Download Bez nadpisu - Dr.Fatimah Al.Shehri

ANTIBIOTICS
2014
Fatimah al-shehri,pharm.D
ANTIBIOTICS
• 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
Inhibition of DNA gyrase:
RNA polymerase
Inhibition of protein synthesis:
Inhibition of folic acid
metabolism:
Penicillins
Cephalosporins
Monobactams
Vancomycin
Quinolones
Rifampicin
Aminoglycosides
Tetracyclines
Erythromycin
Chloramphenicol
Trimethoprim
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, weight,
• allergies, genetic factors,
– Type B AE -
• sex (pregnant, lactating women),
– Type D AE -
• renal and hepatic function,
– Type A AE -
• concurrent medication
– Interactions -
Drug factors
• Cidal vs. Static
• antibacterial spectrum
– (narrow-spectrum, broad-spectrum activity, Grampositives Gram-negatives),
• pharmacokinetics
– Route of administration, penetration to infection
site,
• adverse effects, drug interactions,
convenience, 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 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
Direct toxicity – type A, B
Superinfections – type A
Resistance – primary, secondary, cross-
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.
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.
ATB - MA
CELL WALL
CELL MEMBRANE
DNA
THFA
PABA
Inhibitors of
metabolism
Sulfonamides
Trimethoprim
Inhibitors of cell
wall synthesis
b-Lactams
Vancomycin
Ribosomes mRNA
Inhibitors of
protein synthesis
Tetracyclines
Aminoglycosides
Macrolides
Clindamycin
Chloramphenicol
Inhibitors of cell
membrane
function
Isoniazid
Amphotericin B
Inhibitors of
nucleic acid
function or
synthesis
Fluoroquinolones
Rifampin
(according to Lippincott´s Pharmacology, 2009)
Summary of antimicrobial agents affecting cell wall
synthesis
Agents affecting
the cell wall
b-lactam antibiotics
b-lactamase
inhibitors
Clavulanic acid
Sulbactam
Tazobactam
Other antibiotics
Bacitracin
Vancomycin
Daptomycin
Penicillins
Amoxicillin
Ampicillin
Dicloxacillin
Indanyl carbenicillin
Methicillin
Nafcillin
Oxacillin
Penicillin G
Penicillin V
Piperacillin
Ticarcillin
Cephalosporins
Carbapenems
Ertapenem
Imipenem/cilastatin*
Meropenem
1st generation
Cefadroxil
Cefazolin
Cephalexin
2nd generation
Cefaclor
Cefprozil
Cefuroxime
Cefoxitin
Monobactams
Aztreonam
3rd generation
Cefdinir
Cefixime
Cefotaxime
Ceftazidime
Ceftibuten
Ceftizoxime
Ceftriaxone
4th generation
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
Penicillin G
• 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 - 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.
NATURAL PENICILLINS (narrow
spectrum)
• PENICILLIN G (benzylpenicillin)
– a number of gram-positive and gram-negative cocci, grampositive 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
– a spectrum similar to penicillin G,
– not used for treatment of septicemia because of its higher
minimum bactericidal concentration (MLC).
– is more acid-stable than penicillin G – is for p.o.
Antistaphylococcal penicillins
• methicillin
• Oxacillin*
• nafcillin, cloxacillin, dicloxacillin
• penicillinase-resistant PNCs
oxacillin
• treatment of infections caused by penicillinaseproducing staphylococci.
• Methicillin-resistant strains (MRSA)
– usually susceptible to vancomycin
• rarely to ciprofloxacin, rifampin
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.
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.
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 are.
• 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
– [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 !
• Diarrhea:
– Disruption of saprophytes
– Especially in agents that are incompletely absorbed or with extended
spectrum.
– pseudomembranous colitis may occur.
Adverse reactions
• Nephritis
– acute interstitial nephritis in high doses of 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
Clav. acid
– contain a beta lactam ring,
– do not have significant antibacterial activity
• bind to and inactive beta-lactamases
– 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.
