ANTIBIOTICS Prof. MUDr Jiřina Martínková, CSc 2006/2007

1. ANTIBIOTICS Prof. MUDr Jiřina Martínková, CSc 2006/2007

2. Tab.1.Classification of antibacterial agents: bactericidalbacteriostatic β-lactam agents Erythromycin Aminoglycosides Tetracyclines Co-trimoxazole Chloramphenicol Vancomycin Sulfonamides Trimethoprim

3. Tab.2. Mechanism of action: • Inhibition of cell wall synthesis Penicillins • Cephalosporins • Monobactams • Vancomycin • Inhibition of DNA gyrase: Quinolones • RNA polymerase Rifampicin • Inhibition of protein synthesis: Aminoglycosides • Tetracyclines • Erythromycin • Chloramphenicol • Inhibition of folic acid Trimethoprim • metabolism: Sulfonamides

4. The choice of appropriate antibacterial drugs depends on: • Diagnosis of infection • Broad-spectrum antibiotics for empirical therapy, short-spectrum antibiotics for • selective treatment • - Patients factors • Age, sex (pregnant, lactating women), weight, allergies, genetic factors, renal and hepatic function, concurrent medication • - Drug factors • antibacterial spectrum (short-spectrum, broad-spectrum activity, Gram-positives Gram-negatives), • pharmacokinetics, adverse effects, drug interactions, convenience, cost • The dose and route of administrations: • depends on infection and patient factors. The dose may be guided by plasma concentration measurements • (aminoglycosides, fluorochinolones) • The duration of therapy • depends on the nature of the infection and response to treatment

5. Better communication with the local microbiology laboratory provides the physician with information on local prevalence of organisms and sensitivities MIC is often quoted by laboratories ---- the minimal inhibitory concentration of a particular agent below which bacterial growth is not prevented. It is an in vitro test in a homogenous culture system, while in vivo: -plasma concentration should reach a value several-times higher (8x) - concentration at the site of infection may be considerably lower than the plasma concentration. Therefore, it is necessary to take into consideration pharmacokinetic properties of antibiotics (penetration into site of infection, its metabolism..).

6. β- LACTAM ANTIBIOTICS CHLORAMPHENICOL MACROLIDES TETRACYCLINES AMINOGLYCOSIDES LINCOSAMIDES GLYCOPEPTIDE ANTIBIOTICS POLYMIXIN ANTIBIOTICS FLUOROQUINOLONES METRONIDAZOLE NITROFURANTOIN ANTIMYCOBACTERIAL DRUGS

7. β - LACTAM ANTIBIOTICS: penicillins cephalosporins monobactams carbapenems bacteriostatic, bactericidal

8. β-lactams share general mechanisms of antibacterial • action that involve damage to the cell wall of bacteria. • The steps are: • attachment to specific penicillin-binding proteins • (PBPs) that serve as drug receptors of bacteria • inhibition of cell wall synthesis by blocking • transpeptidation of peptidoglycan, • activation of autolytic enzymes in the cell wall, which • result in lesions that cause bacterial death

9. Resistance: falls into several categories: 1. Certain bacteria (Staphylococcus aureus) produce β-lactamases that inactivate some PNC by breaking the beta-lactam ring 2. Others (oxacillin) are β-lactamase resistant because their beta-lactam ring is protected by part of the R side chain. 3. Other bacteria lack specific receptors or lack permeability of outer layer (drug cannot reach receptors) 4. Autolytic enzymes in the wall are not activated 5. Some microorganisms lack the cell walls or are metabolically inactive 6. Resistance is due to deficiency or inaccessibility of PBPs

10. P e n i c i l l i n s • penicillin G • penicillin V • penicillins resistant to • beta-lactamases • broad spectrum penicillins

11. Penicillin G • highest activity against G-positive organisms, • little activity against G-neg. rods • susceptibility to hydrolysis by β -lactamases Spectrum: infections caused by pneumococci,streptococci, meningococci. Non-beta-lactamase-producing staphylococci, and gonococci, Treponema pallidum and many other spirochetes, Bacillus anthracis, clostridia, actinomyces, Listeria, and Bacteroides (except Bacteroides fragilis).

12. Pharmacokinetics: no absorption from the gut, low distribution to the CNS (importance of inflammation) excretion (kidney, milk, sputum) FORMULATIONS: Penicillin G crystalline salt (Na, K) Crystalline sodium PNC G contains approxim. 1600 U/mg, 1 million U of PNC G = 0.6 g IV, s.c., i.m. at 4-h intervals Procaine penicillin G(suspension) i.m.delayed absorption yielding useful levels for 12-24 h after a single inj. (600 000 U) Penicillin G Benzathine(suspension)a saltof very low water solubility for i.m.inj. That yields low but prolonged drug level. A single inj. of 1.2 million units once every 3-4 weeks provides satisfactory prophylaxis against reinfection by beta-hemolytic streptococci.

