60 years ago… The changes in antibiotic research as shown by patent publications Development of Novel Antibiotic Classes 1930 1940 1950 1960 1970 1980 1990 2000 2003 Daptomycin 1999 Linezolid 1962 Quinolones 1962 Streptogramins 1958 Glycopeptides 1952 Macrolides 1950 Aminoglycosides 1949 Chloramphenicol 1949 Tetracyclines 1940 Beta-Lactams 1936 Sulfonamides Harald Labischinski Products in the Pipeline Product Class Main Segment Status ABT 492 Quinolone Community Ph II DK507k Quinolone Community Ph I Daptomycin Lipopeptide Hospital Reg. Oritavancin Glycopeptide Hospital Ph III Dalbavancin Glycopeptide Hospital Ph III Tigecycline Glycylcycline Hospital Ph III AR 100 Trimethoprime Hospital Ph II BAL 9141 Cephalosporin Hospital Ph II BB-83698 PDF-inhibitor Community Ph I CS-023 Carbapenem Hospital Ph II Until 2008 very few antibiotics will reach the market ! Harald Labischinski 60 years ago… 1942 Gardner and Chain discover a substance with antibacterial activity, produced by a strain of Proactinomyces (later Streptomyces gardneri), which they name proactinomycin A. Macrolide structure • Macrolides are lipophilic molecules with a characteristic central lactone ring bearing 12 to 17 atoms, few if any double bonds and no nitrogen athoms (until the advent of the azalides). • Several amino and/or neutral sugars can bind to the lactone ring. MACROLIDE ANTIBIOTICS 12-membered-ring 14-membered-ring 15-membered-ring 16-membered-ring 17-membered-ring Methymycin Natural Semi-synthetic Azithromycin Natural Semi-synthetic Lankacidin Neomethymycin compounds derivatives compounds derivatives complex YC-17 Litorin Erythromycin A to F Roxithromycin Josamycin Rokitamycin Oleandomycin Dirithromycin Kitasamycin Miokamycin Sporeamicin Flurithromycin Spiramycin Clarithromycin Midecamycin • The macrolides narrow the entrance of the tunnel through which the nascent polypeptide chain is extruded from the ribosome. • In all cases, the crystal structures confirm the broad mechanisms of action previously known from indirect evidence. • The structural detail show exactly which chemical groups in the antibiotics interact with which RNA nucleotides. A Ery14, Cbm16, Tyl16, A C A U Nucleotides C Tel14 mG U C C at which G G mG C G C macrolides C C C G Cbm16, A G interact: G G G A C G 16 U A A A Tyl C C A D Domain V U C A A A 16 A Domain II UG G Tyl Cbm16 C C A Cbm16, C Mutations G 16 U conferring Tyl C G G ψ macrolide C G G G Domain V resistance C A U ψ C G G C C A A A A U G C C A G U 14 14 U U G Ery , Tel G C U A A A GG C U G ψ A A U G A C ψ GG A U U A G C G G G C G A U G U A A U C G C C C T mG Cbm16, C G C ψ A A Tyl16 Tel14 Ery14, Cbm16, Tyl16, Domain II Tel14 Macrolides are inactive against: • Gram-negative rods (e.g. Enterobacteriaceae) because, being hydrophobic and having high molecular weight, they poorly cross the outer membrane The Azalides • In 1982, ring expansion and the introduction of the secondary amino group resulted in slightly decreased in vitro activity against erythromycin-sensitive S.aureus strains. • However, these compounds (named Azalides) showed improved MICs against Gram-negative organisms. • The degree of anti-Gram-negative activity generally correlates positively with the hydrophilicity of the compound. MICs (μg/ml) of macrolide and azalide derivatives R N S.aureus H.influenzae E.coli -CH3 0.39 0.78 6.25 -CH2-CH CH2 0.20 0.78 