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 – 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

– 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

• Bacteriostatic – 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 ErythromycinAminoglycosides TetracyclinesCo-trimoxazole ChloramphenicolVancomycin 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• 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

– based on their:

• pharmacodynamics – Sign of infections– time-dependent killing

• pharmacokinetics– concentration-dependent killing - TDM– 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.

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 dentistryPericoronitisMetronidazole or amoxicillinAntibacterial 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 gingivitisMetronidazole or amoxicillinAntibacterial required only if systemic features of infection; treat for 3 days or until

symptoms resolve

Periapical or periodontal abscessAmoxicillin or metronidazoleAntibacterial required only in severe disease with cellulitis or if systemic features of

infection; treat for 5 days

PeriodontitisMetronidazole or doxycyclineAntibacterial required for severe disease or disease unresponsive to local treatment

(according to Lippincott´s Pharmacology, 2006)(according to Lippincott´s Pharmacology, 2006)

CELL WALLCELL WALLCELL MEMBRANECELL MEMBRANE

DNADNA

THFATHFA

PABAPABARibosomesRibosomes mRNAmRNA

Inhibitors of cell Inhibitors of cell membrane membrane functionfunction

IsoniazidIsoniazidAmphotericin BAmphotericin B

Inhibitors of Inhibitors of nucleic acid nucleic acid function or function or synthesissynthesis

FluoroquinolonesFluoroquinolonesRifampinRifampin

Inhibitors of Inhibitors of metabolismmetabolism

SulfonamidesSulfonamidesTrimethoprimTrimethoprim

Inhibitors of cell Inhibitors of cell wall synthesiswall synthesis

-Lactams-LactamsVancomycinVancomycin

Inhibitors of Inhibitors of protein synthesisprotein synthesis

TetracyclinesTetracyclinesAminoglycosidesAminoglycosidesMacrolidesMacrolidesClindamycinClindamycinChloramphenicolChloramphenicol

ATB - MA

(according to Lippincott´s Pharmacology, 2009)(according to Lippincott´s Pharmacology, 2009)

Summary of antimicrobial agents affecting cell wall synthesis

Agents affecting the cell wall -lactamase

inhibitors

-lactam antibiotics Other antibiotics

Penicillins Cephalosporins Carbapenems Monobactams

1st generation 2nd generation 3rd generation 4th generation

BacitracinVancomycinDaptomycin

Clavulanic acidSulbactamTazobactam

AmoxicillinAmpicillinDicloxacillinIndanyl carbenicillinMethicillinNafcillinOxacillinPenicillin GPenicillin VPiperacillinTicarcillin

ErtapenemImipenem/cilastatin*Meropenem

Aztreonam

CefepimeCefadroxilCefazolinCephalexin

CefaclorCefprozilCefuroximeCefoxitin

CefdinirCefiximeCefotaximeCeftazidimeCeftibutenCeftizoximeCeftriaxone

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

Gram+

-laktamázy

Proteiny vážící penicilin

Cytoplazmatická membrána

Periplazmatický prostor

Peptidoglykanová vrstva

Grampozitivní bakterie

Gram-Gramnegativní bakterie

Zevní membrána

Poriny

-laktamázy

Proteiny vážící penicilin

Cytoplazmatická membrána

Periplazmatický prostorPeptidoglykanová vrstva

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

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.

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).

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

– 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 30-60 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 0.5-1.0

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.

Adverse reactions• Nephritis – acute intersititial

– 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)

beta-lactamase inhibitors

• 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

Clav. acid

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 !!!

