ANTIBIOTICS 2014.

ANTIBIOTICS 2014

ANTIBIOTICS (vs chemotherapeutics)
Antimicrobial drugs (ATBs) effective in the treatment of infections Selective toxicity the ability to kill an invading microorganism without harming the cells of the host advantage of the biochemical differences that exist between microorganisms and human beings. Selective toxicity is relative it is necessary to control the concentration of ATB to attack the microorganism while still being tolerated by the host. Selective antimicrobial therapy ATB choice according sensitivity of bacteria.

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

ATBs therapy The choice The dose and route of administrations
of appropriate antibacterial drug The dose and route of administrations The duration of therapy Monitoring patient must be informed especially about adverse effects - compliance

1. The choice of appropriate
Diagnosis of infection community x hospital infections, acute vs chronical broad-spectrum antibiotics for empirical therapy, narrow-spectrum antibiotics for selective treatment or outpatients Patients factors age, sex (pregnant, lactating women), weight, allergies, genetic factors, renal and hepatic function, concurrent medication Drug factors antibacterial spectrum (narrow-spectrum, broad-spectrum activity, Gram-positives Gram-negatives), cidal vs. static pharmacokinetics – to infection site, adverse effects, drug interactions, convenience, cost

Diagnosis of infection
Empirical th community Narrow spectrum - rely on localization and signs hospital infections Broad spectrum reserved ATB Targeted th Chronical infections E.g. „Diabetic leg“, TBC

Patients factors age (COI childrens), weight (dosage),
allergies, genetic factors, Type B AE sex (pregnant, lactating women), Type D AE (quinolones, sulfonamides) renal and hepatic function, Type A AE - concurrent medication Interactions -

Drug factors Cidal vs. Static antibacterial spectrum pharmacokinetics
narrow-spectrum, broad-spectrum activity, Gram-positives Gram-negatives, pharmacokinetics Route of administration, penetration to infection site, adverse effects, drug interactions, cost

Bacteriostatic vs. bactericidal drugs
arrest the growth and replication of bacteria at serum levels achievable in the patient - limit the spread of infection while the body's immune system attacks, immobilizes, and eliminates the pathogens. If the drug is removed before the immune system has scavenged the organisms, enough viable organisms may remain to begin a second cycle of infection. Intact immune system decreased e.g. in: alcoholism, diabetes, immunosuppresion, malnutrition, advanced age - bactericidal agents are required. Bactericidal kill bacteria at drug serum levels achievable in the patient. - often drugs of choice in seriously ill patients. It is possible for ATB to be bacteriostatic for one organism and bactericidal for another.

Bacteriostatic vs. bactericidal drugs:
Minimum inhibitory concentration (MIC) the lowest concentration of ATB that inhibits bacterial growth. Effective antimicrobial therapy ATB concentration in body fluids should be greater than the MIC. Minimum bactericidal concentration (MBC) the lowest concentration of ATB that results in a 99.9 % decline in colony count after overnight broth dilution incubations. MIC/MIB 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. it is necessary to take into consideration pharmacokinetic properties of antibiotics penetration into site of infection, its metabolism..

Classification of antibacterial agents:
bactericidal bacteriostatic β-lactam agents Erythromycin Aminoglycosides Tetracyclines Co-trimoxazole Chloramphenicol Vancomycin Sulfonamides Trimethoprim

Chemotherapeutic spectra
Narrow spectrum only against a single or a limited group of microorganisms, e.g. INH is active only against mycobacteria. Extended spectrum against G+ organisms and also against a significant number of G- bacteria e.g., ampicillin Broad spectrum e.g. tetracycline and chloramphenicol affect a wide variety of microbial species. !!! alter the normal bacterial flora precipitate a superinfection of an organism, e.g., candida.

Combinations of antimicrobial drugs
It is better to treat patients with the single agent that is most specific for the infecting organism. reduces the possibility of superinfection, decreases the emergence of resistant organisms minimizes toxicity. Combination Special situations e.g., the treatment of tuberculosis, sepsis

Combinations of antimicrobial drugs
Advantages - Synergism e.g., b-Iactams and aminoglycosides – synergism – rare example multiple drugs used in combination indicated only in special situations e.g., infection is of unknown origin Disadvantages – AE may multiply Hepatotoxity of anti-TBC Therapy failure static vs cidal (e.g. TTC X PNC or cephalosporins)

Complications of antibiotic therapy
Hypersensitivity – type B Toxicity – type A, B, C Superinfections – type A Resistance – primary, secondary, cross- Teratogenity – type D

Drug resistance Cross-resistance growth of bacteria is not halted
by the maximal level of that antibiotic that can be tolerated by the host. Primary Some organisms are inherently resistant to an antibiotic e.g., gram-negative organisms are inherently resistant to vancomycin. Secondary spontaneous mutation or acquired resistance and selection. Cross-resistance resistant to more than one antibiotic – eg TTC

Resistance – mechanism
Decreased penetration to bacteria reduced influx (TTC) or increased efflux Metabolic inactivation beta-lactamases Change in target structure

PK - Pharmacokinetics concentration at site of infection vs. infection type and severity CNS, placenta, bones, teeths absorption – distribution - elimination

2a. ROUTE OF ADMINISTRATION
Oral route mild infections, outpatient basis. If i.v. therapy initially switch to oral agents occurs as soon as possible. Parenteral administration drugs that are poorly absorbed from GIT, e.g., vancomycin, the aminoglycosides, amphotericin treatment of serious infections.

2b. RATIONAL DOSING pharmacodynamics pharmacokinetics based on their:
Sign of infections time-dependent killing pharmacokinetics concentration-dependent killing - TDM post-antibiotic effect. Important pharmacodynamic properties with significant influence on the frequency of dosing: concentration-dependent killing post-antibiotic effect.

Concentration-dependent killing
aminoglycosides, fluoroquinolones significant increase in the rate of bacterial killing as the concentration of antibiotic increases from 4- to 64-fold the MIC of the drug for the infecting organism. bolus infusion achieves high peak levels, favoring rapid killing.

Time-dependent killing
beta-lactams, glycopeptides, macrolides, clindamycin killing effect is best predicted by the percentage of time that blood concentrations of a drug remain above the MIC. increasing the concentration of ATB to higher multiples of the MIC does not significantly increase the rate of kill E.g., for PNC and cephalosporins, dosing schedules that ensure blood levels greater than MIC for 60 – 70 % of the time was showed to be clinically effective. severe infections are best treated by continuous infusion of these agents rather than by intermittent dosing.

Post-antibiotic effect (PAE)
A persistent suppression of microbial growth that occurs after levels of antibiotic have fallen below the MIC. Antimicrobial drugs with a long PAE (several hours) often require only one dose per day. E.g., aminoglycosides and fluoroquinolones, particularly against gram-negative bacteria.

Genetic alterations leading to drug resistance
Resistance develops due to the ability of DNA to undergo spontaneous mutation or to move from one organism to another. Spontaneous mutations of DNA: Chromosomal alteration by insertion, deletion, or substitution of one or more nucleotides within the genome. DNA transfer of drug resistance: - of particular concern is resistance acquired due to DNA transfer from one bacterium to another.

Altered expression of proteins in drug-resistant organisms
Modification of target sites: E.g., S. Pneumoniae resistance to b-lactam ATB involves alterations in one or more of the major bacterial penicillin-binding proteins - decreased binding of ATB. - Decreased accumulation: Decreased uptake or increased efflux of an antibiotic - drug is unable to access to the site of its action in sufficient concentrations to injure or kill the organism - TTC. - Enzymic inactivation: The ability to destroy or inactivate ATB. Examples of ATB-inactivating enzymes: 1) beta-lactamases ("penicillinases") hydrolytically inactivate the b-Iactam ring of penicillins, cephalosporins, and related drugs; 2) acetyltransferases - transfer an acetyl group to ATB (inactivation of chloramphenicol, aminoglycosides; and 3) esterases that hydrolyze the lactone ring of macrolides. Multiple drug resistance - significant problem (e.g., methicillin-resistant Staphylococcus aureus is also resistant to all ATBs except vancomycin and possibly ciprofloxacin, rifampin and imipenem/cilastatin).

PROPHYLACTIC ANTIBIOTICS
the use of ATB for the prevention risk of bacterial resistance and superinfection benefits must outweigh the potential risks/AE. Examples Prevention of streptoccocal infections in patients with history of rheumatic heart disease. Patients may require years of treatment. Pretreatment of patients undergoing dental extractions who have implanted prosthetic devices (e.g., artificial heart valves) to prevent seeding of the prosthesis. Prevention of tuberculosis or meningitis in those who are in close contact with infected patients.

Choise in dentistry Pericoronitis Metronidazole or amoxicillin Antibacterial required only in presence of systemic features of infection or of trismus or persistent swelling despite local treatment; treat for 3 days or until symptoms resolve Acute necrotising ulcerative gingivitis Antibacterial required only if systemic features of infection; treat for 3 days or until symptoms resolve Periapical or periodontal abscess Amoxicillin or metronidazole Antibacterial required only in severe disease with cellulitis or if systemic features of infection; treat for 5 days Periodontitis Metronidazole or doxycycline Antibacterial required for severe disease or disease unresponsive to local treatment

ATB - MA CELL WALL CELL MEMBRANE DNA
Inhibitors of cell membrane function THFA Ribosomes mRNA Isoniazid Amphotericin B PABA Inhibitors of nucleic acid function or synthesis Inhibitors of protein synthesis Inhibitors of cell wall synthesis Classification of some antibacterial agents by their sites of action. THFA = tetrahydrofolic acid; PABA = p-aminobenzoic acid Inhibitors of metabolism Tetracyclines Aminoglycosides Macrolides Clindamycin Chloramphenicol Fluoroquinolones Rifampin b-Lactams Vancomycin Sulfonamides Trimethoprim (according to Lippincott´s Pharmacology, 2006)

Summary of antimicrobial agents affecting cell wall synthesis
Agents affecting the cell wall b-lactamase inhibitors b-lactam antibiotics Other antibiotics Clavulanic acid Sulbactam Tazobactam Bacitracin Vancomycin Daptomycin Penicillins Cephalosporins Carbapenems Monobactams Amoxicillin Ampicillin Dicloxacillin Indanyl carbenicillin Methicillin Nafcillin Oxacillin Penicillin G Penicillin V Piperacillin Ticarcillin Ertapenem Imipenem/cilastatin* Meropenem Aztreonam 1st generation 2nd generation 3rd generation 4th generation Cefadroxil Cefazolin Cephalexin Cefaclor Cefprozil Cefuroxime Cefoxitin Cefdinir Cefixime Cefotaxime Ceftazidime Ceftibuten Ceftizoxime Ceftriaxone Cefepime (according to Lippincott´s Pharmacology, 2009)

INHIBITORS OF CELL WALL SYNTHESIS
Bactericidal selectively interfere with synthesis of the bacterial cell wall a structure that mammalian cells do not possess. The cell wall is a polymer called peptidoglycan that consists of glycan units joined to each other by peptide cross-links. require actively proliferating microorganisms To be maximally effective, these agents Little or no effect on bacteria that are not growing do not combine with bacteriostatic ATBs

PENICILLINS 1928, A. Fleming Of most widely effective ATBs and also the least toxic drugs known increased resistance limited their use. The nature of their side chain affects the spectrum, stability to stomach acid, and susceptibility to bacterial degradative enzymes beta-Iactamases Mechanism of action Inhibition of transpeptidase: PNCs inhibit PBP-catalyzed transpeptidase reaction. Production of autolysins G+ cocci produce degradative enzymes - autolysins participate in the remodeling of the bacterial cell wall In the presence of PNC - the degradative action of the autolysins proceeds in the absence of cell wall synthesis. Inactive against organisms devoid peptidoglycan structure of membrane e.g., mycobacteria, fungi Penicillin G 1928, A. Fleming Belong among the most widely effective ATBs and also the least toxic drugs known - increased resistance limited their use. The nature of their side chain affects the spectrum, stability to stomach acid, and susceptibility to bacterial degradative enzymes (beta-Iactamases). Mechanism of action Inhibition of transpeptidase: PNCs inhibit PBP-catalyzed transpeptidase reaction. Production of autolysins - G+ cocci produce degradative enzymes (autolysins - that participate in the remodeling of the bacterial cell wall). In the presence of PNC - the degradative action of the autolysins proceeds in the absence of cell wall synthesis. Inactive against organisms devoid peptidoglycan structure of membrane (e.g., mycobacteria).

