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Antibiotic therapy (presentation provided by Prof. MUDr. J. Beneš, CSc.) History of antibiotics 1910 1932 1928/41 1944 1945 1947 1948 1952 1954 1955 1957 1959 salvarsan prontosil penicillin streptomycin. cefalosporin C chloramphenicol. chlortetracyclin. erythromycin. spiramycin. vancomycin. kanamycin. rifampicin. P.Ehrlich, S.Hata E.Domagk A.Fleming,H.Florey,E.Chain S.A.Waksman G.Brotzu I.Ehrlich B.M.Buggar J.M.Mc.Guire S. Pinnert-Syndico M.H.Cormick H.Umezawa P.Sensi --. = drugs produced by Streptomycetes History of antibiotics II 1960 1960 1962 1966 1968 1981 1982 1990 1991 2000 ampicillin methicillin cefalotin doxycyclin co-trimoxazol amoxicillin/clavulanic acid ciprofloxacin azithromycin clarithromycin linezolid many drugs are semi-synthetic Groups of antibiotics A) ATB inhibiting bacterial cell wall synthesis (peptidoglycan synthesis) B) ATB inhibiting bacterial DNA metabolisms C) ATB inhibiting bacterial proteosynthesis D) ATB inhibiting bacterial metabolic pathways E) ATB damaging bacterial cell membranes Groups of antibiotics A) ATB inhibiting bacterial cell wall synthesis (peptidoglycan synthesis) beta-lactams penicillins cefalosporins monobactams carbapenems glycopeptides Beta-lactams penicillins monobactams: aztreonam cefalosporins carbapenems: imipenem Penicillin strong effect no interactions no toxicity dosage: therapy of tonsillitis erysipelas endocarditis 1,5 mil.U./day 6-12 mil.U. 12-30 mil.U. G+ cocci: streptococci, pneumococci, enterococci G+ rods: B. anthracis, C. diphtheriae, L. monocytogenes G- cocci: Neisseria spp. others: anaerobes, spirochetes Penicillins Penicillin G strong and nontoxic - but .. narrow spectrum half time 30 min acid labile (not orally) anti-staphylococcal penicillins methicilin, nafcilin, oxacillin broader spectrum penicillins (E. coli, H. influenzae, ..., enterococci) ampicillin, amoxicillin longer effect: - procain PNC (24 h) - benzathin PNC (3 weeks) oral forms: - penicillin V - penamecillin anti-Pseudomonas penicillins CARB, TIC, AZL, MEZ piperacillin Mechanisms of resistance inactivation of antibiotic (exoenzymes) cleavage of the molecule adding a side chain inhibition of ATB entry in the G- bacteria cell changes in the target structure alternative metabolic pathway efflux combination of several mechanisms Inhibitors of beta-lactamases sulbactam clavulanic acid clavulanic acid + amoxicillin = Augmentin, Amoksiklav, .... sulbactam + ampicillin = Unasyn (only i.v.) + cefoperazon = Sulperazon (only i.v.) tazobactam + piperacilin = Tazocin (only i.v.) Cefalosporins I. gen II. gen III. gen IV. gen streptococci +++ +++ ++ +++ staphylococci +++ ++ + +++ G- rods (E. coli) + ++ +++ +++ Pseudomonas - - some (ceftazidim) ++ anaerobs + + + + Generations vary in anti-bacterial spectrum, resistance against βlactamases, and pharmacokinetics (penetration in tissues, half-time) Penicillins and cefalosporins PENs more effective against G+, CEFs against GCEFs I. gen ≈ PEN + OXA wound infections, profylaxis in surgery (i.v., orally) CEFs II. gen ≈ aminoPEN + β-lactamase inhibitor UTI, abdominal a respiratory infections (i.v., orally) CEFs III. gen ≈ anti-Pseudomonas PENs G- sepsis, meningitis (ICU needed, i.v.) CEFs IV. gen nosocomial infections/sepsis (ICU, i.v.) Conclusions: beta-lactams Bacterial killing: rapid, strong, no post-ATB effect Pharmacokinetics: short half time (t1/2 0,5-2 hod) good levels in plasma and ECF, not in cells Toxicity, side effects: nontoxic ATB, good for children, pregnant women allergy (PENs > CEFs) dysmicrobia (candidoses, post-ATB colitis) Indications: Acute infections >> chronic infections Severe infections, sepsis >> mild infections Glycopeptides - vancomycin - teicoplanin, daptomycin large molecule not permitting transport through an outer wall of Gramnegative bacteria, inhibitor of cell wall synthesis bactericidal against most Gram-positive bacteria incl. MRSA not absorbed from GIT, active only in blood and extracellular fluid (no transport into cells), elimination in urine possible nephrotoxicity, blood levels should be measured ! Conclusion: - reserve ATBs against (multi) resistant Gram-positive