Cephalosporins

• -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 -Iactamases. • Antibacterial spectrum

– Classified as first, second, third, or fourth generation,• based largely on their bacterial susceptibility patterns and

resistance to -Iactamases. – ineffective against MRSA, L. monocytogenes, Clostridium

difficile, and the enterococci.

cephalexin

Summary of antimicrobial agents affecting cell wall synthesisSummary of antimicrobial agents affecting cell wall synthesis

INHIBITORS OF CELLINHIBITORS OF CELLWALL SYNTHESISWALL SYNTHESIS -LASTAMASE-LASTAMASE

INHIBITORSINHIBITORS

-LASTAMASEANTIBIOTIC

OTHERANTIBIOTIC

PENICILLINS CEPHALOSPORINS CARBAPENEMS MONOBACTAMS

1st GENERATION 2nd GENERATION 3rd GENERATION 4th GENERATION

Clavulanic acidSulbactamTazobactam

BacitracinVancomycin

Imipenem/cilastatinMeropenem*Ertapenem

Aztreonam

Cefepime

AmoxicillinAmpicillinCloxacillinDicloxacillinIndanyl carbenicillinMethicillinNafcillinOxacillinPenicillin GPenicillin VPiperacillinTicarcillin

CefadroxilCefazolinCephalexinCephalothin

CefaclorCefamandoleCefprozilCefuroximeCefotetanCefoxitin

CefdinirCefiximeCefoperazoneCefotaximeCeftazidimeCeftibutenCeftizoximeCeftriaxone

(according to Lippincott´s Pharmacology, 2006)(according to Lippincott´s Pharmacology, 2006)

PharmacodynamicsFirst 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

Pharmacodynamics • Third 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.

Adverse effects• Allergy:

– 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.

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 -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

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. • 90 - 100 % excreted by glomerular filtration

– adjust dosage in renal failure – accumulation of the drug– normal half-life: 6-10 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• 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

Daptomycin– 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

Topical ATBBacitracin• 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

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

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

Aktivovanáaminokyselina

Volná tRNA

Donorové místo(petidylové)

mRNA

Akceptorové místo(aminoacylové)

tRNA

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, 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.

Doxycycline

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

– 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

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

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

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

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

Aminoglycosides• Concentration-dependent killing

– 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

• !!! perform TDM – 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

(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.

Gentamicin

S. Croes et al. / European Journal of Pharmaceutical Sciences 45 (2012) 90–100

Aminoglycosides• Ototoxicity:

– 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).

Aminoglycosides

• Neuromuscular paralysis • 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.

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

– 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

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:

– 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.

Macrolide antibiotic

• Metabolism: – 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!

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

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

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

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

– 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“

Chloramphenicol• 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!!

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

– 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.

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

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

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

– 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 -Iactams;

– resistant tuberculosis – typhoid fever

• in third world countries

Fluoroquinolones• Norfloxacin

– 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

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 35 - 70 % 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

Fluoroquinolones - AE• well tolerated • GIT: the most common

– 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 – 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).

(according to Lippincott´s (according to Lippincott´s Pharmacology, 2006)Pharmacology, 2006)

Pteridine precursor + pAminobenzoic acidPteridine precursor + pAminobenzoic acid (PABA)(PABA)

Amino acidAmino acidsynthesissynthesis

PurinePurinesynthesissynthesis

ThymidineThymidinesynthesissynthesis

MicroorganismsMicroorganisms Humans and microorganismsHumans and microorganisms

HH22NN

HH22NN

COOHCOOH

SS

OO

OO

SulfanilamideSulfanilamide(and other(and other

sulfonamides)sulfonamides)

TrimethoprimTrimethoprim

Folic acidFolic acid

GlutamateGlutamate

Tetrahydrofolic Tetrahydrofolic acidacid

Dihydro-Dihydro-pteroatepteroatesynthetasesynthetase

Dihydro-Dihydro-folatefolatereductasereductase

2 NADPH 2 NADPH + 2 H+ 2 H++ 2 NADPH 2 NADPH

NHRNHR

Inhibition of tetrahydrofolate synthesis by sulfonamides and trimethoprim

Sulfamethoxazole

Trimetoprim

PABA

DHF

Sulfonamides

• Bacteriostatic– 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

Sulfonamides• well absorbed after oral administration

– 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.

Sulfonamides1. Well absorbed orally, short-acting:

– Sulfadiazine, – Sulfadimidine, Sulfisoxazole, Sulfamethoxazole

2. Well absorbed orally, long-acting: – Sulfamethopyrazine

3. Poorly absorbed in GIT: Sulfasalazine (sulfapyridine)

4. Used topically: Silver sulfadiazine, sulfacetamide

Sulfonamides - AE

• Nephrotoxicity – 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

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.