Antibacterial spectrum
limited Lower ability to cross the bacterial peptidoglycan cell wall and to reach PBP G+ Mainly – higher permeability of CW G- have an outer lipopolysaccharide membrane surrounding the cell wall a barrier to the water-soluble PNCs Contain water-filled channels (porins) that permit transmembrane entry. Pseudomonas aeruginosa lacks porins, making these organisms intrinsically/primarilly resistant to many antimicrobial agents. Note: For this reason, PNCs have little use in the treatment of intracellular pathogens. - water-soluble PNCs cannot reach the site of action

NATURAL PENICILLINS (narrow spectrum)
PENICILLIN G (benzylpenicillin) a number of gram-positive and gram-negative cocci, gram-positive bacilli, and spirochetes. Susceptible to inactivation by beta-lactamases. Unstable in low pH – is for parenteral therapy PROCAINE PENICILLIN G prolonged action, i.m. BENZATHINE PENICILLIN G Very long action; depo form, i.m. PENICILLIN V (phenoxymethylpenicillin) a spectrum similar to penicillin G, is more acid-stable than penicillin G – is for p.o. not used for treatment of septicemia because of its higher minimum bactericidal concentration (MLC). Penicillin G from Penicilium chrysogenum

Antistaphylococcal penicillins
methicillin Oxacillin* nafcillin, cloxacillin, dicloxacillin penicillinase-resistant PNCs treatment of infections caused by penicillinase-producing staphylococci. Methicillin-resistant strains (MRSA) usually susceptible to vancomycin rarely to ciprofloxacin, rifampin oxacillin

Extended spectrum penicillins
AMPICILLIN and AMOXICILLIN Destroyed by beta-lactamases !!! spectrum similar to penicillin G, but are more effective against some gram-negative bacilli - Hemophilus influenzae, E. Coli Widely used in the treatment of respiratory infections; amoxicillin is employed prophylactically by dentists for patients with arteficial heart valves who are to undergo extensive oral surgery. Resistance a problem because of their inactivation by plasmid-mediated penicillinase (E. coli and H. influenzae - frequently resistant). Formulation with a beta-lactamase inhibitor (e.g. clavulanic acid, sulbactam) can protect the PNC from enzymatic action. Ampicillin drug of choice for the gram-positive bacillus Listeria monocytogenes.

Antipseudomonal - Acylureido penicillins
Piperacillin effective against P. aeruginosa as well as a large number of gram-negative organisms. It is susceptible to breakdown by beta-lactamase – formulation with tazobactam Mezlocillin, azlocillin – similar – but currently not registered in CR REVERSED SPECTRUM PNCs: MECILLINAM More potent against Gram-negative enteric bacteria, hydrolyzed by beta-lactamases. Pivmecillinam is a pro-drug, hydrolyzed to mecillinam.

Resistance Beta-lactamases Decreased permeability Altered PBP
G- naturally, but exporter has also been described Altered PBP

Penicillins - pharmacokinetics
Route of administration determined by the stability of the drug to gastric acid and by the severity of the infection. only oral formulations Penicillin V, amoxicillin, amoxicillin+clavulanic acid only parenteral PNC G, acylureido Depot forms: Procaine penicillin G and benzathine penicillin G administered IM; serve as depot forms. Slowly absorbed into the circulation and persist at low levels over a long time period both ampicillin

Pharmacokinetics - Absorption
incomplete Most of PNCs after oral administration reach the intestine in sufficient amounts to affect the composition of the intestinal flora. amoxicillin is almost completely absorbed it is not appropriate therapy for the treatment of salmonella-derived enteritis therapeutically effective levels do not reach the organisms in the intestinal crypts Absorption of PNC V and all the penicillinase-resistant PNCs is impeded by food in the stomach they must be administered minutes before meals or 2-3 hours postprandially. Other PNCs are less affected by food.

Pharmacokinetics - Distribution
Extracellular All PNCs cross the placental barrier (TYPE A) but none have been shown to be teratogenic. Penetration into certain sites is insufficient e.g. bone or cerebrospinal fluid Increased during inflammation. During the acute phase (first day), the inflamed meninges are more permeable to PNC - increased ratio in the amount of drug in CNS compared to the amount in the serum. As the inflammation subsides, permeability barriers are reestablished. Levels in the prostate are insufficient to be effective against infections. Metabolism: Host metabolism of the beta-Iactam antibiotics is usually insignificant.

PEN - pharmacokinetics - excretion
Kidney tubular secretion and glomerular filtration Patients with impaired renal function - adjust dosage regimens ! T1/2 of penicillin G can increase from a normal of hour to 10 hours in renal failure. Probenecid inhibits the secretion of penicillins !! Biliary route Nafcillin, oxacillin [Note: This is also the preferential route for the acylureido penicillins in cases of renal failure.] breast milk and into saliva

PEN - adverse reactions
PNCs are among the safest drug Hypersensitivity – type I-IV: The most important The major cause is metabolite, penicilloic acid, which reacts with proteins and serves as a hapten to cause an immune reaction. Cca 5% of patients have some kind of reaction from urticaria to angioedema and anaphylaxis Cross-allergic reactions among the beta-lactam antibiotics ! !!! Mononucleosis vs ampicillin – 100% rash Diarrhea: Disruption of saprophytes Especially in agents that are incompletely absorbed or with extended spectrum. pseudomembranous colitis may occur. Primary resistance - organisms that lack the peptidoglycan cell wall (e.g. mycoplasma) or have cell wall that is impermeable to the drug. Acquired resistance to PNCs by plasmid transfer - clinical problem. Beta-lactamase activity: Enzymes hydrolyze the cyclic amide bond of the beta-lactam ring - loss of bactericidal activity. Enzymes are constitutive or (more commonly) acquired by the transfer of plasmids. Some of the beta-lactam ATBs are poor substrates for beta-lactamases and resist cleavage - they have activity against beta-lactamase producing organisms. - Decreased permeability of PNCs through the outer cell membrane prevents reaching the target penicillin-binding protein. The presence of an efflux pump can also reduce the amount of intracellular drug. - Altered penicillin binding proteins: Modified PBPs show a lower affinity for beta-lactam antibiotics, requiring greater concentrations of the drug to effect binding and inhibition of bacterial growth.

Adverse reactions Nephritis – acute intersititial Neurotoxicity
All PNCs could but especially methicillin Neurotoxicity PNCs are irritating to neuronal tissue and can provoke seizures if injected intrathecally or if very high blood levels are reached epileptic patients are especially at risk. Cation toxicity: PNCs generally administered as the Na or K salt. Hoigné syndrom if the suspension of PNC is by mistake injected i.v. - embolisation of pulmonary veins - tachypnea, anxiety, dyspnea Nikolau’s syndrom suspension of PNC by mistake i.a. - embolisation in arteries - even amputation necessary) Platelet dysfunction - decreased aggregation (observed with the antipseudomonal PNCs and, to some extent wit penicillin G). Concern when treating patient predisposed to hemorrhage or receiving anticoagulants. – especially piperacilin for more than 2 weeks

beta-lactamase inhibitors
Clav. acid clavulanic acid, sulbactam, tazobactam contain a beta lactam ring, do not have significant antibacterial activity bind to and inactive beta-lactamases AUGMENTIN (amoxycillin and clavulanic acid) TIMENTIN (ticarcillin and clavulanic acid) Piperacillin + tazobactam Ampicillin + sulbactam Not all beta-Iactamases are inhibited. E.g., tazobactam (compounded with piperacillin) does not affect P. aeruginosa beta-Iactamase. Therefore, this organism remains refractory to piperacillin.

Penicillins and aminoglycosides
synergistic enhanced antimicrobial activity facilitate the entry of aminoglycosides Because cell wall synthesis inhibitors alter the permeability of bacterial cells, these drugs can should never be placed in the same infusion fluid, the positively charged aminoglycosides form an inactive complex with the negatively charged PNCs.

Clinical uses of penicillins
Given p.o. - in more severe cases i.v.; often in combination with other ATB. bacterial meningitis (e.g. by N. meningitidis, S. pneumoniae): benzylPNC, high doses i.v. bone and joint infections (e.g. S. aureus): flucloxacillin skin and soft tissue infections (e.g. Streptococcus pyogenes or S. aureus): benzylPNC, flucloxacillin; animal bites: co-amoxiclav pharyngitis (from S. pyogenes): phenoxylmethylPNC otitis media (S. pyogenes, H. influenzae): amoxicillin bronchitis (mixed infections common): amoxicillin pneumonia: amoxicillin urinary tract infections (e.g. with E. coIl): amoxicillin gonorrhea: amoxicillin (+ probenecid) syphilis: procaine benzylPNC endocarditis (e.g. with Streptococcus viridans or Enterococcus faecalis) serious infections with Pseudomonas aeruginosa: piperacillin. This list is not exhaustive !!!

cephalexin Cephalosporins b-Iactam - closely related both structurally and functionally to the penicillins. Mostly semisynthetic - mode of action as penicillins same resistance mechanisms - however, they tend to be more resistant than the PNCs to b-Iactamases. Antibacterial spectrum Classified as first, second, third, or fourth generation, based largely on their bacterial susceptibility patterns and resistance to b-Iactamases. ineffective against MRSA, L. monocytogenes, Clostridium difficile, and the enterococci.

Summary of antimicrobial agents affecting cell wall synthesis
INHIBITORS OF CELL WALL SYNTHESIS b-LASTAMASE INHIBITORS b-LASTAMASE ANTIBIOTIC OTHER ANTIBIOTIC Clavulanic acid Sulbactam Tazobactam Bacitracin Vancomycin PENICILLINS CEPHALOSPORINS CARBAPENEMS MONOBACTAMS Imipenem/cilastatin Meropenem* Ertapenem Amoxicillin Ampicillin Cloxacillin Dicloxacillin Indanyl carbenicillin Methicillin Nafcillin Oxacillin Penicillin G Penicillin V Piperacillin Ticarcillin Aztreonam 1st GENERATION 2nd GENERATION 3rd GENERATION 4th GENERATION Cefadroxil Cefazolin Cephalexin Cephalothin Cefaclor Cefamandole Cefprozil Cefuroxime Cefotetan Cefoxitin Cefdinir Cefixime Cefoperazone Cefotaxime Ceftazidime Ceftibuten Ceftizoxime Ceftriaxone Cefepime (according to Lippincott´s Pharmacology, 2006)

Pharmacodynamics First generation: cephadroxil, cefazolin
act as penicillin G substitutes – G+; resistant to the staphylococcal penicillinase; activity against Proteus mirabilis, E. coli, and Klebsiella Pneumoniae (the acronym PEcK) . Second generation: Cefuroxime, cefprozil Greater activity against three additional G- organisms: H. influenzae, Enterobacter aerogenes, and some Neisseria species (HENPEcK); Activity against gram-positive organisms is weaker. effective against Bacteroides fragilis related cephamycin - cefoxitin [sef OX i tin] - little activity against H. influenzae.