•
•
•
•
AUGMENTIN (amoxycillin and clavulanic acid)
TIMENTIN (ticarcillin and clavulanic acid)
Piperacillin + tazobactam
Ampicillin + sulbactam
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
ANTIBIOTIC
b-LASTAMASE
INHIBITORS
OTHER
ANTIBIOTIC
Clavulanic acid
Sulbactam
Tazobactam
Bacitracin
Vancomycin
PENICILLINS
Amoxicillin
Ampicillin
Cloxacillin
Dicloxacillin
Indanyl carbenicillin
Methicillin
Nafcillin
Oxacillin
Penicillin G
Penicillin V
Piperacillin
Ticarcillin
CEPHALOSPORINS
CARBAPENEMS
Imipenem/cilastatin
Meropenem*
Ertapenem
1st GENERATION
2nd GENERATION
Cefadroxil
Cefazolin
Cephalexin
Cephalothin
Cefaclor
Cefamandole
Cefprozil
Cefuroxime
Cefotetan
Cefoxitin
MONOBACTAMS
Aztreonam
3rd GENERATION 4th GENERATION
Cefdinir
Cefixime
Cefoperazone
Cefotaxime
Ceftazidime
Ceftibuten
Ceftizoxime
Ceftriaxone
Cefepime
(according to Lippincott´s Pharmacology, 2009)
Pharmacodynamics
First generation:
• cephalexin, cephalotin, 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, cefoxitin
• 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; cefoxitin is the most potent.]
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.
– Ceftriaxone or cefotaxime
• agents of choice in the treatment of meningitis.
– Ceftazidime - against Pseudomonas aeruginosa.
• 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 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 to PNCs should not
receive cephalosporins
– with caution in individuals who are allergic to PNCs - cca 15 % show
cross-sensitivity
• In contrast, the incidence of allergic reactions to cephalosporins is 1-2 % in
patients without a history of allergy to PNCs.
• Disulfiram-like effect
– cefamandole, cefoperazone if ingested with alcohol or alcoholcontaining 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
• 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
– High levels of especially imipenem may provoke seizures
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 with
antibodies induced by other beta-lactam - an alternative for
patients allergic to penicillin.
ATB - Glycopeptides
• vancomycin,
• teicoplanin, telavancin, dalbavalcin (similar, longer acting)
• Reduce cell wall synthesis
– bactericidal
– prevents the transglycosylation step in peptidoglycan
polymerization
• Indications (G+) MRSA, MRSE, 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.
– quinopristin/dalfopristin and linezolid for vancomycinresistant
• Oral vancomycin
– limited to treatment for potentially life-threatening
antibiotic-associated colitis due to C. difficile or
staphylococci.
vancomycin
• Slow i.v. infusion
– 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
– often 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”)
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.
ATB - Glycopeptides
• Dalbavalcin
– 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.
• Telavancin
• A semisynthetic lipoglycopeptide derived from vancomycin.
– Active versus G+ bacteria, incl. strains with reduced susceptibility to
vancomycin.
– T1/2 approx. 8 hrs once-daily i.v. dosing
– 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.
daptomycin
– Cyclic lipopeptide fermentation product of Streptomyces roseosporus.
• treatment of resistant G+ incl. MRSA and VRE
– (vancomycin-resistant enterococci).
• bactericidal - concentration-dependent killing;
– admin. i.v. via infusion
• Mechanism: probably depolarisation of cell membrane
– K efflux and death; inhibition of DNA, RNA, protein synthesis.
•
Complicated skin infection, endocarditis, bacteriemia by S. Aureus
– not for pneumonia (inactivated by pulmonary surfactans).
• 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 ATB
Bacitracin
• a mixture of polypeptides - inhibits bacterial cell wall synthesis
• 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.
PROTEIN SYNTHESIS INHIBITORS
TETRACYCLINES
Demeclocycline
Doxycycline
Minocycline
Tetracycline
AMINOGLYCOSIDES
Amikacin
Gentamicin
Neomycin
Netilmicin
Streptomycin
Tobramycin
MACROLIDES/KETOLIDES
Azithromycin
Clarithromycin
Erythromycin
Telithromycin
CHLORAMPHENICOL
CLINDAMYCIN
QUINUPRISTIN/DALFOPRISTIN
LINEZOLID
(according to Lippincott´s
Pharmacology, 2009)
Tetracyclines
• Doxycycline, Tigecyclin
Doxycycline
– 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.