6.25 -CH-C CH 0.20 1.56 25 -CH-C N 0.78 1.56 25 -NH2 0.70 0.78 12.5 erythromycin A 0.10 3.12 100 Guidelines for antimicrobial therapy of pharyngitis (Sanford Guide, 1998) PRIMARY •Penicillin V po x 10 days REGIMEN: or if compliance unlikely •Benzathine penicillin IM as a single dose ALTERNATIVE •Oral 2nd gen. cephalosporins x 10 days REGIMENS: or •Erythromycin x 10 days or •Azithromycin / Clarithromcin Guidelines for antimicrobial therapy of streptococcal tonsillopharyngitis, scarlet fever and peritonsillar cellulitis (J. D. Nelson, 1996-97) •Penicillin V 25-50 mg/kg/day PO div q6-8h x 10 days or •Benzathine penicillin 25,000 u/kg IM as a single dose (max 1.2 milion u) alternatives: •Oral cephalosporins •Erythromycin or clindamycin for penicillin-allergic patients (Caution: ~5% of Group A strep resistant) 60 % 1996 1979 1990 2.3 % Erythromycin-resistant S.pyogenes 1989 in Asia and Oceania 18 % S.pyogenes In Finland, the frequency of resistance to erythromycin in group A streptococci from blood cultures increased from 4% in 1988 to 24% in 1990. From January to December 1990, the frequency of resistance in isolates from throat swabs increased from 7% to 20%, and resistance in isolates from pus increased from 11% to 31%. (Seppälä et al., NEJM 326:292-297, 1992) Nationwide reductions in the use of macrolide antibiotics for outpatient therapy were followed by a steady decrease in the frequency of erythromycin- resistance, from 16.5% in 1992 to 8.6% in 1996. (Seppälä et al., NEJM 337:441-446, 1997) Erythromycin-resistant S.pyogenes in Monza 55% 37,1% 4,6% 5,1% 1993 1994 1995 1996 no data available < 5% 5 - 15% 16-25% > 25% Incidence of macrolide resistance in S. pyogenes (G. Cornaglia and P. Huovinen, 12th ECCMID, Berlin, 1999) GUIDELINE ON THE PHARMACODYNAMIC SECTION OF THE SPC FOR ANTI-BACTERIAL MEDICINAL PRODUCTS Susceptibility should be categorized as follows: * Group A : Resistance not yet described or still uncommon (< 10%) * Group B : Resistance occurs in 10%-50% * Group C : Inherent or frequently occurring resistance (> 50%) The ‘B’ category implies an intrinsic risk of therapeutic failure when empiric therapy is chosen and no microbiological information is available. The potential benefits must be weighted against the risk of failure. no data available < 5% 5 - 15% 16-25% > 25% Incidence of macrolide resistance in S. pyogenes G. Cornaglia and A. Bryskier, in E. L. Kaplan and J.-C. Péchére (eds.), 2003 no data < 5% 5 - 15% 16-25% > 25% available Incidence of macrolide resistance in S.pyogenes 1999 - 2002 Antimicrobial Resistance (%) among S.pyogenes in Russia (N=470, 2000-2001) Аntibiotic Central N.-W.* South Ural Siberia Russia Erythromycin 9 10 0 3 25 10 Аzithromycin 9 10 0 3 25 10 Clarithromycin 9 10 0 3 25 10 Clindamycin 0 0 0 6 0 0.4 Levofloxacin 0 0 0 0 0 0 Telithromycin 0 0 0 0 0 0 Kozlov et al., AAC 2002 Outpatient antibiotic sales in 1997 in the E.U. 7 6 5 4 Macrolides - lincos. 