Pharmacodynamics Third generation Fourth generation
Inferior to first-generation in activity against G+ cocci, enhanced activity against gram-negative bacilli + most other enteric organisms plus Serratia marcescens !!! Resistence is increasing – „collateral damage“ - multiresistnecy Ceftriaxone or cefotaxime agents of choice in the treatment of meningitis. Ceftazidime, cefoperazone - against Pseudomonas aeruginosa. Cefixim, cefpodoxim – oral formulations Fourth generation Cefepime, Cefpirom only parenteral Wide spectrum, active against streptococci and staphylococci Not MRSA Also effective against aerobic G- organisms e.g., enterobacter, E. coli, K. pneumoniae, P. mirabilis, and P. aeruginosa

Pharmacokinetics Some orally, most IV or IM
their poor oral absorption. All distribute very well into body fluids adequate therapeutic levels in the CSF - only with the third-generation ceftriaxone or cefotaxime effective in the treatment of neonatal and childhood meningitis caused by H. influenzae Cefazolin Prophylaxis in dentistry and orthopedics - ability to penetrate bone Prophylaxis - prior to surgery because of its half-life (2 h) and activity against penicillinase-producing S. aureus. All cephalosporins cross the placenta - not teratogenic Elimination through tubular secretion and/or glomerular filtration dose must be adjusted in severe renal failure !!! Biotransformation is not clinically important. Cefoperazone and ceftriaxone - excreted in bile into the feces - frequently employed in patients with renal insufficiency. adequate therapeutic levels in the CSF, regardless of inflammation,

Adverse effects Allergy: Disulfiram-like effect Bleeding:
Patients who have had an anaphylactic response or Stevens-Johnson syndrome to PNCs should not receive cephalosporins with caution in individuals who are allergic to PNCs - cca 3-5 % show cross-sensitivity Disulfiram-like effect cefoperazone if ingested with alcohol or alcohol-containing medications. They block the second step in alcohol oxidation - accumulation of acetaldehyde. Toxicity is due to the presence of the methylthiotetrazole (MTT) group Bleeding: agents with MTT group - because of anti-vitamin K effects. Administration of the vitamin corrects the problem. Nephrotoxicity, diarrhea. In contrast, the incidence of allergic reactions to cephalosporins is 1-2 % in patients without a history of allergy to PNCs.

Clinical uses of the cephalosphorins
Septicaemia (e.g. cefuroxime, cefotaxime) Pneumonia caused by susceptible organisms Meningitis (e.g. cefriaxone, cefotaxime) Biliary tract infection Urinary tract infection (especially in pregnancy, or in patients unresponsive to other drugs) Sinusitis (e.g. cefadroxil).

CARBAPENEMS imipenem, meropenem, ertapenem, doripenem
Broad-spectrum including penicilase producing G+/-, anaerobes and P. aeruginosa Etrapenem not active against P.aeruginosa Administered i.v., penetrates well into CNS. Excreted by glomerular filtration Dose adjust in renal insuficiency Imipenem undergoes cleavage by a dehydropeptidase found in the brush border of the proximal renal tubule to form an inactive metabolite that is potentially nephrotoxic - cilastatin. Meropenem, ertapenem – not cleaved in the kidney !! Adverse effects: nausea, vomiting, and diarrhea Eosinophilia and neutropenia - less common than other b-lactams High levels of especially imipenem may provoke seizures Meropenem and doripenem less

Monobactams - aztreonam
resistant to the action of beta-lactamases beta-lactam rings is not fused to another ring Only P. aeruginosa and other G- bacteria only for combination in empiric therapy lack of activity against gram-positive organisms or anaerobes. IV or IM, excreted in the urine can accumulate in patients with renal failure. relatively nontoxic may cause phlebitis, skin rash, and occasionally, abnormal liver function tests. Low immunogenic potential, little cross-reactivity an alternative for patients allergic to penicillin.

ATB - Glycopeptides vancomycin, teicoplanin, telavancin, daptomycin
longer acting Reduce cell wall synthesis bactericidal prevents the transglycosylation step in peptidoglycan polymerization Indications (G+) MRSA, MRSE (epidermidis), enterococcal infections and pseudomembranous colitis caused by Clostridium difficile The emergence of staphylococci resistant to most antibiotics except vancomycin led to the reintroduction of this agent. Vancomycin acts synergistically with the aminoglycosides can be used in the treatment of enterococcal endocarditis individuals with prosthetic heart valves MRSA, methicillin-resistant Staphylococcus epidermidis

vancomycin increased incidence of vancomycin-resistant bacteria
e.g., Enterococcus faecium, Enterococcus faecalis necessary to restrict the use of vancomycin to the treatment of serious infections caused by beta-Iactam-resistant, patients with gram-positive infections who have a serious allergy to the beta-Iactams. Daptomycin, quinopristin/dalfopristin or linezolid for vancomycin-resistant strains Oral vancomycin limited to treatment for potentially life-threatening antibiotic-associated colitis due to C. difficile or staphylococci.

vancomycin Slow i.v. infusion - 60-90 min
systemic infections or for prophylaxis. not absorbed after oral administration treatment of antibiotic-induced colitis due to C. difficile. Inflammation allows penetration into the meninges necessary to combine with other ATB – e.g., ceftriaxone. % excreted by glomerular filtration adjust dosage in renal failure – accumulation of the drug normal half-life: hours; over 200 hours in end-stage renal disease. Adverse effects at the infusion site (fever, chills, and/or phlebitis), flushing ("red man syndrome”) - histamine release – rapid infusion shock as a result of rapid administration Rashes Ototoxicity and nephrotoxicity – more common when administered with other drug (e.g., an aminoglycoside) that can also produce these effects – dose dependent

Telavancin Similar G+ spectrum as vancomycin
A semisynthetic lipoglycopeptide derived from vancomycin. Similar G+ spectrum as vancomycin Resistant Staphylococcus and Sterptococcus sp. Not effective against VRE or E.faecium T1/2 approx. 8 hrs - once-daily i.v. dosing Excreted by kidney, TDM not necessary Two mechanisms: like vancomycin - it inhibits cell wall synthesis by binding to the D-Ala-D-Ala terminus of peptidoglycan in the growing cell wall. In addition - it targets the bacterial cell membrane and causes disruption of membrane potential and increases membrane permeability. AE Nausea, vomiting, insomnia, foamy urine Prolongation of QT interval MRSA, methicillin-resistant Staphylococcus epidermidis Dalbavalcin (not registered) improved activity against many G+ bacteria incl. methicillin-resistant and vancomycin-intermediate S aureus. It is not active against most strains of vancomycin-resistant enterococci. Extremely long T0.5 (6-11 days) it allows once-weekly i.v. administration. In clinical trials.

Daptomycin treatment of resistant G+ incl. MRSA and VRE
Cyclic lipopeptide - product of Streptomyces roseosporus treatment of resistant G+ incl. MRSA and VRE vancomycin-resistant enterococci Complicated skin infection, endocarditis, bacteriemia by S. Aureus not for pneumonia (inactivated by pulmonary surfactans). bactericidal - concentration-dependent killing; administered i.v. via infusion Mechanism: depolarisation and of cell membrane K efflux and death; inhibition of DNA, RNA, protein synthesis. 90-95 % bound to plasma protein; cleared renally adjust dosage in renal impairment!, not metabolized Adverse effects: myopathy (discontinue statins), constipation, nausea, headache, insomnia, hepatic transmaninases very rarely - colistin for salvage parenteral therapy of infections caused by strains of Acinetobacter baumannii and P. aeruginosa that are resistant to all other agent)

Topical ATB Bacitracin
a mixture of polypeptides - inhibits bacterial cell wall synthesis Similar to vancomycin Spectrum - gram-positive organisms Use is restricted to topical application because of its nephrotoxicity Polymyxin B and colistin (polymyxin E) Cationic detergent properties, bactericidal on G – (pseudomonas, coliform); not absorbed from GIT Adverse effect: neuro- and nephrotoxicity Topical use: orally -gut sterilisation, topical treatment (eye, ear, skin) – !! Inhalation – P. Aeruginosa in cystic fibrosis – not absorbed Rarely systemic i.v. – P. aeruginosa very rarely - colistin for salvage parenteral therapy of infections caused by strains of Acinetobacter baumannii and P. aeruginosa that are resistant to all other agent) fosfomycin Inhibition of wall synthesis; against G+ and G- Synergism with piperacilin, aminoglycosieds, 3rd generation of cephalosporines

Topical ATB – mupirocin
pseudornonic acid - produced by Pseudomonas fluorescens. Rapidly inactivated after absorption systemic levels are undetectable. Active against G+ cocci, incl. methicillin-resistant S. aureus. inhibits staphylococcal isoleucyl tRNA synthetase Resistance due to the presence of a second isoleucyl tRNA. synthetase gene is plasmid-encoded - complete loss of activity. Hospital strains More than 95% of staphylococcal isolates are still susceptible. I: ointment for topical treatment of minor skin infections e.g., impetigo Application over large infected areas (decubitus ulcers, open surgical wounds) not recommended leading to mupirocin-resistant strains very rarely - colistin for salvage parenteral therapy of infections caused by strains of Acinetobacter baumannii and P. aeruginosa that are resistant to all other agent)

Protein Synthesis lnhibitors
targeting the bacterial ribosome, differ structurally from those of the mammalian cytoplasmic ribosome. !!!!! Human mitochondrial ribosome, more closely resembles the bacterial ribosome Most drugs that interact with the bacterial target usually spare the host cells, high levels of drugs such as chloramphenicol or the tetracyclines may cause toxic effects as a result of interaction with the mitochondrial ribosomes.

Inhibitors of protein synthesis

Protein synthesis inhibitors
Tetracyclines Doxycycline, minocycline Glycylcyclines Tigecycline Aminoglycosides Gentamicin, amikacin, tobramycin, streptomycin, neomycin Macrolides/ketolides Erthromycin, clarythromycin, azithromycin, telithromycin Others Chlormphenicol, clindamycin, linezolid, quinuprostin/dalfopristin

Tetra/glycyl-cyclines
Doxycycline Doxycycline, Tigecyclin related compounds - consist of 4 fused rings with a system of conjugated double bonds. Entry into susceptible organisms by passive diffusion and by an energy-dependent transport protein mechanism. Nonresistant strains concentrate the tetracyclines intracellularly. Bacteriostatic- bind reversibly to the 30S subunit of the bacterial ribosome block access of the amino acyl-tRNA to the mRNA-ribosome complex at the acceptor site.

Tetracyclines Broad spectrum antibiotics
G+ and G- Also Vibrio cholerae - doxycycline also effective against intracellular organisms - drugs of choice for rickettsial, mycoplasma and chlamydial infections. TTCs - widespread cross resistance inability of the organism to accumulate the drug limits their clinical uses Any organism resistant to one tetracycline is resistant to all TTC. The majority of penicillinase-producing staphylococci are now also insensitive to tetracyclines Tigecycline may be active agains TTC resistant strains

Tetracyclines - PK Doxycycline completely absorbed Widely distributed
Altered by dairy foods or antacides Nonabsorbable chelates formed with divalent and trivalent cations Al3+, Ca2+, Mg2+ problem if the patient self-treats the epigastric upsets caused by tetracycline ingestion with antacids. Widely distributed Soft tissues – liver, spleen, skin Concentrated in teeth/bones – Ca2+-hydroxyapetite Even tumors with higher Ca2+ content – eg. Gastric Ca Placenta – high penetration – FDA category D Teratogens – bones and teeth development CSF – insuficient Minocycline may be used for eradication of meningococcal carrier state – but inefective in meningitis Minocycline penetrates cerebrospinal fluids

Tetracyclines - PK Metabolism - lipophilic
Concentrate in liver, glucuronidation, Excreted to bile – enterohepatic recycling - feces Especially doxycycline Renal excretion cca 40 % of administered dose Dose reduction required only in severe renal insuficiency Not effective in UTIs Excreted also in breast milk COI

Tetracyclines - Adverse effects
Epigastric distress irritation of the gastric mucosa alleviated if the drug is taken with foods other than dairy products. Deposition in the bone and primary dentition during calcification in growing children discoloration and hypoplasia of the teeth and a temporary stunting of growth. COI - pregnancy and in children younger than 8 years or before the second dentition Hepatotoxicity – dose dependent Phototoxicity Even severe sunburns – sun/UL light exposed areas Phototoxicity: Most frequently with doxycycline and demeclocycline