13. P e n i c i l l i n s • penicillin G • penicillin V • penicillins resistant to • beta-lactamases • broad spectrum penicillins

14. Penicillin V • similar antibacterial spectrum to penicillin G • well absorbed from the gut • indicated in mild infections of the respiratory tract or its associated structures, mainly in children (pharyngitis, otitis, sinusitis) • in a daily dose of 1-4 g (divided to 6 doses) • drug of first choice in nasopharyngitis due to beta-hemolyt. streptococci for 10 days

15. P e n i c i l l i n s • penicillin G • penicillin V • penicillins resistant to • beta-lactamases • broad spectrum penicillins

16. Penicillins resistant to β-lactamases The sole indication for their use is infection by β-lactamase-producing staphylococci oxacillin, cloxacillin, dicloxacillin, nafcillin acid- stable and reasonably well absorbed from the gut are suitable for treatment of mild localized staphylococcal infections

17. P e n i c i l l i n s • penicillin G • penicillin V • penicillins resistant to • beta-lactamases • broad spectrum penicillins

18. Broad spectrum penicillins • differ from PNC - G in having greater activity against G- neg. bacteria • inactivated by β-lactamases • include: ampicillin • amoxicillin - complete absorption from the GIT • +++ • Especially effective against G-neg. aerobic rods, incl. Pseudomonas: • carbenicillin • ticarcillin • mezlocillin - azlocillin- piperacillin

19. Broad spectrum PNC can be protected from destruction by β -lactamases inhibitors such as:clavulanic acid, sulbactam, or tazobactam co-amoxicillin (clav. acid + amoxicillin) sultamicillin (sulbactam + ampicilin) co-piperacillin (tazobactam + piperacillin) such mixtures are protectedagainst β -lactamase producing H. influenzae or coliform. organisms

20. A d v e r s e r e a c t i o n of PNCs • allergic reactions type I-IV • All PNCs and cross-reactants are cross-sensitizing. • Any preparation containing PNC (foods or cosmetics) may • induce sensitization. • Anaphylactic shock (0.05% of recipients), fever, joint swelling, • intense itching, variety of skin rashes, oral lesions, • interstitial nephritis, hemolytic anemia • irritation of the CNS: increasedexcitability of neurons • ---convulsions due to a direct influence • (testing antiepileptic activity) • gastrointestinal upset(more pronounced with oral • broad spectrum PNC - amoxicillin)-nausea,vomiting,diarrhea • superinfection with staphylococci, yeasts causes • enteritis, vaginitis

21. β - LACTAM ANTIBIOTICS: penicillins cephalosporins monobactams carbapenems bacteriostatic, bactericidal

22. C e p h a l o s p o r i n s (derivatives of 7-aminocephalosporanic acid) First generation: • Spectrum: • G-positive cocci (pneumococci, viridans • streptococci, gr. A hemolytic streptococci, and S. aureus. • G-neg bacteria: Escherichia coli, Klebiella pneumonie. Cephalexin, cephazolin Second generation: Active against organisms affected by first-generation drugs, but they have an extended G-neg coverage (Enterobacter, Klebsiella and indol-positive Proteus are usually sensitive). Cefaclor( in patients who are allergic to PNC),cefamandole, cefuroxime(crosses the blood-brain barrier)

23. Third generation: • expanded G-neg coverage (active against Enterobacter, Citrobacter, beta-lactamase producing strains of H. influenzae). • some of them are ineffective against G-pos. organisms, mainly staphylococci and enterococci (resistant organisms, as well as fungi often proliferate and may induce superinfection) • ability to reach the CNS, levels in cerebrospinal fluid are sufficient • to inhibit most pathogens • cefotaxime, ceftriaxone, ceftazidime • are indicated in: • meningitis, sepsis (of unknown cause in the immunocompetent patient), in neutropenic febrile immunocompromised patients (in combination with aminoglycosides)

24. β - LACTAM ANTIBIOTICS: penicillins cephalosporins monobactams carbapenems bacteriostatic, bactericidal

25. M o n o b a c t a m s • active against G-neg. rods (incl. Pseudomonas and Serratia, H. influenzae, Neisseria meningitidis) • resistant to β-lactamases • no activity against G-pos. bacteria or anaerobes aztreonam, IV