bacteria - good for treatment of sepsis and severe acute infections if not possible to treat with other ATBs (e.g.: endocarditis, osteomyelitis, pneumonia) Glycopeptides Vancomycin Indications: peroral therapy of colitis caused by Clostr. Difficile as a result of antibiotic therapy or parenteral ther. of infect. caused by MRSA ADV. EFF.: nephrotoxicity, (ototoxicity) Teicoplanin similar to vancomycin Groups of antibiotics B) ATB inhibiting bacterial DNA metabolism (fluoro) quinolones rifampicin Fluoroquinolons I. gen.: weak effect; limited spectrum (Gram-neg. only); limited absorbtion; effective only in UTI NAL, OXO, PIP;; norfloxacin II. gen.: fluoroquinolons, systemic distribution; broader spectrum (+ staphylococci, chlamydiae, Mycoplasma spp., Mycobacterium spp.) ciprofloxacin, ofloxacin, PEF, LEVO III. gen.: excellent absorbtion, half-time 6-20 hrs; high concentrations in lungs; broader spectrum (pneumococci); higher cost moxifloxacin, ... Characteristics of fluoroquinolones broad spectrum (Gram-negative bacteria, staphylococci, intracellular bacteria) bactericidal good pharmacokinetics: good absorbtion from GIT good penetration in tissues and cells elimination in various routes low cost adverse events: GIT complaints: nauzea, anorexia allergy, fotosensibilization CNS: dizziness, agitation, insomnia, seizures connective tissues: tendinitis, tendon ruptures arrythmia, torsade de pointes not allowed for children and pregnant women interaction with other drugs (P450, CYPIA2) theophyllin, warfarin, H2 blockers, ... resistance can develop very easily Torsade de pointes ATB rezistance (%) in invasive isolates E. coli in the Czech Republic in 2000-2006 25 20 15 10 5 0 2001 2002 2003 2004 2005 2006 (n=1189) (n=1598) (n=1777) (n=1982) (n=2257) (n=1045) red line – fluoroquinolones, black line – aminoglycosides, blue line – 3rd gen. cefalosporins Appropriate usage of FQ (with respect to ATB policy) enteric fever, extra-intestinal salmonellosis zoonoses (tularemia, brucellosis etc.) prostatitis acute exacerbation of chronic bronchitis lower respiratory tract infections in cystic fibrosis common UTI gastroenteritis, enterocolitis biliary infections (+ prophylaxis) uretritis (STD) nosocomial infections, sepsis Rifampicin Broad spectrum: Gram-positive and -negative bacteria, including intracellular pathogens – but it is registered for therapy of mycobacterial infection Resistance can develop very easily, it should not be used in monotherapy ! Good absorbtion from GIT if taken without food. Good distribution into tissues and cells. The drug is metabolized in liver (cytochromes P450). Elimination in urine. Adverse events: hepatotoxicity, drug interactions Groups of antibiotics C) ATB inhibiting bacterial proteosynthesis macrolides (+ azalides + ketolides) lincosamids tetracyclines chloramphenikol oxazolidinons + aminoglycosides Macrolides 12-chain: veterinary drugs 14-chain: erythromycin, clarithromycin, roxithromycin 16-chain: spiramycin – less interaction potential than above azalides (15-chain): azithromycin ketolides: telithromycin • streptococci, pneumococci, Branhamella catarrhalis, Bordetella pertussis, Legionella spp. • oral anaerobic flora, actinomycetes • mycoplasmata, chlamydiae • Borrelia burgdorferi and other spirochetes • Campylobacter spp., Helicobacter spp. (clarithromycin) (+ mycobacteria) erythromycin molecule Macrolides Advantages • excellent penetration in many tissues and cells • high concentration in leucocytes • leucocytes transport the antibiotic into the site of infection • absence of toxicity • comfort dosage Disadvantages • • • • • static effect on bacteria weak effect drug interactions (P450) ERY: nauzea, vomiting resistance develops easily Macrolides Usage: - mild infections, mucosal infections - infections in young persons with good immunity - infections with intracellular pathogens (respiratory infections, urogenital infections) Not recomendable: - usage in severe infections (sepsis) - usage in persons with decreased immunity - frequent usage (→ resistance) Lincosamides lincomycin clindamycin Partial absorbtion from GIT, good penetration into tisues and cells, metabolization in