Tetracyclines - Adverse effects
Superinfections: candida (e.g. in the vagina) or resistant staphylococci in the intestine Pseudomembranous colitis due to an overgrowth of Clostridium difficile Dysmicrobia - hypovitaminosis B and K anorectal and anogenital syndrome (itching in anal and genital area) antianabolic effect – hypodynamia benign, intracranial hypertension (pseudotumor cerebri) headache and blurred vision - rarely in adults decreased activity of pancreatic lipase and amylase Vestibular problems: (e.g., dizziness, nausea, vomiting) occur with minocycline, which concentrates in the endolymph of the ear and affects the function Phototoxicity: Most frequently with doxycycline and demeclocycline

Tetracyclines – clinical uses
Antibiotics of first choice for rickettsial, mycoplasma and chlamydial infections, brucellosis, cholera, and Lyme disease .. (and plaque) Second choice infections with several different organisms. useful in mixed infections of the respiratory tract and in acne. democloxyline inhibits the action of ADH Used for chronic hyponatraemia caused by inappropriate secretion of antidiuretic hormone e.g., by some malignant lung tumours Phototoxicity: Most frequently with doxycycline and demeclocycline plague

Tigecycline Spectrum similar to doxycycline
But also – MRSA, multidrug resistant S. pneumoniae, VRE, some anaerobes Not active agains Proteus or Pseudomonas sp. Tigecycline developed to overcome TTC resistance Used in complicated skin, soft tissue and intraabdominal infections Administered i.v. Rapidly distributed in tissues – not effective during bacteremias Bile/Fecal excretion AE - similar to TTCs including teeths and bones

Aminoglycosides amikacin, gentamicin, tobramycin and streptomycin
Commonly used aminoglycosides Other neomycin, netilmicin, kanamycin In combinations for serious infections due to aerobic gram-negative bacilli Use is limited by the occurrence of serious toxicities Partially replaced by safer ATB 3rd generation cephalosporins, fluoroquinolones, carbapenems only against aerobic organisms anaerobes lack the oxygen-requiring transport system Streptomycin - used to treat tuberculosis (kanamycin also effective), tularemia. Bactericidal - inhibit bacterial protein synthesis bind to the isolated 30S ribosomal subunit Suffix –mycin – those derived from Streptomyces -micin – those derived from Micromonospora

Aminoglycosides Concentration-dependent killing postantibiotic effect
Cmax, TDM postantibiotic effect immunity required - polymorphonucleares Once daily dosing prevents toxicity The exceptions are pregnancy, neonatal infections, and bacterial endocarditis administered every eight hours etc. – based on CLcr synergize with beta-Iactams or vancomycin enhance diffusion of aminoglycosides into the cell used only in combination

Aminoglycosides - PK must be given parenterally to achieve adequate serum levels. the highly polar polycations - not absorbed orally not NEOMYCIN – severe nephrotoxicity - only topical – skin, GIT Oral administration in hepatic failure – reduce microflora and amonium production Extracellular distribution Not to the cerebrospinal fluid penetration is poor even when the meninges are inflamed!. Except for neomycin, they may be administered intrathecally. nephrotoxicity and ototoxicity Accumulate in the renal cortex and in the endolymph and perilymph of the inner ear teratogenic All cross the placental barrier and may accumulate in fetal plasma and amniotic fluid. All rapidly excreted into the urine (short t1/2), predominantly by glomerular filtration (CLCR). Accumulation occurs in patients with renal failure, and requires dose modification.

Aminoglycosides C. Resistance Rapid onset mostly, three following mechanisms: - Decreased uptake: The oxygen-dependent transport system for aminoglycosides or porins is absent. - Altered receptor: The 30S ribosomal subunit binding site has a lowered affinity for aminoglycosides. - Enzymatic modification: important, plasmid-associated (synthesis of e.g.,acetyltransferases, nucleotidyltransferases, and phosphotransferases - nine or more of these enzymes !) modify and inactivate antibiotics. Each type of enzyme has its own specificity, therefore, cross-resistance is not an invariable rule. Netilmicin and amikacin are less vulnerable to these enzymes than other antibiotics of this group !!

Aminoglycosides !!! perform TDM Patient factors predispose to toxicity
gentamicin, tobramycin, netilmicin, and amikacin Cmax – Cmin – regular dosing Only Cmin – once daily doses Patient factors predispose to toxicity Age, renal functions - CLCR, sepsis- increased Vd The elderly are particularly susceptible to nephrotoxicity and ototoxicity !! previous exposure to aminoglycosides functional cummulation

Gentamicin (a) Blood concentrations of aminoglycosides - 7 mg kg1 day1
OD (solid line), TD (dotted line) and continuous simulated infusions (dash-dotted line) versus the time in days. Also shown is the target trough level (TTL), (2 mg L1). (b) The corresponding reductions in number of viable bacteria versus the predicted time of eradication in days. The horizontal dashed-dotted line represents the target value for efficacy. S. Croes et al. / European Journal of Pharmaceutical Sciences 45 (2012) 90–100

Aminoglycosides Ototoxicity: Nephrotoxicity:
related to high peak plasma levels and the duration of treatment ATBs accumulates in the endolymph and perilymph of the inner ear, and toxicity correlates with the number of destroyed hair cells in the organ of Corti. Deafness may be irreversible, it is known to affect fetuses in utero. Patients simultaneously receiving other ototoxic drug (e.g., diuretics furosemide, bumetanide, ethacrynic acid or cisplatin) - particularly at risk. Vertigo and loss of balance especially in patients receiving streptomycin Nephrotoxicity: Retention of the aminoglycosides by the proximal tubular cells disrupts calcium-mediated transport processes this results in kidney damage (from mild, reversible impairment to severe, acute tubular necrosis, which can be irreversible). Vestibular and cochlear -

Aminoglycosides Neuromuscular paralysis Allergic reactions
Mostly after direct intraperitoneal or intrapleural application of large doses Due to decrease in both the release of acetylcholine from prejunctional nerve endings and the sensitivity of the postsynaptic site. Patients with myasthenia gravis are particularly at risk. Prompt administration of calcium or neostigmine can reverse the block. Allergic reactions Contact dermatitis - a common reaction to topically applied neomycin.

Spectinomycin – not registered 2013
structurally related to aminoglycosides interacts with the 30S ribosomal subunit inhibit protein synthesis. only for treatment of acute gonorrhea caused by penicillinase-producing Neisseria gonorrhea and/or uncomplicated gonorrhea of the genitalia or rectum, in patients who are allergic to PNC. Administered as a single i.m. injection Spectinomycin-resistant gonococci have been reported resistance appears to be a chromosomal mutation but no cross-resistance to other effective agents occurs Hypersensitivity reactions can develop

Macrolide antibiotic erythromycin, roxithromycin, azithromycin, clarithromycin, spiramycin telithromycin derivative of erythromycin (a ketolide) ATBs with a macrocyclic lactone structure Very similar bacterial coverage Ketolides active agains macrolide-resistant Only few indications where it is a drug of first choice, mostly as an alternative to penicillin in allergy to beta-lactam ATBs. clarithromycin (methylated form of erythrom.) lactone structure to which one or more deoxy sugars are attached

Macrolide antibiotic binding irreversibly to a 50S subunit of the bacterial ribosome - inhibition of the translocation step of protein synthesis - bacteriostatic ERYTHROMYCIN CLARITHROMYCIN AZITHROMYCIN

Macrolide antibiotic ERY * nonregistered Clarithromycin Azithromycin
used in patients allergic to the PNCs as PNC G - especially G + bacteria and spirochaetes, N.gonorrhoae intracellular - Chlamydia, Mycoplasma,Legionella, Corynebacterium diphterie Antistaphylococcal antibiotic – not MRSA Clarithromycin similar to erythromycin, but it is also effective against Haemophilus influenzae. higher activity than ERY against intracellular pathogens (e.g., Chlamydia, Legionella, Moraxella, Urea plasma species) and Helicobacter pylori Azithromycin Less active against streptococci and staphylococci than erythromycin; more active against respiratory infections due to H. influenzae and Moraxella catarrhalis. Mycobacterium avium but not tuberculosis The preferred therapy for urethritis caused by Chlamydia trachomatis. Telithromycin spectrum similar to azithromycin, less vulnerable to resistance Corynebacterium diphterie – G+ bacilli

Macrolide antibiotic Resistance to erythromycin - a serious clinical problem Most strains of staphylococci in hospital isolates are resistant to this drug. Several mechanisms: the inability of the organism to take up ATB or the presence of an efflux pump (it limits the amount of intracellular drug); a decreased affinity of the 50S ribosomal subunit for ATB; plasmid-associated erythromycin esterase. Clarithromycin and azithromycin show cross-resistance with erythromycin, telithromycin can be effective against macrolide-resistant organisms.

Macrolide antibiotic Administration: Distribution: Absorbed orally
Azithromycin available for IV infusion, Food interferes with absorption of Erythro and Azithromycin but can increase that of clarithromycin. Distribution: Distributed well in all body fluids except the CSF. Erythro - one of the few ATBs that diffuses into prostatic fluids unique characteristic of accumulating in macrophages. All drugs concentrate in the liver. Inflammation allows for greater tissue penetration Serum levels of azithromycin are low; concentrated in neutrophils, macrophages, and fibroblasts. longes half-life and largest Vd. Also clarithromycin, azithromycin, and telithromycin are widely distributed in the tissues. IV erythromycin - high incidence of thrombophlebitis, intramuscular injections are painful – but injection of azithromycin much safer

Macrolide antibiotic Metabolism: Excretion:
are extensively metabolized with exception of AZI. inhibit the oxidation of CYP-450 system Excretion: Erythromycin and azithromycin concentrated and excreted in an active form in the bile. Partial reabsorption occurs via enterohepatic circulation. Inactive metabolites are excreted into the urine. clarithromycin and its metabolites are eliminated by the kidney as well as the liver adjust dosage in compromised renal function! Interference with the metabolism of drugs such as theophylline and carbamazepine has been reported for clarithromycin. Clarithromycin is oxidized to the 14-hydroxy derivative, which retains antibiotic activity.

Macrolide antibiotic - AE
Epigastric distress: common - it can lead to poor compliance for erythromycin. Clarithromycin and azithromycin - better tolerated by the patient, but GIT problems are also most common side effects. Cholestatic jaundice: All of them especially with the estolate form of erythromycin, presumably as the result of a hypersensitivity reaction the lauryl salt of the propionyl ester of erythromycin Ototoxicity: Transient deafness - erythromycin, especially at high dosages. Telithromycin – hepatotoxicity, prolongation of QTc interval, may worsen myastenia gravis Contraindications: Patients with hepatic dysfunction - treat with caution - if at all - with erythromycin, telithromycin, or azithromycin - they accumulate in the liver. Patients renal disease – telithromycin with caution. Telithromycin may worsen myasthenia gravis.

Macrolide antibiotic - interactions
Inhibition of CYP450 Erythromycin, telithromycin, and clarithromycin accumulations of co-administered drugs E.g., theophylline, warfarin, carbamazepine, cyclosporine and statins Increased absorption of digoxine form GIT ATB eliminates a species of intestinal flora that ordinarily inactivates digoxin lower secretion by MDR1

Clindamycin mechanism as macrolides
antagonism when co-administered infections caused by anaerobic bacteria (e.g. Bacteroides fragilis). Also active against non-enterococcal, gram-positive cocci. Note: Clostridium difficile is resistant to clindamycin. orally (well absorbed) or parenterally. Distributes well into all body fluids except the CSF. Penetration into bone occurs even in the absence of inflammation. It undergoes extensive oxidative metabolism to inactive products, excreted into the bile or urine by glomerular filtration. Therapeutic levels of the drug are not achieved in the urine. Accumulation in patients with either severely compromised renal function or hepatic failure.

Clindamycin - AE skin rashes GIT disturbances impaired liver function
the most serious adverse effect is potentially fatal pseudomembranous colitis !! caused by overgrowth of Clostridium difficile - vancomycin or metronidazole vancomycin is usually effective in the treatment. (Vancomycin should be reserved for a condition that does not respond to metronidazole).