• bind reversibly to the 30S subunit of the
bacterial ribosome
– block access of the amino acyl-tRNA to the mRNAribosome complex at the acceptor site.
Tetracyclines
• Broad spectrum antibiotics
– G+ and G– also effective against intracellular organisms - drugs of
choice for rickettsial, mycoplasma and chlamydial
infections.
• 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.
– The majority of penicillinase-producing staphylococci
are now also insensitive to tetracyclines
• Tigecycline develop to overcome TTC resistance
Tetracyclines - PK
• 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
– 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
Tetracyclines - PK
• Metabolism - lipophilic
– Concentrate in liver, glucuronidation,
– Excreted to bile – enterohepatic recycling
• 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
• Phototoxicity
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.
• 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
Aminoglycosides
• amikacin, gentamicin, tobramycin and streptomycin
– Commonly used aminoglycosides
– Other aminoglycosides
• neomycin, netilmicin, kanamycin
• 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
– susceptible organisms have an oxygen-dependent system that
transports the ATB across the cell membrane.
– bind to the isolated 30S ribosomal subunit
Aminoglycosides
• Concentration-dependent killing +
postantibiotic effect
– Cmax, TDM, immunity - polymorphonucleares
– Once daily dosing prevents toxicity
– The exceptions are pregnancy, neonatal infections,
and bacterial endocarditis - administered every
eight hours.
• 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 – only topical – severe nephrotoxic
• 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
– gentamicin, tobramycin, netilmicin, and amikacin
to
– Cmax - Cmin
• 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 acummulation,
Aminoglycosides
• Ototoxicity:
– directly 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
– 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 (methylated form of erythrom.)
• telithromycin - derivative of erythromycin (a
ketolide)
– spiramicin, yosamicin
• ATBs with a macrocyclic lactone structure
– to which one or more deoxy sugars are attached.
• ERYTHROMYCIN
– few indications where it is a drug of first choice,
– mostly as an alternative to penicillin in allergy to betalactam 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
–
–
–
–
as PNC G - especially G + bacteria and spirochaetes, N.gonorrhoae
used in patients allergic to the PNCs
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.
– 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,
• IV erythromycin - high incidence of thrombophlebitis, intramuscular
injections are painful.
– 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; the drug is concentrated
in neutrophils, macrophages, and fibroblasts. It has the longest
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:
– 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
• Erythromycin, telithromycin, and clarithromycin inhibit the
hepatic metabolism of a number of drugs, which can lead to
toxic accumulations of these compounds.
• E.g., theophylline, warfarin, carbamazepine, cyclosporine and
statins
• Interaction with digoxin may occur in some patients - ATB
eliminates a species of intestinal flora that ordinarily
inactivates digoxin
– greater reabsorbtion and lower secretion by MDR1
quinupristin/dalfopristin
– 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 (incompatibility with saline).
• 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: Total bilirubin is elevated in about 25% of patients,
resulting from a competition with the antibiotic for excretion.
Interactions
Ability of quinupristin/dalfopristin to inhibit CYP3A4 isozyme - concomitant
administration with drugs metabolized by this pathway may lead to
toxicities.
Interaction with digoxin - the same mechanism as in erythromycin.
linezolid
• New ATB; against resistant G+ organisms
– (e.g., methicillin- and vancomycin-resistant S. aureus,
vancomycin-resistant Enterococcus faecium and
Enterococcus faecalis, and PNC-resistant streptococci).
• 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
C. Antibacterial spectrum
– Primarily against G+ organisms
• e.g., staphylococci, streptococci, and enterococci, as well as Corynebacterium
species and Listeria monocytogenes) - its main clinical use.
• Moderately active against Mycobacterium tuberculosis.
– Bacteriostatic (cidal against the streptococci and Clostridium
perfringens).
D. 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.
linezolid
• Adverse effects
–
–
–
–
Well-tolerated.