liver, elimination in bile in urine Spectrum: • only Gram-positive microbes (streptococci and staphylococci) • anaerobes • protozoa (Toxoplasma, Plasmodium, Entamoeba) No toxicity, can be used in children or pregnant women – but there is a risk of post-antibiotic colitis (Clostr. difficile) Lincosamides lincomycin clindamycin Usage: infections due to streptococci, staphylococci, anaerobes mild to moderate infections – not sepsis subacute or recurrent infections • • • • infections in mouth cavity wound infections, skin and soft tissue infections infections of bones and joints pneumonia after aspiration + malaria, toxoplasmosis, amebosis Tetracyclins 1. generation: tetracyclin, oxytetracyclin 2. generation: doxycyclin, minocyclin 3. generation: tigecyclin Good absorbtion from GIT, good penetration into tissues and cells, metabolization in liver, elimination into bile and urine. Long half-time. Spectrum: • very broad originally (various Gram-positive and –negative pathogens, anaerobes, chlamydiae, mycoplasmata) • but many resistant strains nowadays • never effective against Pseudomonas spp., enterococci, Bacteroides fragilis Tetracyclins 1. gen. tetracyclin, oxytetracyclin 2. gen. doxycyclin, minocyclin 3. gen. tigecyclin Indications: • infections caused by mykoplasmata, chlamydiae, rickettsiae - especially „atypical pneumonia“ - STD like uretritis, prostatitis • zoonoses (lyme borreliosis, tularemia, brucellosis, ...) Adverse events: nausea, vomiting hepatotoxicity storage in bones and teeth (= not allowed for pregnant women and children up to 8 years) Candida superinfections Aminoglycosides streptomycin neomycin gentamicin, tobramycin, .. amikacin, isepamicin, .. Mode of action: • inhibition of proteosynthesis • damage of cell wall in Gram-positive and –negative bacteria → synergy with beta-lactams and glycopeptids Spectrum: • Gram-negative rods (E. coli, Pseudomonas spp, ...) and staphylococci → direct bactericidal effect • Streptococci and enterococci: only synergic with other ATB Aminoglycosides do not affect anaerobes, intracellular pathogens, and encapsulated bacteria! Aminoglycosides streptomycin neomycin gentamicin, tobramycin, .. amikacin, isepamicin, .. for tuberculosis treatment for external usage only sepsis (community-acquired) sepsis (nosocomial) Adverse events: • nephrotoxicity (cumulative) • ototoxicity (especially high doses) • neurotoxicity (when combined with myorelaxant drugs) Usage: narrow therapeutic window, serum levels should be monitored once daily dosing in most situations Groups of antibiotics D) ATB inhibiting bacterial metabolic pathways 1/ inhibition of folic acid synthesis - sulphonamides - trimethoprim 2/ unspecific inhibitors of bacterial metabolism - nitroimidazols (metronidazol) - nitrofurantoin Sulphonamides and trimethoprim Inhibition of folic acid synthesis (→ lack of thymin) Gram-positive bacteria: pneumococi, staphylococci Gram-negative bacteria: E. coli and other enterobacteria plus: Pneumocystis jiroveci sulphonamides also active against Toxoplasma gondii and Plasmodium spp. enterococci are always resistant in vivo, independently on results of in vitro tests sulphamethoxasol + trimethoprim = co-trimoxazol (5 : 1) Good absorbtion from GIT, good penetration into tissues; metabolization in liver → various drug interactions; elimination via urine above all Co-trimoxazol urinary tract infections diarrhea due to enteric bacteria enteric fever mild to moderate infections caused by pneumococci and staphylococci pneumonia due to Pneumocystis jiroveci (including HIV/AIDS prophylaxis) Adverse events: mainly sulphonamides allergy, incl. Stevens-Johnson syndrome drug fever myelotoxicity Drug interactions: warfarin, hydantoin, salicylates, indomethacin .. Nitroimidazoles metronidazole, ornidazole, tinidazole anaerobic bacteria incl. Bacteroides fragilis protozoa: Trichomonas, Entamoeba, Giardia Excellent absorbtion and tissue penetration. Metabolization in liver. infections due to anaerobic bacteria, especially in abdominal cavity postantibiotic colitis (Clostridium difficile) protozoal infections (see above) Adverse events: GIT intolerance, disulphiram effect, encephalopathy