Quinupristin/dalfopristin * not registered
A mixture of two streptogramins (30 : 70) reserved - vancomycin-resistant Enterococcus faecium (VRE) and G+ Bactericidal with long postantibiotic effect each component binds to a separate site on the 50S bacterial ribosome, forming a stable complex. They synergistically interrupt protein synthesis. I.v. in 5% dextrose solution They penetrate macrophages and polymorphonucleocytes important (because VRE are intracellular). Levels in the CSF are low. undergo metabolism – further via biliary excretion to feces The products are less active than the parent in the case of quinupristin and are equally active in the case of dalfopristin. Urinary excretion is secondary Noneffective against Enterococcus faecalis Enzymatic processes (e.g., a ribosomal enzyme that methylates the target bacterial ribosomal RNA site can interfere in quinupristin binding). Enzymatic modification can sometimes change the action from bactericidal to bacteriostatic. Plasmid-associated acetyl transferase inactivates dalfopristin. Active efflux pump.

Quinupristin/dalfopristin
Adverse effects Venous irritation common when administered through a peripheral line. Arthralgia, myalgia when higher levels of the drugs are employed. Hyperbilirubinemia about 25% of patients, resulting from a competition with the antibiotic for excretion. quinupristin/dalfopristin inhibit CYP3A4 isozyme /MDR1 interactions digoxin

linezolid against resistant G+ organisms
methicillin- and vancomycin-resistant S. aureus, vancomycin-resistant Enterococcus faecium (VRE – alternative to daptomycin) and Enterococcus faecalis, PNC-resistant streptococci Cl. perfringens Bacteriostatic - Inhibits of bacterial protein synthesis block the formation of the 70S initiation complex by binding to 50S subunit. Resistance Decreased binding to the target site. Cross-resistance with other ATBs does not occur.

linezolid Pharmacokinetics AE- Well-tolerated
Completely absorbed on oral administration I.v. is also available. Widely distributed in the body. Two metabolites (oxidation products) - one has antimicrobial activity. CYP450 enzymes are not involved in their formation. Excretion both by renal and nonrenal routes. AE- Well-tolerated GIT upset (nausea, and diarrhea), headache and rash thrombocytopenia in cca 2 % (when longer than 2 weeks) - reversible. Peripheral neuropathies or optic neuritis Longer use – more than 28 D Do not take tyramine food Safe but similar compound produced „cheese reaction“ early oxazolidinones showed to inhibit MAO activity - reversible increase in the pressor effects of pseudoephedrine was shown

Chloramphenicol Resistance Broad-spectrum
wide range of G+ and gram– organisms; also some intracellular - e.g. rickettsiae P. aeruginosa is not affected, nor are the chlamydiae. Excellent activity against anaerobes. use is restricted to life-threatening infections because of its toxicity mostly bacteriostatic depending on the organism. bactericidal - to H. influenzae bacterial 50S ribosomal subunit inhibit protein synthesis at the peptidyl transferase reaction Toxicity? similarity of mammalian mitochondrial ribosomes to those of bacteria, high circulating chloramphenicol levels - bone marrow toxicity!! Resistance - Presence of an R factor (which codes for an acetyl-CoA transferase that inactivates chloramphenicol). - Inability to penetrate the organism - change in permeability may be the basis of multidrug resistance.

Chloramphenicol Administered intravenously or orally
Completely absorbed after the oral route (its lipophilic nature). Widely distributed including the CSF it readily enters the normal CSF. glucuronidation in the liver - primary route Glucuronide is then secreted by the renal tubule. Only about 10% of the parent compound are excreted by glomerular filtration. inhibits the hepatic mixed-function oxidases also secreted into breast milk Ind. - serious life-threatening infections H. influenzae, Bacteroides fragilis and meningitis where PNCs cannot be used In typhoid fever: amoxycillin and cotrimoxazole less toxic

Chloramphenicol - AE Hemolytic anemia Reversible anemia
in patients with low levels of glucose 6-phosphate dehydrogenase. Reversible anemia is dose-related and occurs concomitantly with therapy Aplastic anemia (pancytopenia), idiosyncratic and usually fatal !!! is independent of dose and may occur after therapy has ceased !!! Potential teratogenic effects GIT Dysmicrobia, GIT disturbances, diarrhea, hypovitaminosis B and K Gray baby syndrome: in neonates if the dosage is not properly adjusted Low capacity to glucuronate chloramphenicol drug, which accumulates to levels that interfere with the function of mitochondrial ribosomes poor feeding, depressed breathing, cardiovascular collapse, cyanosis (hence the term "gray baby") and death. Adults who have received very high doses – may also exhibit this toxicity. Interactions inhibits some hepatic P450 and blocks the metabolism of drugs warfarin, phenytoin, tolbutamide. Gray baby syndrome: in neonates if the dosage is not properly adjusted. Low capacity to glucuronylate chloramphenicol and they have underdeveloped renal function - a decreased ability to excrete the drug, which accumulates to levels that interfere with the function of mitochondrial ribosomes - poor feeding, depressed breathing, cardiovascular collapse, cyanosis (hence the term "gray baby") and death. Adults who have received very high doses of the drug can also exhibit this toxicity. Interactions - it inhibits some hepatic P450 and blocks the metabolism of drugs (warfarin, phenytoin, tolbutamide) - elevation of their concentrations - potentiation of their effects.

Metronidazol Inhibition of DNA replication in microorganism Spectrum
Anaerobes, Trichomonas vaginalis and Entamoeba histolytica, C. difficile. For infections - Bacteroides fragilis, anaerobes in abdominal cavity, diarhea by C. difficile, cerebral abscesses, trichomodal inf. Choice for tetanus. PK P.o. excellent absorption, penetrate bones teeths, CNS abscesses/CSF; placenta milk. Metabolized in liver, kidney excretion. AE: Metalic taste, GIT, CNS (dizzines, vertigo , headache, depression) dark urine, dissulfiram like effect – COI alcohol, pregnancy 1st trimester imidazol - ornidazol, tinidazol – další imidazolové deriváty – toho času neregistrované

fusidic acid against G+ bacteria by inhibiting protein synthesis
steroid structure registered for topical treatment otherwise well absorbed, does not cross CSF, concentrates in bones. Used mainly in PNC-resistant staphylococcal infections (with other antistaphylococcal effective agent). GIT disturbances, skin eruption, jaundice.

Fluoroquinolones enter the bacteria by passive diffusion via water-filled channels Block DNA gyrase (topoisomerase II) and topoisomerase IV inhibit the replication of bacterial DNA Binding to both enzyme and the DNA forms a ternary complex that inhibits the resealing step, cause cell death by inducing cleavage of the DNA. Bactericidal - concentration-dependent killing. Effective against G- organisms e.g. Enterobacteriacea, Pseudomonas species, H. influenzae, Moraxella catarrhalis, Intracellular Legionellaceae, chlamydia, and mycobacteria - except for M. avium intracellulare complex Effective in the treatment of gonorrhea but not syphilis. The newer agents - moxifloxacine, levofloxacin good activity against some G+ organisms e.g., Streptococcus pneumoniae) Activity against some anaerobes Topoisomerase IV is required for bacteria cell division – especially in G+ Activity against some anaerobes - sparfloxacin, gatifloxacin, and moxifloxacin. They lower the incidence of postsurgical urinary tract infections (UTIs). cross-resistance with other antimicrobial drugs rare, but this is increasing in the case of multidrug-resistant organisms.

Fluoroquinolones First-generation quinolones – not registered in CR
nalidixic acid moderate G- - minimal serum concentrations uncomplicated urinary tract infections Second-generation Ciprofloxacin, ofloxacin, norfloxacine, pefloxacin, prulifloxacin Extended G- activity; also some activity against G+ atypical organisms e.g., Mycoplasma pneumoniae and Chlamydia pneumoniae, legionella. Bacillus anthracis - Ciprofloxacin

Fluoroquinolones Third-generation Fourth-generation
Levofloxacin Retain expanded G- activity; Improved activity against atypical organisms and specific G+ bacteria. Fourth-generation Moxifloxacine improved G+ coverage, maintains G- activity, anaerobic coverage. active against many anaerobic and G+ organisms. New fluoroquinolones are rarely appropriate as first-Iine drugs Preventing resistance

Fluoroquinolones Ciprofloxacin Against many systemic infections
Useful in treating infections caused by many Enterobacteriaceae and other G- bacilli. E.g., traveler's diarrhea Not in serious infections by MRSA, enterococci, and pneumococci Gonorhea, complicated UTI Anthrax Prophylaxis after exposition and therapy P. aeruginosa The most potent of the fluoroquinolones for infections treatment of pseudomonal infections associated with cystic fibrosis. An alternative to more toxic drugs (e.g. aminoglycosides). It may act synergistically with b-Iactams; resistant tuberculosis typhoid fever in third world countries C. Examples of clinically useful fluoroquinolones

Fluoroquinolones Norfloxacin Levofloxacin
Not effective in systemic infections. More potent than nalidixic acid, effective against both gram-negative (including Pseudomonas aeruginosa) and gram-positive organisms. complicated and uncomplicated UTIs and prostatitis. Levofloxacin an isomer of ofloxacin S. pneumoniae and other respiratory infections Complicated UTI + prostatitis Except for syphilis An alternative therapy in patients with gonorrhea. Anthrax – prophylaxis and also therapy Gonorhea sensitive

Fluoroquinolones Moxifloxacin Enhanced activity against G+ organisms
e.g., S. Pneumoniae excellent activity against anerobes (e.g., Bacteroides fragilis). P. aeruginosa very poor activity

Fluoroquinolones - PK Absorption: 85 to 95 % after p.o.
exception - only % of norfloxacin is absorbed I.v. preparations of levo-, cipro-floxacin available antacids (with Al or Mg), or dietary supplements (with Zn or Fe, divalents) - interference. distribute well into all tissues and body fluids Levels are high in bone, urine, kidney, and prostatic tissue (but not prostatic fluid), and concentrations in the lung exceed those in serum. Low into CSF except for ofloxacin accumulate in macrophages and polymorphonuclear leukocytes effective against intracellular organisms. excreted by the renal route. once-daily dosing Those with the longest half-lives levofloxacin, moxifloxacin I.v. preparations of ciprofloxacin, levofloxacin, gatifloxacin, and ofloxacin are available. Binding to plasma proteins 10 – 40 %.

Fluoroquinolones - AE well tolerated GIT: the most common CNS:
nausea, vomiting, diarrhea (3 – 6 % of patients). CNS: headache and dizziness or light-headedness. Patients with epilepsy – CAUTION [Ciprofloxacin interferes in the metabolism of theophylline and may evoke seizures.] Phototoxicity: Avoid sunlight – discontinue at the first sign of phototoxicity Hepatotoxicity: Trovafloxacin - serious liver injury – only for life-threatening infections. Therapy – not longer than 14 days. Connective tissue problems COI in pregnancy, in nursing mothers, and in children under 18 years articular cartilage erosion (arthropathy) occurs in immature experimental animals. Tendinitis In adults - they can infrequently cause ruptured tendons Even sevaral months after end of therapy

Fluoroquinolones prolongation the QT interval Drug interactions:
Especially moxifloxacin not use in those who are predisposed to arrhythmias Drug interactions: antacids and cations Reduce absorption inhibition of drug metabolism may raise the serum levels of warfarin, theophylline, caffeine, and cyclosporine

FOLIC ACID ANTAGONISTS
Coenzymes containing folic acid required for the synthesis of purines and pyrimidines and other compounds necessary for cellular growth and replication. In the absence of folic acid, bacteria cannot grow or divide. Humans cannot synthesize folic acid and must obtain preformed folate as a vitamin from the diet. Many bacteria are impermeable to folic acid, and must synthesize folate de novo. sulfonamides inhibit the synthesis of folic acid – dihydropteroate red. trimethoprim prevents the conversion of folic acid to its active, coenzyme form (tetrahydrofolic acid). Both compounds interfere with the ability of bacterium to divide.