GIT upset, nausea, and diarrhea
headache and rash
thrombocytopenia in cca 2 % (when longer than 2 weeks) reversible.
– Although no reports on linezolid inhibition of MAO activity
- patients are cautioned not to consume large quantities of
tyramine-containing foods. (early oxazolidinones showed
to inhibit MAO activity - reversible increase in the pressor
effects of pseudoephedrine was shown).
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,
• protein synthesis in these organelles may be inhibited at high circulating
chloramphenicol levels - producing 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) and
• 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.
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
Metronidazol
• Inhibition of DNA replication in microorganism
• Spektrum
– Anaerobes, Trichomonas vaginalis and Entamoeba histolytica, C.
difficile.
• PK
– P.o. excellent absorption, penetrate bones teeths, CNS abscesses/CSF;
placenta milk.
– Metabolized in liver,kidney excretion.
• For infections caused by Bacteroides fragilis, anaerobes in
abdominal cavity, diarhea by C. difficile, cerebral abscesses,
trichomodal inf.
Choice for tetanus.
• AE:
– Metalic taste, GIT, dizzines, vertigo , headache, depression, dark urine,
dissulfiram like effect – COI alcohol, pregnancy 1st trimester
Rifampin
• Broad spectrum
– G+ and G-, meningococci, H. influenzae
– Including treatment of tuberculosis, leprosy – in combinations
• Bactericidal
– Blocks bacterial DNA-dependent RNA polymerase - inhibits RNA synthesis.
• Absorbed after p.o. administration.
• Good distribution
– adequate levels in CSF even in the absence of inflammation.
• Enterohepatic circulation.
• Induce activity of hepatic enzymes/transporters
– it shortens its half-life (i.e. autoinduction)
– Therapy of cholestasis
• Elimination: via the bile into feces or via urine.
– have an orange-red color.
Rifampin
• Adverse effects:
– mostly a minor problem: nausea, vomiting, rash,
and fever.
– jaundice can occur in patients with hepatopathy,
alcoholics, and the elderly.
• Interactions:
– Induction of cytochrome P450 enzymes
• - it can decrease the half-lives of other coadministered;
higher dosage of these drugs may be necessary.
• E.g., clofibrate, digoxin, ketoconazole, sulfonylureas,
warfarin, oral contraceptives, prednisone, quinidine,
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 bacteriua 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, Legionellaceae, chlamydia, and
mycobacteria - except for M. avium intracellulare complex
• Effective in the treatment of gonorrhea but not syphilis.
• The newer agents - mocifloxacine, levofloxacin, gatifloxacin,
sparfloxacin
– good activity against some G+ organisms
• (e.g., Streptococcus pneumoniae).
– Activity against some anaerobes
Fluoroquinolones
• First-generation quinolones
– nalidixic acid
– moderate G- - minimal serum concentrations
– uncomplicated urinary tract infections
• Second-generation
–
–
–
–
Ciprofloxacin, levofloxacin, norfloxacine,
Extended G- activity;
also some activity against G+
atypical organisms
• e.g., Mycoplasma pneumoniae and Chlamydia pneumoniae,
legionella.
• Bacillus anthracis - Ciprofloxacin
Fluoroquinolones
• Third-generation
– Sparfloxacin , gatifloxacin
– retain expanded G- activity;
– improved activity against atypical organisms and specific G+ bacteria.
• Fourth-generation
– Moxifloxacine, trovafloxacin
– 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
• (excepting serious infections by MRSA, enterococci, and
pneumococci).
• Useful in treating infections caused by many Enterobacteriaceae and
other G- bacilli. E.g., traveler's diarrhea caused by E. coli
– Drug of choice for prophylaxis and treatment of anthrax.
– The most potent of the fluoroquinolones for P. aeruginosa
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;
– also of benefit in treating resistant tuberculosis.
Fluoroquinolones
• Norfloxacin
– Not effective in systemic infections.
• More potent than nalidixic acid, effective against both gramnegative (including Pseudomonas aeruginosa) and gram-positive
organisms.
• complicated and uncomplicated UTIs and prostatitis.
• Levofloxacin
– an isomer of ofloxacin.
