cells and PBMCs, while remaining non-toxic to MT-4 cells at concentrations greater than 100 ug/ml. In rabbits,AMD-8664 had oral bioavailability greater than 50% and a half-life of 6.4 h. Similar results were obtained in rats. In both species, it was well tolerated when administered as a single dose In a late breaker session, high concentrations of the CXCR4 antagonists T-134 and T-140 Kyoto University) increased the levels of CCR5 expression and R5 HIV-1 infectivity.The T-134-resistant X4 HIV showed several mutations in the V1-V4 domains of gp120. It was postulated that amino acid substitutions in the envelope glycoprotein of X4 HIV-1 may confer resistance to T-134. Herpes viruses The 4-hydroxyquinolone PNU-145185 (Chiron/Pharmacia) is a selective, non-nucleoside inhibitor of herpes virus polymerase. It did not inhibit human polymerase or the polymerases of other viruses but had good activity against HSV-1, HSV-2, CMV,VZV. PD-0084430 (Pfizer) is a potent non-nucleoside inhibitor of cytomegalovirus (CMV). It had EC50 values against CMV comparable to ganciclovir, but was active against ganciclovirresistant strains. Respiratory viruses T-705 (Toyama) is a highly selective replication inhibitor of influenza virus. It showed potent virucidal activity against influenza A, B and C. In mouse models, oral T-705 was superior to the neuraminidase inhibitor oseltamivir; it completely prevented death when given up to 25 h after infection. It also reduced symptoms and virus titers in ferrets. Pleconaril (Sanofi-Synthelabo/ViroPharma) inhibits viral uncoating of picornaviruses, such as the human rhinoviruses (HRVs) which cause over 50% of the colds. In patients suffering from rhinorrhea, the compound (400 mg tid) reduced both symptoms and illness duration by 2 days. AG7088 (Agouron) is a rhinovirus 3C protease inhibitor with broad-spectrum activity against all HRV serotypes and related picornaviruses. Comparison of over 30 HRVs and 18
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Georgopapadakou enteroviruses revealed strong conservation of the catalytic and RNA-binding regions of the viral 3C protease, consistent with the observed activity of AG 7088 against all these serotypes. These observations support the atractiveness of AG7088 as a clinical candidate and the 3C protease as an antiviral target. SUMMARY As with last year’s ICAAC, the new compounds presented this year were largely members of known classes. In the antibacterial area new quinolones, β-lactams and ketolides are progressing in clinical development, while in antifungals several new azoles and echinocandins are in late clinical development. In antivirals, NNRTIs and chemoreceptor antagonists for HIV, DNA polymerase inhibitors for herpes viruses and inhibitors of viral uncoating and 3C protease are being developed. New technologies, both in molecular diagnostics and drug discovery or refinement are coming of age and may impact therapy and therapeutics.Although drug resistance is clearly increasing in bacteria, fungi and viruses, available drugs are also increasing (antivirals) or improving (quinolones, azoles). It is an exciting time for infectious diseases, full of challenges and opportunities.
Received 2 October 2000; Accepted 5 October 2000 Correspondence to: Nafsika H. Georgopapadakou PhD, DuPont Pharmaceuticals, Experimental Station, E400/3456A, PO Box 80400, DE 19880–0400, USA.Tel: +302 695 8525; Fax: +1 302 695 7407; E-mail: [email protected]
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