3 2 DDD / 1,000inhabitants/ day DDD 1 0 France Portugal Luxembourg Greece Ireland Austria Sweden Netherlands (Cars et al., 2001) S.pyogenes resistance to erythromycin and consumption of macrolides 30 4 3,5 ( man et al., JAC 2001) 25 Čiž 3 20 2,5 Resistance (SLO) Resistance (ESP) 15 2 Consumption (SLO) Consumption (ESP) 1,5 10 DDD/1000 inhabitants/day 1 5 0,5 (Granizo et al., JAC 2000) 0 0 '94 '95 '96 '97 '98 units x 100 20000 18000 16000 14000 12000 10000 Azithromycin 8000 Clarithromycin 6000 Roxithromycin 4000 16-membered 2000 Erythromycin 0 90 91 92 93 94 95 96 Macrolide market in Italy 1990-1996 Relationship between erythromycin resistance in S.pneumoniae and S.pyogenes 80 60 resistance (%) 40 20 0 S.pneumoniae 0 20 40 60 80 S.pyogenes resistance (%) (Gómez-Lus et al., AAC 1999) Antibiotic resistance in Streptococcus pneumoniae 70 60 50 40 30 20 10 0 Isolatesnon susc.to erythromycin (%) 0 20 40 60 80 Isolates non susceptible to penicillin (%) In many European countries, macrolide resistance in pneumococci has overcome the level of beta-lactam resistance, and rates are still increasing. Mean proportion of S.pneumoniae penicillin non-susceptible (PNSP) in Europe EARSS Annual Report Mean proportion of erythromycin non-susceptible S.pneumoniae in Europe EARSS Annual Report Mean proportions of erythromycin non- susceptible and penicillin non-susceptible S.pneumoniae in Europe EARSS Annual Report 2003 Resistance to penicillin and erythromycin in S. pneumoniae Different phenotypes of macrolide-resistant streptococci c-MLSB i-MLSB M R R R C14 - C15 RC RI S CLINDA R S/R S C16 > 64 µg/ml ~ 16 µg/ml ~ 16 µg/ml MIC (ERY) 1979 MLSB 1989 M 1992 M 1996 MLSB 1995 M / MLSB Prevalent phenotypes of resistance to macrolide antibiotics Incidence of macrolide resistance mechanisms among macrolide- resistant Streptococcus pyogenes (Nagai et al., AAC 2002) i-ermA c-ermA i-ermB c-ermB mefA 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% ALL Incidence of macrolide resistance mechanisms among macrolide- resistant Streptococcus pyogenes (various sources, 2002-2003) i-ermA c-ermA i-ermB c-ermB mefA 100% 80% 60% 40% 20% 0% Do the different phenotypes imply different clinical outcomes ? In randomized, double blind trials of antibiotic therapy for acute otitis media, clinical success rates were 93% for patients with bacteriological success, 62% for those with bacteriological failure, and 80% for those with non- bacterial otitis media. We conclude that if efficacy is measured by symptomatic response, drugs with excellent antibacterial activity will appear less efficacious than they really are and drugs with poor antibacterial activity will appear more efficacious than they really are. We have called this tendency towards false optimism the “Pollyanna phenomenon”, after the blindly optimistic heroine of the novel Pollyanna. Marchant et al., J. Pediatr 1992; 120:72-7 The “Pollyanna phenomenon” 100 90 80 70 60 50 Efficacy (%) 40 30 20 Bacteriological Clinical efficacy Clinical efficacy efficacy (bacterial AOM) (clinical AOM) The main goals for future macrolides • to increase the activity against generally susceptible species • to develop new molecules showing little or no cross-resistance with existing macrolides • to expand the antibacterial spectrum • to increase the intracellular uptake and bioactivity within the various cellular compartments MACROLIDE ANTIBIOTICS 12-membered-ring 14-membered-ring 15-membered-ring 16-membered-ring 17-membered-ring Natural Semi-synthetic compounds derivatives Josamycin Rokitamycin Kitasamycin Miokamycin Spiramycin Midecamycin 16-membered-ring macrolides • All 16-membered • On the iMLS strains, B compounds were active the activity of the 16- against almost all membered macrolides isolates with the M proved to be dependent phenotype.