Trimethoprim

• 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 20- 50 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).

Trimethoprim• 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) !!!

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.

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

– Administered orally – distributed throughout the body fluids – but safe

• no decomposition of the drug occurs at pH 7.4 - 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 !!!• COI - patients with hepatic insufficiency

– 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 –– 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 10-20 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

– 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.

(according to Lippincott´s Pharmacology, 2009)

Summary of drugs used to treat mycobacterial

infections.ANTIMYCOBACTERIAL AGENTS

Drugs used to treat tuberculosis

Drugs used to treat leprosy

EthambutolIsoniazidPyrazinamideRifamycins

First-line drugs

AminoglycosidesAminosalicylic acidCapreomycinCycloserineEthionamideFluoroquinolonesMacrolides

Second-line drugs

ClofazimineDapsoneRifampin

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.

(according to Lippincott´s Pharmacology, 2009)

Cumulative percentage of strains of Mycobacterium tuberculosis showing resistance to streptomycin

0

50

100

Per

cent

age

resi

stan

t

0 40 80 120

Days after initiation of treatment

(according to Lippincott´s Pharmacology, 2009)

One of several recommended multi-drug schedules for the treatment oftuberculosis

Intensive phase Continuation phase

Isoniazid

Rifampin

Pyrazinamide

Ethambutol orstreptomycin

0 1 2 3 4 5 6Months

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, -hydroxylated fatty acids found in mycobacterial cell walls

– Covalent blockade of synthetic enzymes– enoyl acyl carrier protein reductase (InhA) and a -ketoacyl-ACP synthase

(KasA)• Narrow spectrum

– Bactericidal in rapidly growing mycobacteria

Isoniazid - PK

• Readily absorbed– Food and antacides impair.

• Distributed equally– Easily penetrates cells, even into CNS

• Undergoes N-acetylation– Inactivation – slow acetylators – accumulation– Metabolites - urine

(according to Lippincott´s Pharmacology, 2009)

Bimodal distribution of isoniazid half-lives caused by rapid and slowacetylation of the drug

In rapid acetylators, isoniazid has a short half-life (~1hr)

In slow acetylators, isoniazid has a long half-life (~3 hrs)

50 100 150 200 250Half-life (min)

0

10

20

Nu

mb

er

of s

ub

ject

s

Isoniazid - AE– 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

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

Rifamycins - AE– 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

Pyrazinamide• orally effective, bactericidal

– 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

Ethambutol• bacteriostatic

– 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

(according to Lippincott´s Pharmacology, 2009)

Summary of antifungal drugs. ANTIFUNGAL DRUGS

Drugs for subcutaneous and systemic mycoses

Drugs for cutaneous mycoses

VoriconazolePosaconazoleMicafunginKetoconazoleItraconazoleFlucytosineFluconazoleCaspofunginAnidulafunginAmphotericin B

TerconazoleTerbinafineNystatinMiconazoleGriseofulvinEconazoleClotrimazoleButoconazole

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

Amphotericin B - AE• Fever and chills

– 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

Azole antimycotics• Ketoconazole, itraconazole, fluconazole, voriconazole• Fungistatic - inhibit C-14 -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

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

(according to Lippincott´s Pharmacology, 2009)

Summary of some azole fungistatic drugs.

KETOKONAZOLE FLUCONAZOLE VORICONAZOLE POSACONAZOLE

Spectrum Narrow Expanded Expanded Expanded

Route(s) of administration Oral Oral, IV Oral, IV Oral

t1/2 (hours) 6-9 30 6-24 20-66

CSF penetration No Yes Yes Yes

Renal excretion No Yes No No

Interaction with other drugs Frequent Occasional Frequent Frequent

Inhibition of mammalian

sterol synthesis

Dose-dependent inhibitory effect No inhibition No inhibition No inhibition

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 (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

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 - 200 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.

Griseofulvin

• dermatophytic infections of the nails– Largely replaced by terbinafine for the treatment.

• Fungistatic - requires treatment of 6 - 12 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