26. β - LACTAM ANTIBIOTICS: penicillins cephalosporins monobactams carbapenems bacteriostatic, bactericidal

27. C a r b a p e n e m s • wide spectrum with good activity against many G-neg. rods, • G-pos. organisms, and anaerobes. • resistant to β -lactamases • imipenem IV • is inactivated by dihydropeptidases in renal tubules resulting in • low urinary concentrations. Consequently, it is administered • together with an inhibitorof renal dihydropeptidase, cilastatin, • for clinical use • penetrates body tissue and fluids well, including the cerebrospinal • fluid • indicated for infections caused by susceptible organisms that are resistant to other available drugs. Since Pseudomonas may rapidly develop resistance to imipenem, the simultaneous use of • an aminoglycoside is required. Febrile neutropenic patients.

28. Adverse effects: • nauzea, vomiting, diarrhea, skin rashes, and reactions at • the infusion sites. • excessive levels in patients with renal failure may lead • to seizures meropenem is a safer carbapenem. Its usage is similar to that of imipenem.

29. MACROLIDES

30. MACROLIDES bacteriostatic and bactericidal • Spectrum similar to PNC : • against G-pos. bacteria and spirochetes, but not against • most G-neg. organisms • distinctively, they are effective against several unusual organisms including Mycoplasma pneumoniae, Legionella and Chlamydia • erythromycin • Pharmacokinetics: • well absorbed, distributed adequately to most sites except brain and CSF • inactivated by hepatic N-demethylation • E. is remarkably safe antibiotic, may be used in pregnancy and children

31. Tab. 3. Comparison of macrolides erythromycin clarithromycin azithromycin oral dose frequency usually qds bd od GIT adverse effects common less common less common tissue penetration reasonable high extremely high

32. Indications: • respiratory infections (including Mycoplasma • pneumoniae, psittacosis, Campylobacter enteritis) • useful alternative to penicillin in penicillin-allergic patients • useful for skin infections • Interactions: erythromycin inhibits CYP450 and causes • accumulation of theophylline, and warfarine.

33. CHLORAMPENICOL

34. CHLORAMPHENICOL • is a potent inhibitor of microbial protein synthesis, • binds reversibly to a receptor site on the50S subunit of • the bacterial ribosome. There, it interferes with the • incorporation of amino acids into newly formed peptides • by blocking the action of peptidyl transferase. Ch. has a broad spectrum, is bacteriostatic for many G-neg.bacteria and for rickettsiae. Some salmonellae are susceptible, but plasmid-mediated resistance to chloramphenicol has appeared (results from the production of chloramphenicol acetyl- transferase). Effective against streptococci and staphylococci. • Pharmacokinetics: • after oral administration - well absorbed and penetrates tissues • exceptionally well including the CNS- a unique property for the • treatment of central nervous system infections • inactivated by conjugation with glucuronic acid

35. Indications (limited to): • Salmonella infections - typhoid fever (many strains are • now resistant, and cotrimoxazole is often used) • serious infections with H. influenzae : meningitis, • pneumonia • anaerobic or mixed infections in the CNS (brain abscess) • as an alternative to tetracyclines in several rickettsial inf.

36. Adverse effects: • nausea, vomiting, diarrhea • hematologic: dose-related erythroid suppression is • common and predictable • aplastic anemia occurs unpredictably with • an incidence of approxim. 1:40 000. This is irreversible in • 50% of cases. • Gray baby syndrome: • the gray color of the skin is due to shock (hypotension and • tissue hypo-perfusion). Chl. accumulates in neonates • (mainly in premature) due to reduced glucuronidation • in the immature liver.

37. TETRACYCLINES

38. TETRACYCLINES inhibit microbial protein synthesis • are broad spectrum antibiotics, • bacteriostatic for many G-pos. and neg. bacteria, • including some anaerobes, • for rickettsiae, chlamydiae, mycoplasmas, and for some • protozoa • Pharmacokinetics: • well absorbed orally, their absorption is impaired by • food due to chelation with divalent ions (milk and its • products - Ca 2+), and antacids (Mg 2+, Fe 2+) • undergo elimination by both the liver (enterohepatic • circulation-high concentrations in bile) and the kidney • (high concentrations in the urine) • t1/2 varies from 6 to 12 hr (the shorter acting drugs are • given four times daily, the longer ones once daily)