– Primarily used in the treatment of prostatitis due to E. coli
and of sexually transmitted diseases (excepting syphilis).
• An alternative therapy in patients with gonorrhea.
– Very good activity against respiratory infections due to S.
Pneumoniae.
Fluoroquinolones
• Gatifloxacin
– Very good activity against respiratory infections due to S.
pneumoniae.
• Trovafloxacin, moxifloxacin
– Enhanced activity against G+ organisms
• (e.g., S. Pneumoniae) and also excellent activity against anerobes
(e.g., Bacteroides fragilis).
– P. aeruginosa
• trovafloxacin, the antibiotic is usually combined with
aminoglycosides
• Moxifloxacin has very poor activity against P. aeruginosa.
– Trovafloxacin – serious hepatotoxicity – it should be
restricted to life-threatening inf.
Fluoroquinolones - PK
- Absorption: 85 to 95 % after p.o.
- (exception - only 35 - 70 % of norfloxacin is absorbed).
- I.v. preparations of new 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.
- Penetration into CSF is low (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, sparfloxacin, and trovafloxacin
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:
– Discontinue therapy 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.
• In adults - they can infrequently cause ruptured tendons.
• Sparfloxacin and moxifloxacin prolong the QT interval
Fluoroquinolones
• Contraindications:
– Sparfloxacin and moxifloxacin (prolong the QT interval) not use in those who are predisposed to arrhythmias or
are taking antiarrhythmics.
• Drug interactions:
– The effect of antacids and cations on the absorption (see
above).
– The second, third- and fourth-generation inhibition of drug
metabolism - may raise the serum levels of warfarin,
theophylline, caffeine, and cyclosporine.
• Cimetidine interferes with elimination of the fluoroquinolones.
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).
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 5aminosalicylate - 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.
• Exceprion - 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
1. 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
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 = cotrimoxazole.
– 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
• 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.
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.
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.
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 enoyl acyl carrier protein reductase (InhA)
and a b-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
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
– Hepatitis and idiosyncratic hepatotoxicity
• Due toxic metabolite;
• more frequent in alcoholics, rifampin
– Optic neuritis, seizures
• rare
• 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
• fluoroquinolones
– moxifloxacin and levofloxacin,
– treatment of multidrug- resistant tuberculosis
• para-aminosalicylic acid
– Competitive inhibitor resembling PBA
• ethionamide
– Analogue of isoniazide – similar issues
• cycloserine
– Inhibits cell-wall synthesis – seizures, neuropathies (respond to pyridoxine)
• capreomycin
– Parenterally - reserved for multidrug-resistant tuberculosis.
– monitoring - nephrotoxicity and ototoxicity.
• Macrolides
– Azithromcin and clarithromycin – M. avium
Summary of antifungal
drugs.
ANTIFUNGAL DRUGS
Drugs for subcutaneous
and systemic mycoses
Voriconazole
Posaconazole
Micafungin
Ketoconazole
Itraconazole
Flucytosine
Fluconazole
Caspofungin
Anidulafungin
Amphotericin B
(according to Lippincott´s
Pharmacology, 2009)
Drugs for cutaneous
mycoses
Terconazole
Terbinafine
Nystatin
Miconazole
Griseofulvin
Econazole
Clotrimazole
Butoconazole
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 a 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.
• anaphylaxis, convulsions
– Small test dose initially
• Renal impairment
– in glomerular filtration and tubular function, loss of K a Mg.
– Adequate hydration is necessary.
• Hypotension
– A shock-like fall in BP with hypokalemia requiring K supplementation
• 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
synthesis.
nucleic acid and protein
• 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 a-demethylase (P450)
– block demethylation of lanosterol to ergosterol – disruption of membrane structure and function
• Spectrum
– many fungi, incl. histoplasma, blastomyces, candida, coccidioides, but
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 subcutaneous
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 immunocpmpromised - posa
Summary of some azole fungistatic drugs.
(according to Lippincott´s Pharmacology,
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
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)
• 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.
• induces hepatic CYP450 activity
– Number of interactions. e.g., oral antosoagulant 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 a.
– 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).