Inhibition of tetrahydrofolate synthesis by sulfonamides and trimethoprim
Microorganisms Humans and microorganisms 2 NADPH + 2 H+ 2 NADPH Amino acid synthesis Dihydro- pteroate synthetase Dihydro- folate reductase H2N COOH Folic acid Tetrahydrofolic acid Purine synthesis Pteridine precursor + pAminobenzoic acid (PABA) Glutamate O Thymidine synthesis . Mechanism of action Folic acid - synthesized from PABA, pteridine, and glutamate. All sulfonamides are analogs of PABA. Because of their structural similarity to PABA, SA compete with this substrate for the bacterial enzyme, dihydropteroate synthetase. They thus inhibit the synthesis of bacterial folic acid. H2N S NHR Sulfanilamide (and other sulfonamides) Trimethoprim O (according to Lippincott´s Pharmacology, 2006)

Sulfamethoxazole PABA Trimetoprim DHF

Sulfonamides C. Resistance Bacteriostatic Spectrum
All sulfa drugs, incl. co-trimoxazole Structurally related to p-aminobenzoic acid (PABA) Spectrum Active against selected enterobacteriaceae, chlamydia, and nocardia. sulfadiazine in combination with the dihydrofolate reductase inhibitor pyrimethamine is the preferred form of treatment for toxoplasmosis and chloroquine-resistant malaria. Complete cross-resistance Change of targets C. Resistance Only organisms that synthesize their own folic acid are sensitive to the sulfonamides. Humans are not affected (as well as bacteria that do not synthesize folic acid). Organisms resistant to one member of this drug family are resistant to all. Resistance - irreversible, it may be due to altered dihydropteroate synthetase decreased cellular permeability to drugs enhanced production of the natural substrate, PABA.

Sulfonamides well absorbed after oral administration I.v. sulfonamides
An exception - sulfasalazine - not absorbed reserved for treatment of chronic inflammatory bowel disease (e.g., Crohn disease or ulcerative colitis). Intestinal flora split sulfasalazine into sulfapyridine and 5-aminosalicylate - anti-inflammatory effect I.v. sulfonamides Rarely - reserved for patients who are unable to take them orally. The risk of sensitization not usually applied topically Exception - creams of silver sulfadiazine - effective in reducing burn-associated sepsis.

Sulfonamides - PK Bound (in a different extent) to serum albumin
Kernicterus Distribution in the body, good penetration into CSF even without inflammation. They can pass the placental barrier - COI. Metabolism: acetylated (NAT), primarily in the liver. The metabolite (without antimicrobial activity) retains the toxic potential to precipitate at neutral or acidic pH. crystalluria ("stone formation") and potential damage to the kidney. Excretion by glomerular filtration depressed kidney function - accumulation of both the parent compounds and metabolites. may also be eliminated in breast milk.

Sulfonamides Well absorbed orally, short-acting:
Sulfadiazine, Sulfadimidine, Sulfisoxazole, Sulfamethoxazole Well absorbed orally, long-acting: Sulfamethopyrazine Poorly absorbed in GIT: Sulfasalazine (sulfapyridine) Used topically: Silver sulfadiazine, sulfacetamide

Sulfonamides - AE Nephrotoxicity Hypersensitivity - common
a result of crystalluria sulfisoxazole and sulfamethoxazole – more soluble at urinary pH than the older SA. Adequate hydration and alkalization of urine is necessary Note: It is contraindicated to use acidic drugs (salicylates) or food (oranges etc.) which may lead to acidic pH of urine during therapy with sulfonamides !!! Hypersensitivity - common rashes, fever, angioedema, anaphylactoid reactions, Stevens-Johnson syndrome more frequently with the longer-acting agents Hepatitis Stevens–Johnson syndrome (SJS) is a milder fo)rm of toxic epidermal necrolysis (TEN

Sulfonamides - AE Hemopoietic disturbances
Hemolytic anemia in patients with glucose 6-phosphate dehydrogenase deficiency. Granulocytopenia and thrombocytopenia can also occur. Nausea, vomiting, headache, mental depression Kernicterus: In newborns - the displacement of bilirubin from its binding to serum albumin and its penetration into CNS (baby's blood-brain barrier is not fully developed). Drug interactions- displacement from serum albumin Transient potentiation of the hypoglycemic effect of oral antidiabetic drugs (e,g, tolbutamide) or the anticoagulant effect of warfarin Free methotrexate levels may also rise. F. Contraindications: Danger of kernicterus - avoid in newborns and infants less than two months of age, as well as for pregnant women at term. Sulfonamides form complexes with formaldehyde - should not be given to patients receiving methenamine. Drugs containing PABA (e.g. local anesthetics - derivatives of PABA) antagonize the effect of sulfonamides (PABA is released from their structure during metabolism).

Trimethoprim Resistance in G- bacteria
inhibitor of bacterial dihydrofolate reductase; antibacterial spectrum similar to SA. May be used alone in the treatment of acute UTIs, and in the treatment of bacterial prostatitis and vaginitis. trimethoprim is fold more potent than SA. Relative selective to bacterial – low toxicity Mostly compounded with sulfamethoxazole = co-trimoxazole. Other folate reductase inhibitors: pyrimethamine (used with SA in parasitic infections), methotrexate (in cancer chemotherapy). Resistance in G- bacteria presence of altered dihydrofolate reductase with lower affinity for trimethoprim or overproduction of the enzyme decrease drug permeability.

Trimethoprim a weak base It also penetrates the CSF
Pharmacokinetics similar to sulfamethoxazole. a weak base higher concentrations of trimethoprim in relatively acidic prostatic and vaginal fluids. It also penetrates the CSF mostly excreted unchanged through the kidney. some O-demethylation Adverse effects folic acid deficiency megaloblastic anemia, leukopenia, granulocytopenia – especially in pregnant women and patients with a poor diets The blood disorders can be reversed by the simultaneous administration of folinic acid, which does not enter bacteria. nausea, vomiting, skin rashes

co-trimoxazole Trimethoprim compounded with sulfamethoxazole
Selected because of similar PK profiles Sequential blockade in the synthesis of tetrahydrofolic acid doses of both drugs are 1/10 of those needed if drug were used alone. 20 parts sulfamethoxazole to 1 part trimethoprim - empirical Broader spectrum than SA UTls and respiratory tract infections, Pneumocystis pneumonia and ampicillin- or chloramphenicol-resistant systemic salmonella infections. Oral most commonly – i.v. exists Resistance Iess frequent than to either of the drugs alone Reduction of the incidence of adverse effects the hypersensitivity reactions caused by sulfonamides occur (they are not dose-dependent – type B AE) !!! More lipid soluble than sulfamethoxazole - greater Vd. Generally administered orally. An exception: i.v. administration to patients with severe pneumonia caused by E. jeroveci or when the drug can not be taken by mouth. Both agents distribute throughout the body. Trimethoprim concentrates in the relatively acidic milieu of prostatic and vaginal fluids - the use of the trimethoprim-sulfamethoxazole in infections at these sites. Both parent drugs and their metabolites are excreted in the urine.

co-trimoxazole - AE Dermatological
Reactions involving the skin are very common and may be severe in the elderly. GIT: Nausea, vomiting, glossitis, stomatitis - not unusual. Hematological: Megaloblastic anemia, leukopenia, thrombocytopenia may be reserved by administration of folinic acid it protects the patient and does not enter the microorganism Hemolytic anemia - in patients with glucose 6-phosphate dehydrogenase deficiency due to the sulfamethoxazole. Immunocompromised patients with Pneumocystis (carinii) jiroveci pneumonia frequently drug-induced fever, rashes, diarrhea, and/or pancytopenia. Interactions: Prolonged prothrombin time (when warfarin used) was reported. Half-life of phenytoin may be increased - inhibition of its metabolism. Methotrexate levels may rise - displacement from albumin by sulfamethoxazole.

URINARY TRACT ANTISEPTICS
Urinary tract infections - UTIs e.g. acute cystitis, pyleonephritis common in the elderly and in young women. Cca 80 % caused by E. coli other – Staphylococcus saprophyticus, Klebsiella pneumoniae, Proteus mirabilis Systemic th co-trimoxazole, amoxicillin, (TTC) Antiseptics methenamine, nalidixic acid, norfloxacine, nitrofurantoin restricted for this disease They are concentrated in the urine They do not achieve antibacterial levels in the circulation

Methenamine * not registered in CR
Bioactivate/decompose at an acidic pH of 5.5 or less in the urine producing formaldehyde, which is toxic to most bacteria. The reaction is slow 3 hours to reach 90% decomposition formulated with a weak acid (e.g., mandelic acid) which lowers the pH of the urine Safe – given orally Bacterial resistance to formaldehyde does not develop !!! Urea-splitting bacteria that alkalinize the urine (e.g. proteus) usually resistant to methenamine Ind - lower UTls. Primarily used for chronic suppressive therapy

methenamine PK AE COI - patients with hepatic insufficiency
Administered orally distributed throughout the body fluids – but safe no decomposition of the drug occurs at pH systemic toxicity does not occur Eliminated in the urine AE GIT distress albuminuria, hematuria and rashes at higher doses: Sulfonamides react with formaldehyde - must not be used concomitantly with methenamine !! COI - patients with hepatic insufficiency In addition to formaldehyde, ammonium ion is produced in the bladder. Because the liver rapidly metabolizes ammonia to form urea elevated levels of circulating ammonium ions are toxic to the CNS !!! mandelic acid may precipitate

nitrofurantoin narrow spectrum and toxicity
Not frequent use Sensitive bacteria reduce the drug to active agent that inhibits various enzymes and damages DNA Activity is greater in acidic urine bacteriostatic, useful against E. coli; other common urinary tract G- bacteria may be resistant. Gram+ cocci are susceptible. Rapidly excreted by glomerular filtration Complete absorption after p.o. administration - milk urine brown Resistance: constitutive - associated with inability to reduce the nitrogen group in the presence of oxygen.

Nitrofurantoin - AE GIT disturbances frequent – Acute pneumonitis
nausea, vomiting and diarrhea - Ingestion with food or milk ameliorates these symptoms !! Acute pneumonitis And other pulmonary effects, (e.g., interstitial pulmonary fibrosis) in patients chronically treated. Neurological problems e.g. headache, nystagmus, and polyneuropathies with demyelination (footdrop) Hemolytic anemia contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency, neonates and pregnant women. Hypersensitivity reactions

nalidixic acid, norfloxacin
DNA gyrase (topoisomerase II) inhibit replication of bacterial DNA against most of the G- bacteria causing UTIs, most G+ organisms are resistant. Pk – see there Plasma levels of free nalidixic acid are insufficient for treatment of systemic infections !!! The concentration of nalidixic acid achieved in the urine is times greater than that in the plasma !! Excretion urine - !!!! Milk!!! Placenta – teratogens Adverse effect: mostly nausea, vomiting, and abdominal pain, urticaria, photosensitivity, liver function may be affected if therapy lasts longer than 2 weeks CNS problems (from headache and malaise to visual disturbances) are rare.