39. cross the placenta to reach the fetus and are also • excreted in milk • tetracycline, oxytetracycline • doxycycline, minocycline –neweragents(absorption is 90-100%, slow elimination) • indication: • drugs of choice in infections with Mycoplasma pneumoniae, chlamydiae, rickettsiae, and some spirochetes • useful in G pos. and neg. bacterial infections, related to • the respiratory and urinary tract, sinusitis • Lyme disease, brucelosis, tularemia, leptospirosis

40. Adverse effects: • due to alteration of normal flora in the gut • vitamin B complex and vit K deficiency • nausea, vomiting, diarrhea • superinfection due to resistant organisms: candida, pseudomonas, clostridia, resistant coliforms---anal • itching, vaginal or oral candidiasis, enterocolitis, shock • in childrenTTC are readily bound to calcium deposited in newly formed bone or teeth in young children • (pregnancy, children under 8 years of age !). Discoloration • of teeth and enamel dysplasia, deformity of bones, growth inhibition • impaired hepatic function in patients with preexisting hepatic insufficiency or when high doses are given IV • IVinj. can lead to venous thrombosis • phototoxicity (sensitisation to sunlight)

41. AMINOGLYCOSIDES

42. AMINOGLYCOSIDES • are transported into cells and block bacterial protein synthesis by • binding to the 30S ribosome • their penetration through the cell membrane of the bacterium • depends partialy on oxygen-dependent active transport---they have • minimal action against anaerobic organisms • Spectrum: powerful bactericidal agents • against many aerobic G-neg and some G- pos. organisms • used with a penicillin in infections caused by streptococci, • listeria or pseudomonas Pharmacokinetics:poorly absorbed from the gut, administration IV and i. m. , distribution into extracellular fluid, excretion by glomerular filtration without metabolic transformation… T1/2 2-3 hr

43. AMINOGLYCOSIDES • CLGE is highly correlated with CLCR CLCR or creatininemiais used for prediction of the individual dosage regimen in patients with renal impairment (renal insufficiency or renal failure- Fig.4). Another possibility how to predict the dosage regimen is TDM (therapeutic drug monitoring - see below) Fig. 4 shows the simple way of the dosage regimen prediction using a nomogram. The dose is calculated according to the body weight (mg/kg), the interval between the doses is adjusted according to clearance of creatinine (CLcr) or creatininemia

44. Tab.4. A nomogram for GE dosage regimens according to creatininemia and /or creatinine clearance

45. Indication: • monotherapy in urinary infections • with simultaneous administration of PNC or CEPH in severe infections (sepsis, pneumonia) caused by G-neg. bacteria that are likely to be resistant to other drugs • (patients with these infections are aften immunocompromised) • topical eye drops for treating eye infections • Adverse effects- toxicity: dose-related, with the potential for • increasing with duration of treatment • ototoxicity: irreversible destruction of the sensory cells in the • cochlea and vestibular organ of the ear---vertigo, ataxia and loss • of balance (vestibular damage) auditory disturbances, including • deafness (cochlear damage) • nephrotoxicity consists of damage to the kidney tubules, can be • reversed if the use of the drug is stopped • paralysis due to neuromuscular blockade (not used during general anesthesia!)

46. 1st generation: neomycin (local use), streptomycin and kanamycin (antiTBC) • 2nd generation • gentamicine, tobramycine, amikacin, netilmicin • main properties: • - both bactericidal effects and toxicity are more related to plasma concentrations than to the dose • the therapeutic window is narrow • That is why: • TDM-therapeutic drug monitoring - detection of plasma concentration is used for the individual dosage regimen (and toxicity) prediction • in preterm neonates • in the elderly (glomerular filtration diminishes) • in patients with renal dysfunction • What are limits? • Ctrough (plasma concentration) just before next dose • Cpeak (at 0.5 h after i.v. 30-min inf) • dosage: TDS---OD

47. Tab.5. Recommended CtroughCpeak mg/L mg/L gentamicin tobramycin 0.5-2 6 -10 netilmicin amikacin 1-8 20 -30

48. TDM NEWBORNS during the first week of the postnatal age (mainly for immaturity) CHILDREN, ADULTS impairment of renal function

49. Fig. 1 demonstrates postnatal development (in days and months) of hepatic elimination (the upper part) and renal elimination (the lower part). The data show the time when the adult value of glomerular filtration is reached: in one-month interval approx. In case of immature neonates, this interval can be even prolonged. It means that gentamicin elimination in neonates is slow (if compared to children and/or adults). Drug accumulation The dosage regimen should be adjusted according to the individual patient need

50. Fig.1. POSTNATAL DEVELOPMENT OF SPECIFIC HEPATIC AND RENAL FUNCTION (from Gladtke 1979).