Acquired rezistance is rare. Nitrofurantoin „urinary antiseptic agent“ therapeutical concentrations only in urine short half-time, metabolization in various tissues Spectrum: E. coli and other enterobacteria, + enterococci urinary tract infections - therapy urinary tract infections – long term prophylaxis external usage: vaginal globules, pastae in dermatology Adverse events: GIT intolerability, allergy Acquired rezistance is very rare! Groups of antibiotics E) ATB damaging bacterial cell membranes - colistin Colistin bactericidal against various Gram-negative bacteria, including Pseudomonas spp. ultimum refugium in therapy of multiresistant infections a) parenteral application: nephrotoxicity, neurotoxicity b) external application: used in dermatology MUDr. P. Potměšil, PhD. Selected topics about antibiotics/antivirals Some important interactions or adverse effects of selected antibiotics Ciprofloxacin cannot be used with agomelatine (newer antidepressant) Clarithromycin (e.g. for respiratory infections) should not be used with buspirone (anxiolytic) or dosage of buspirone should be reduced Tetracyclines (e.g. Doxycyklin for borreliosis) make complexes with Ca, Al, Fe and Mg cations (take doxycyclin 2-3h before or 4-5h after use of food supplements, milk products, antacides etc.) Macrolides can cause damage of vestibulocochlear nerve or hepatic impairment in high and longterm dosage Antibiotics used in eradication of Helicobacter pylori infection Amoxycillin Clarithromycin – contraindicated with statins that lower cholesterol (simvastatin etc.) or with antineoplastic agents lapatinib, dasatinib (azitromycin) Metronidazol Antibiotics have to be used together with proton pump inhibitor = PPI (omeprazol, pantoprazol etc.) 1/ Amoxicillin + metronidazol + PPI 2/ Claritromycin + PPI Antibiotics used for therapy of acne I. Topical use 1/ Erytromycin, or erytromycin in combination with zinc (Zineryt lot.) 2/ Clindamycin, or clindamycin in combination with benzoylperoxide (Duac gel) 3/ Metronidazol - acne rosacea 4/ Chloramphenicol 5/ Acidum fusidicum – (Fucidin cream) II. Peroral therapy A/ Tetracyclines 1/ Doxycyclin (some forms of acne) 2/ Tetracyclin B/ Macrolides 1/ Erytromycin 2/ Azitromycin – less effective than tetracyclines but can be better tolerated, pulse therapy recommended C/ Clindamycin Antibiotics for therapy of borreliosis (caused by borrelia burgdorferi) Doxycycline (tetracycline) Cefuroxim-axetil (cephalosporin II. gen.) Azitromycin (macrolide) Pharmacotherapy of HIV infection drugs are applied in combinations – combined antiretroviral therapy (cART) A) Inhibition of HIV entry 1/ maraviroc - peroral antagonist of CCR5 receptor (chemokine coreceptor for HIV entry) B) Inhibition of HIV replication 1/ reverse transcriptase inhibitors zidovudine tenofovir,stavudine,zalcitabine, didanosine, nevirapine, efavirenz 2/ inhibitors of HIV integrase. - patients have to be scrreened for CCR5 genotype before prescription 2/ enfuvirtide - inhibiton of HIV fusion with cell - only s.c. Raltegravir 3/ HIV protease inhibitors ritonavir, nelfinavir, fosamprenavir, saquinavir, indinavir Acyclic nucleoside phosphonates (ANP) (N-(2-fosfonometoxyalkyl) purines). Antivirals effective against DNA viruses and retroviruses. Approved are: tenofovir (HIV), adefovir (HBV) and cidofovir (CMV). (Tenofovir increases production of cytokine IL-10 and chemokines MIP-1α, MCP-3 that can block HIV entry/replication thus tenofovir has low risk of resistence). Therapy of chronic viral hepatitis B/C Hepatitis B 1/ tenofovir or entekavir first line choice for longterm use today because of very good efficacy and low resistance 2/ other drugs: adefovir, lamivudine, telbivudine or pegylated interferon alfa Hepatitis C 1/ standard therapy is combination of peg. interferon-alfa + ribavirin 2/ New drugs Boceprevir, telaprevir Possible ATB for selected nosocomial infections Pseudomonas aerug.: 1/ ticarcillin Resistent Staph. Aureus: 1/ Vancomycin + rifampicin or gentamicin 2/ Teicoplanin (for Vanc. resistent Staph. A.) (co-ticarcillin not actually registered in Czech Rep.) 2/ ceftazidim + aminoglycosides 3/ imipenem, meropenem 4/ fluoroquinolones