AntimycobacteriaIs

Mycobacteria Bacteria with lipid-rich cell walls genus Mycobacterium
stain poorly with the Gram stain, but once stained, the walls cannot be easily decolorized they are termed „acid-resitant“. genus Mycobacterium Tuberculosis - Mycobacterium tuberculosis Leprosy as well as several tuberculosis-like human infections (avium) Intracellular patogens slow-growing granulomatous lesions - major tissue destruction. 4 first-Iine agents for antituberculosis therapy Ethambutol, Isoniazid, Pyrazinamide, Rifamycins Second-Iine medications either less effective, more toxic, or have not been studied as extensively. useful in patients who cannot tolerate the first-Iine drugs or resistant to the first-Iine agents. Má neobvyklý voskový plášť na povrchu buňky (především z kyseliny mykolové), který je nepropustný pro Gramovo barvení; místo něj se proto používají acid-fast techniky. M. tuberculosis je vysoce aerobní, bakterie potřebuje vysoké hladiny kyslíku. Primárně je tato bakterie patogenem v dýchací ústrojí savců, napadá plíce, kde způsobuje tuberkulózu

Mycobacterium tuberculosis infection starts with the inhalation of bacilli, either as an aerosol droplet generated by the cough of a patient with tuberculosis (TB) or as a dust microparticle of dried sputum, followed by deposition of the bacteria in the lung alveolar space. The lungs, where the major events of pulmonary TB are orchestrated, consist of the conducting airways, which are lined by mucosal tissue, and the lung parenchyma, which surrounds thin-walled alveoli that are specialized for gas exchange. b | The alveoli are lined by type I and type II epithelial cells and are separated by thin walls of interstitium containing pulmonary capillaries. In the alveolar cavity, the main hosts for the bacilli are alveolar macrophages. After initial bacterial multiplication in alveolar macrophages, the bacteria are taken up by dendritic cells (DCs), which carry M. tuberculosis to the draining thoracic lymph nodes70. Alternatively, DCs sampling the alveolar mucosa may carry bacilli to the lung parenchyma, leading to initiation of the local inflammatory foci. c | In the draining lymph nodes, DCs carrying bacilli undergo apoptosis, and the mycobacterial antigenic peptides that are released are presented by the activated lymph node-resident DCs to the specific naive cells through cross-presentation. On antigen presentation, activated T cells proliferate, become effector T cells (which type depending on the cytokine milieu; for example, single- versus multiple-cytokine-producing polyfunctional helper CD4+ T cell subsets) and leave the lymph node to reach the blood circulation through the efferent lymphatics and the thoracic duct. d | Effector T cells originating in the draining lymph nodes home back from the blood through pulmonary capillaries to the site of inflammation under the influence of chemokines and other mediators. Extravasations of the mononuclear cells thus initiate the formation of signature 'tubercle' structures at the site of the infection, leading to containment of the infection. The classic TB granuloma is made up of a central core of infected macrophages surrounded by epithelioid and foamy macrophages and a peripheral rim of lymphocytes (B cells, CD4+ T cells and CD8+ T cells) in association with a fibrous cuff of extracellular matrix laid by fibroblasts.

Summary of drugs used to treat mycobacterial infections.
ANTIMYCOBACTERIAL AGENTS Drugs used to treat tuberculosis Ethambutol Isoniazid Pyrazinamide Rifamycins First-line drugs Aminoglycosides Aminosalicylic acid Capreomycin Cycloserine Ethionamide Fluoroquinolones Macrolides Second-line drugs Drugs used to treat leprosy Clofazimine Dapsone Rifampin (according to Lippincott´s Pharmacology, 2009)

CHEMOTHERAPY FOR TUBERCULOSIS
lungs, genitourinary tract, skeleton, and meninges. presents therapeutic problems organism grows slowly - treated for 6 months to 2 Y resistant organisms readily emerge particularly in patients who have had prior therapy multidrug therapy 2 M four combination – 4 M two combination compliance „directly observed therapy“ DOT - centers widespread worldwide 30 million people having active disease, 8 million new cases occur, and approximately 2 million people die of the disease each year. or who fail to adhere to the treatment protocol. It is currently estimated that about one-third of the world's population is infected with M. tuberculosis, with serious infections of the lungs, genitourinary tract, skeleton, and meninges

Days after initiation of treatment
Cumulative percentage of strains of Mycobacterium tuberculosis showing resistance to streptomycin 100 Percentage resistant 50 Days after initiation of treatment (according to Lippincott´s Pharmacology, 2009)

One of several recommended multi-drug schedules for the treatment of
tuberculosis Intensive phase Continuation phase Isoniazid Rifampin Pyrazinamide Ethambutol or streptomycin Months (according to Lippincott´s Pharmacology, 2009)

Isoniazid hydrazide of isonicotinic acid
synthetic analog of pyridoxine. most potent of the antitubercular drugs never given as a single its introduction revolutionized the treatment of tuberculosis. prodrug that is activated by a mycobacterial catalase-peroxidase (KatG) Block production of mycolic acids Mycolic acid - a unique class of very-Iong-chain, b-hydroxylated fatty acids found in mycobacterial cell walls Covalent blockade of synthetic enzymes enoyl acyl carrier protein reductase (InhA) and a b-ketoacyl-ACP synthase (KasA) Narrow spectrum Bactericidal in rapidly growing mycobacteria This is associated with several different chromosomal mutations, each of which results in one of the following: mutation or deletion of KatG (producing mutants incapable of prodrug activation), varying mutations of the acyl carrier proteins, or overexpression of InhA. Cross-resistance does not occur between isoniazid and other antitubercular drugs.

Isoniazid - PK Readily absorbed Distributed equally
Food and antacides impair. Distributed equally Easily penetrates cells, even into CNS Undergoes N-acetylation Inactivation – slow acetylators – accumulation Metabolites - urine 4. Pharmacokinetics: Orally administered isoniazid is readily absorbed. Absorption is impaired if isoniazid is taken with food, particularly carbohydrates, or with aluminum-containing antacids. The drug diffuses into all body fluids, cells, and caseous material (necrotic tissue resembling cheese that is produced in tubercles). Drug levels in the cerebrospinal fluid (CSF) are about the same as those in the serum. The drug readily penetrates host cells and is effective against bacilli growing intracellularly. Infected tissue tends to retain the drug longer. Isoniazid undergoes N-acetylation and hydrolysis, resulting in inactive products. [Note: Acetylation is genetically regulated, with the fast acetylator trait being autosomally dominant. A bimodal distribution of fast and slow acetylators exists (Figure 34.4).] Chronic liver disease decreases metabolism, and doses must be reduced. Excretion is through glomerular filtration, predominantly as metabolites (Figure 34.5). Slow acetylators excrete more of the parent compound. Severely depressed renal function results in accumulation of the drug, primarily in slow acetylators.

20 Number of subjects 10 50 100 150 200 250 Half-life (min)
Bimodal distribution of isoniazid half-lives caused by rapid and slow acetylation of the drug In rapid acetylators, isoniazid has a short half-life (~1hr) In slow acetylators, isoniazid has a long half-life (~3 hrs) 20 Number of subjects 10 (according to Lippincott´s Pharmacology, 2009) Half-life (min)

Isoniazid - AE Type B – hypersensitivity
Quite safe Type B – hypersensitivity Type A/C – dose and duration accentuate Peripheral neuritis paresthesias of the hands and feet due to a relative pyridoxine deficiency Mostly corrected by supplementation of 25 to 50 mg per day of pyridoxine Excreted into breast milk it can cause B6 deficiency in children Optic neuritis, seizures rare Hepatitis and idiosyncratic hepatotoxicity Due toxic metabolite; more frequent in alcoholics, rifampin Interactions Inhibits metabolism of phenytoin – CNS toxicity 5. Adverse effects: The incidence of adverse effects is fairly low. Except for hypersensitivity, adverse effects are related to the dosage and duration of administration. a. Peripheral neuritis: Peripheral neuritis (manifesting as paresthesias of the hands and feet), which is the most common adverse effect, appears to be due to a relative pyridoxine deficiency. Most of the toxic reactions are corrected by supplementation of 25 to 50 mg per day of pyridoxine (vitamin B6). [Note: Isoniazid can achieve levels in breast milk that are high enough to cause a pyridoxine deficiency in the infant unless the mother is supplemented with the vitamin] b. Hepatitis and idiosyncratic hepatotoxicity: Potentially fatal hepatitis is the most severe side effect associated with isoniazid. It has been suggested that this is caused by a toxic metabolite of monoacetylhydrazine, formed during the metabolism of isoniazid. Its incidence increases among patients with increasing age, among patients who also take rifampin, or among those who drink alcohol daily. c. Drug interactions: Because isoniazid inhibits metabolism of phenytoin (Figure 34.6), isoniazid can potentiate the adverse effects of that drug (for example, nystagmus and ataxia). Slow acetylators are particularly at risk . d. Other adverse effects: Mental abnormalities, convulsions in patients prone to seizures, and optic neuritis have been observed. Hypersensitivity reactions include rashes and fever.

Rifamycins: Rifampin, rifabutin and rifapentine
DNA dependent RNA synthase Structurally similar to macrocyclic ATB Broad spectrum Mycobacteria TBC/leprae and atypical mycobacteria - M.kansasii, G+, G- prophylactically for individuals exposed to meningitis caused by meningococci or Haemophilus influenzae PK Lipophilic – good absorbtion p.o., widely distributed incl CNS, metabolized – bile/urine Rafapentine – long t1/2 – once week dosage possible Warn patients - orange-red colored feces, urine, tears Enzyme inducers a. Mechanism of action: Rifampin blocks transcription by interacting with the b subunit of bacterial but not human DNA-dependent RNA polymerase. [Note: The drug is thus specific for prokaryotes.] Rifampin inhibits mRNA synthesis by suppressing the initiation step. b. Antimicrobial spectrum: Rifampin is bactericidal for both intracellular and extracellular mycobacteria, including M. tuberculosis, and atypical mycobacteria, such as M. kansasii. It is effective against many gram-positive and gram-negative organisms and is frequently used prophylactically for individuals exposed to meningitis caused by meningococci or Haemophilus influenzae. Rifampin is the most active antileprosy drug at present, but to delay the emergence of resistant strains, it is usually given, in combination with other drugs. Rifabutin, an analog of rifampin, has some activity against Mycobacterium avium-intracellulare complex but is less active against tuberculosis. d. Pharmacokinetics: Absorption is adequate after oral administration. Distribution of rifampin occurs to all body fluids and organs. Adequate levels are attained in the CSF even in the absence of inflammation. The drug is taken up by the liver and undergoes enterohepatic cycling. Rifampin itself can induce the hepatic mixed-function oxidases, leading to a shortened half-life. Elimination of metabolites and the parent drug is via the bile into the feces or via the urine (Figure 34.7). [Note: Urine and feces as well as other secretions have an orange-red color; patients should be forewarned. Tears may permanently stain soft contact lenses orange-red.]

Rifamycins - AE GIT, skin Hepatitis Flu-like syndrome Interactions
Well tolerated GIT, skin nausea, vomiting, and rash Hepatitis Risk patients – alcoholics, rifampicin, hepatotoxins Flu-like syndrome fever, chills, and myalgias other rarely renal failure, hemolysis rifabutin less active but can cause uveitis and skin hyperpigmentation Interactions Enzyme inducers e. Adverse effects: Rifampin is generally well tolerated. The most common adverse reactions include nausea, vomiting, and rash. Hepatitis and death due to liver failure is rare; however, the drug should be used judiciously in patients who are alcoholic, elderly, or have chronic liver disease due to the increased incidence of severe hepatic dysfunction when rifampin is administered alone or concomitantly with isoniazid. Often, when rifampin is dosed intermittently, or in daily doses of 1.2 grams or greater, a flu-Iike syndrome is associated with fever, chills, and myalgias and sometimes is associated with acute renal failure, hemolytic anemia, and shock. f. Drug interactions: Because rifampin can induce a number of cytochrome P450 enzymes, it can decrease the half- lives of other drugs that are coadministered and metabolized by this system (Figure 34.8). This may lead to higher dosage requirements for these agents. 2. Rifabutin: Rifabutin [rif-a-BYOO-tin], a derivative of rifampin, is the preferred drug for use in tuberculosis-infected with the human immunodeficiency virus (HIV) patients who are concomitantly treated with protease inhibitors or non nucleoside reverse transcriptase inhibitors, because it is a less potent inducer of cytochrome P450 enzymes. Rifabutin has adverse effects similar to those of rifampin but can also cause uveitis, skin hyperpigmentation, and neutropenia. 3. Rifapentine: Rifapentine [rih-fa-PEN-teen] has activity comparable to that of rifampin but has a longer half-life than rifampin and rifabutin, which permits weekly dosing. However, for the intensive phase (initial 2 months) of the short-course therapy for tuberculosis, rifapentine is given twice weekly. In the subsequent phase, rifapentine is dosed once per week for 4 months. To avoid resistance issues, rifapentine should not be used alone but, rather, be included in a three to four-drug regimen.

Pyrazinamide orally effective, bactericidal Lipophilic AE
mechanism – unknown enzymatically hydrolyzed to pyrazinoic acid – the active form of the drug Pyrazinamidase required – lacking = resistance Lipophilic Penetrates well incl CNS Concentrated in acidic environment of Iysosomes as well as in macrophages. It undergoes extensive metabolism. AE rash, hepatotoxicity Potentiated by other anti-TBCs – 5 % of treated Precipitate gouty attack Urate retention - rare D. Pyrazinamide Pyrazinamide [peer-a-ZIN-a-mide] is a synthetic, orally effective, bactericidal, antitubercular agent used in combination with isoniazid, rifampin, and ethambutol. It is bactericidal to actively dividing organisms, but the mechanism of its action is unknown. Pyrazinamide must be enzymatically hydrolyzed to pyrazinoic acid, which is the active form of the drug. Some resistant strains lack the pyrazinamidase. Pyrazinamide is active against tubercle bacilli in the acidic environment of Iysosomes as well as in macrophages. Pyrazinamide distributes throughout the body, penetrating the CSF. It undergoes extensive metabolism. About one to five percent of patients taking isoniazid, rifampin, and pyrazinamide may experience liver dysfunction. Urate retention can also occur and may precipitate a gouty attack (Figure 34.9).

Ethambutol bacteriostatic PK - oral AE
specific for most strains of M. tuberculosis and M. kansasii inhibits arabinosyl transferase synthesis of the mycobacterial arabinogalactan cell wall PK - oral Incl CNS – useful in tuberculous meningitis. parent drug and metabolites are excreted by glomerular filtration and tubular secretion. AE optic neuritis results in diminished visual acuity and loss of ability to discriminate between red and green. Visual acuity should be periodically examined. Discontinuation of the drug results in reversal of the optic symptoms. gout may be exacerbated urate excretion is decreased by the drug;

Second line – anti-TBC Less active, more toxic or more active against atypical strains of mycobacteria streptomycin – see aminoglycosides streptomycin-resistant organisms may be treated with kanamycin or amikacin capreomycin – similar to aminoglycosides Parenterally - reserved for multidrug-resistant tuberculosis. monitoring - nephrotoxicity and ototoxicity. fluoroquinolones moxifloxacin and levofloxacin, treatment of multidrug- resistant tuberculosis para-aminosalicylic acid Competitive inhibitor resembling PABA ethionamide Analogue of isoniazide – similar issues cycloserine Inhibits cell-wall synthesis – seizures, neuropathies (respond to pyridoxine) Macrolides Azithromcin and clarithromycin – M. avium

Aminosalicylic acid and ethionamide can inhibit the acetylation of isoniazid
Acetylated isoniazid (according to Lippincott´s Pharmacology, 2009)

Summary of antifungal drugs.
Drugs for subcutaneous and systemic mycoses Voriconazole Posaconazole Micafungin Ketoconazole Itraconazole Flucytosine Fluconazole Caspofungin Anidulafungin Amphotericin B Drugs for cutaneous mycoses Terconazole Terbinafine Nystatin Miconazole Griseofulvin Econazole Clotrimazole Butoconazole (according to Lippincott´s Pharmacology, 2009)

Drugs for subcutaneous and systemic mycoses - Amphotericin B

Drugs for subcutaneous and systemic mycoses - Amphotericin B
polyene ATB choice for life-threatening, systemic mycoses Sometimes in combination with flucytosine lower (less toxic) levels of amphotericin are possible. binds to ergosterol in the plasma membranes - forms pores (channels) electrolytes (particularly K) and small molecules leak from the cell - cell death. Against a wide range of fungi, incl. Candida albicans, Histoplasma capsulatum, Cryptococcus neoformans, Coccidioides immitis, Blastomyces dermatitidis, many strains of aspergillus. also protozoal infection, leishmaniasis. Administered by slow, i.v. infusion. Also liposome prepartions - reduced renal and infusion toxicity – but high cost. Lipophilic – but no into CSF, cross placenta 3. Resistance: infrequent ( ergosterol content of the fungal membrane). The more dangerous intrathecal route. Low levels of the drug and metabolites appear in the urine over a long period; some are also eliminated via the bile. Dosage adjustment is not required in compromised renal or hepatic function.

Amphotericin B - AE Fever and chills Hypotension
Liposomes or microemulsion usually subside with repeated administration. Premedication with a corticosteroid or an antipyretic helps to prevent it. Hypotension A shock-like fall in BP with hypokalemia requiring K supplementation anaphylaxis, convulsions Small test dose initially Renal impairment in glomerular filtration and tubular function, loss of K a Mg. Adequate hydration is necessary. Anemia: Normochromic, normocytic anemia by reversible suppression of erythrocyte production). Neurologic effects: Intrathecal administration - serious problems. Thrombophlebitis: Adding heparin to the infusion can

Flucytosine – 5-FC Pyrimidine antimetabolite
often used with amphotericin B Cryptococcus neoformans and Candida albicans. Amphotericin B increases cell permeability - more 5-FC to the cell - synergistic action. Seletive uptake and conversion to 5-FU Enters via a cytosine-specific permease enzyme which is not found in mammalian cells then converted to 5-fluorodeoxyuridine 5'- monophosphate - false nucleotide - inhibits thymidylate synthase - DNA Also incorporated into fungal RNA - nucleic acid and protein synthesis Good oral absorption, penetration into CNS, renal elimination AE GI disturbances (nausea, vomiting, diarrhea) – common reversible neutropenia, thrombocytopenia, reversible hepatic dysfunction 2. Spectrum: fungistatic. Combination with itraconazole (treatment of chromoblastomycosis). Combination with amphotericin B for (candidiasis or cryptococcosis) . 3. Resistance:  enzymes in the conversion of 5-FC to 5-fluorouracil (5-FU) and  synthesis of cytosine during therapy  5-FC not used single. Resistance is  in combination with second antifungal agent. 4. PK: Well absorbed orally. Distribution; penetrates well into CSF Metabolism by intestinal bacteria. Renal excretion  adjust dose in compromised renal function. 5. Adverse effects: reversible neutropenia, thrombocytopenia, occasionaly bone marrow depression (caution in patients with radiation, chemotherapy, drugs) reversible hepatic dysfunction GI disturbances (nausea, vomiting, diarrhea) – common severe enterocolitis Some may be related to 5-FU formed by intestinal organisms from 5-FC.

Azole antimycotics Ketoconazole, itraconazole, fluconazole, voriconazole Fungistatic - inhibit C-14 a-demethylase (P450) block demethylation of lanosterol to ergosterol disruption of membrane structure and function Spectrum many fungi, incl. histoplasma, blastomyces, candida, coccidioides, ketoconazole not aspergillus species. Adverse effects: Allergies dose-dependent GI disturbances (nausea, anorexia, vomiting) Hepatotoxic - transient serum transaminases; hepatitis - rarely - immediate withdraw Endocrine effects (gynecomastia,  libido, impotence, menstrual irregularities) via the block of androgen and adrenal (testosterone) synthesis - Ketoconazol Teratogenic in animals - not administer in pregnancy Interactions Inhibition of CYP450 !!! - ketoconazol Only orally (it requires gastric acid for dissolution - absorbed through the gastric mucosa). Drugs that raise gastric pH (antacids, H2-histamine receptor blockers, proton-pump inhibitors) - impair absorption. Extensively bound to plasma proteins Rifampin (inducer of CYP450) can shorten the duration of action of azoles. Drugs that decrease gastric acidity -  absorption of ketoconazole. Ketoconazole and amphotericin B should not be used together (decrease in ergosterol reduces action of amphotericin B).

lanosterol ergosterol cholesterol

Drugs for cutaneous and systemic mycoses
Ketoconasole Absorption dependent on pH in stomach Not into CNS Extensive metabolism in the liver – bile Enzyme inhibitor Itraconasole Broader spectrum - aspergillosis, and histoplasmosis Similar PK to ketoconazole Also P450 inhibitor but without endocrine effect Fluconazole Also for i.v – excellent CNS penetration Lack of P450 interactions incl endocrine Kidney excretion Voriconazole, posaconazole New, broadest spectrum, resistant aspergilosis (vori), prevention of candidosis in immunocompromised - posa

Summary of some azole fungistatic drugs.
KETOKONAZOLE FLUCONAZOLE VORICONAZOLE POSACONAZOLE Spectrum Narrow Expanded Route(s) of administration Oral Oral, IV t1/2 (hours) 6-9 30 6-24 20-66 CSF penetration No Yes Renal excretion Interaction with other drugs Frequent Occasional Inhibition of mammalian sterol synthesis Dose-dependent inhibitory effect No inhibition (according to Lippincott´s Pharmacology, 2009)

Echinocandins Caspofungin, micafungin, anidulafungin
A second-line antifungal for those who have failed or cannot tolerate amphotericin B or itraconazole. against aspergillus and candida species. inhibit synthesis of the fungal cell wall inhibiting the synthesis of b(1,3)-o-glucan – cell death parenterally only Lipophilic - slowly metabolized (hydrolysis and N-acetylation) Adverse effects: fever, rash, nausea, phlebitis flushing due to histamine release The first member of the echinocandins Elimination by urinary and fecal routes. should not be coadministered with cyclosporine.

Drugs for cutaneous mycotic infections Terbinafine
Drug of choice for dermatophytoses and, esp. onychomycoses E.g. candida Therapy is prolonged - usually about 3 months Fungicidal - inhibits fungal squalene epoxidase synthesis of ergosterol+ accumulation of toxic amounts of squalene - death of the fungal cell. Only low affinity to human SE (cholesterol pathway) Lipophillic - deposited in the skin, nails, and fat Orally active - More than 99 % bound to plasma proteins. Half-life to 400 hours - reflects the slow release from these tissues. Accumulates in breast milk - should not be given to nursing mothers. Extensively metabolized Adverse effects: GIT disturbances (taste, diarrhea, dyspepsia, and nausea), headache, rash are common visual disturbances Transient elevations in serum liver enzyme- rarely hepatotoxicity. deposited in the skin, nails, and fat Orally active (BAV about 40 % - first-pass metabolism). More than 99 % bound to plasma proteins. Half-life ( 200 to 400 hours ) - reflects the slow release from these tissues. Accumulates in breast milk  should not be given to nursing mothers. Extensively metabolized (but probably no significant risk of reduced clearance of other drugs); urinary excretion – in renal impairment or hepatic cirrhosis reduced clearance. Adverse effects: resolve upon drug discontinuation - GI disturbances (diarrhea, dyspepsia, and nausea), headache, rash are common Taste and visual disturbances Transient elevations in serum liver enzyme Rarely hepatotoxicity and neutropenia.

Griseofulvin dermatophytic infections of the nails
Largely replaced by terbinafine for the treatment. Fungistatic - requires treatment of months in duration dependent on the rate of replacement of healthy skin or nails. It accumulates in newly synthesized, keratin-containing tissue causes disruption of the mitotic spindle and inhibition of fungal mitosis. P.o. - absorption is enhanced by high-fat meals. AE - mild GIT, neurological, phototoxicity induces hepatic CYP450 activity Number of interactions. e.g., oral anticoagulant drugs Blockade of alcohol dehydrogenase Patients should not drink alcoholic beverages during therapy griseofulvin potentiates the intoxicating effects of alcohol

Others Nystatin - polyene antibiotic
Its structure, chemistry, mechanism of action, and resistance resemble those of amphotericin B. Only for topical treatment of candida infections due systemic toxicity Not absorbed from GIT Oral agent ("swish and swallow") for the treatment of oral candidiasis. Excretion in the feces. Adverse effects: rare (nausea, vomiting) Miconazole, clotrimazole, butoconazole, terconazole Topical azole formulations AE - associated with contact dermatitis, vulvar irritation, and edema. Miconazole is a potent inhibitor of warfarin metabolism bleeding in warfarin-treated patients even when applied topically k. undecylenová Bakteriostaticky i na některé bakterie – Proteus, Pseudomonas F. ciklopirox Aktivně se hromadí v mykotické bb. - fungicid – stěna i funkce amorolfin Lak na nehty – blokuje syntézu ergosterolu

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