2010-04-10
Antimicrobial
drugs
Michał Karbownik
Department of Pharmacology
E. coli
Medical University of Łódź
I. PRINCIPLES
1. Review of microbiology
2. Antimicrobial agents
3. Mechanisms of action
4. Rational antimicrobial therapy
5. Selection of antimicrobial agents
1. Review of microbiology
Gram staining
Gram positive
Gram negative
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Bacteria cell shape
Other characteristics of bacteria
Aerobic and anaerobic organisms
•
•
•
•
•
Obligate anaerobes (e.g. Bacteroides fragilis)
Aerotolerant organisms
Facultative anaerobes
Microaerophiles
Obligate aerobes
Sporing organisms
• e.g. Bacillus, Clostridium
Intracellular infections
•Mycobacterium
•Rickettsiae, Coxiella, Chlamydia
2. Antimicrobial agents
- are used to treat infections caused by
microorganisms, including fungi and protozoa
Antibiotics
Chemotherapeutics
• Antagonistic to the growth of bacteria
• Natural compounds or their derivatives
• Act in high dilution (≠ gastric juice,
hydrogen peroxide)
• Synthetic
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Classification of antimicrobial agents
•Chemical structure:
Beta-lactam
Glycopeptides
Aminoglycosides
Macrolides
Tetracycline
Others
•Mechanism of action
Inhibitors of cell wall synthesis
Inhibitors of protein synthesis
Others
•Effect of action
•Spectrum of action
3. Mechanisms of action
Selective toxicity
bacterium cell
human cell
Sites of Action of Different Types of
Antibacterial Drugs
Inhibition
of methabolism
Inhibition
of protein
synthesis
Inhibition
of nucleic
acid
function
Inhibition
of cell
membrane
function
Inhibition
of cell wall
synthesis
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Different effects –
Bacteriostatic and bactericidal drugs
Addition of drug
Effects of bactericidal and bacteriostatic
agents on the growth of bacteria in vitro
MIC – Minimum Inhibitory Concentration
MBC – Minimum Bactericidal Concentration
MIC – the lowest concentration of antibiotic that inhibits
bacterial growth
MBC – the lowest concentration of antibiotic that results in
99,9% killed bacteria
Bactericidal
Bcteriostatic
Chemotherapeutic spectra
e.g.
Isoniasid
Nalidixic acid
e.g.
Ampicilin
Co-trimoxazole
e.g.
Tetracycline
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Antibiotic action
Flash of
lightning
Antibiotics act slowly
Constant drug concentration
MIC
Rigorous drug administration
(every few houres)
Three times daily (tid)
Every 8 houres (q8h)
Twice daily (bid)
Every 12 houres (q12h)
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Concentration--dependent killing
Concentration
high peak levels
MIC
Drug administration
Concentration--dependent killing
Concentration
Once-a-day bolus infusion:
•Aminoglycosides
•Fluorochinolones
No concentration-dependent killing:
•β-lactams
•Glycopeptides
•Macrolides
•Clindamycin
Post--antibiotic effect (PAE)
Post
MIC
Persistent suppresion
of microbial growth:
Drug administration
•Aminoglicosides
•Fluoroquinolones
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Adverse effects
1. Relative selective toxicity:
Protein synthesis inhibitors
Mitochondrial ribosomes
2. Direct toxicity
3. Hypersensitivity
4. Superinfections (overgrowth of opportunistic organisms)
5. Absorption of other substances (e.g. contraceptives)
4. Rational antimicrobial
therapy
• When should we use
antimicrobial drugs?
• Drug resistance
• When should we use
antimicrobial drugs?
1. Treatment of
pathogen infection
Phisiological flora of:
•skin
•GI tract
•GU tract, etc.
Viral infections
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2. Prophylaxis
Restricted to clinical situations in which the benefits
outweigh the potential risk
A. Patients with history of rheumatic heart disease
B. Patients undergoing dental extractions
C. Prevention of tuberculosis or meningitis
D. Prior to certain surgical procedures
E. Treatment of pregnant HIV-infected mothers to
prevent the child from infection
• Drug resistance
Maximum
antibiotic level
tolerated by
the host
Bacteria
•Inherent resistance
•Acquired resistance
Acquired bacteria resistance
Genetic alterations
•
•
Spontaneous mutation of DNA (rifampicin-resistant
Mycobacterium tuberculosis
DNA transfer (resistance plasmids)
Altered expresions of proteins
•
•
•
Modification of target sites (β-lactam-resistant
Streptococcus pneumoniae – altered penicilin-binding
protein)
Decreased drug accumulation (decreased uptake,
increased efflux: gram-negative bacteria to β-lactams,
tetracyclines, chloramphenicol)
Enzymic inactivation (β-lactamases, acetyltransferases –
aminoglycosides, esterases – macrolides)
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Consequences of drug resistance
•Prolonged infections
•Increased recovery time and cost of treatment
•More toxic and less effective treatment needed
•Higher mortality rates
How to avoid drug resistance
spreading?
spreading
?
A. Prescribe antimicrobial drugs only if necessary
Antibiotics do not cure patients with viral infection.
Be careful! Patient can force you to prescribe antibiotic.
B. Prescribe antimicrobial drugs for the proper period of time
C. Make certain that patient understands the therapy and will
•not skip or delay doses
•complete antibiotic course
•not borrow the prescribed antibiotic to someone else
• Drug
resistance
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5. Selection of antimicrobial
agents
Organism’s identity
Susceptibility to a particular agent
Site and severity of the infection
Patient factors
Safety of the agent
Cost of therapy
Organism’s identity
Laboratory techniques useful in diagnosis
of microbial diseases:
•Direct microscopic visualisation
•Cutivation and identification
•Detection of microbial antigens
•Detection of RNA or DNA
•Detection of host immune response
Susceptibility to a
particular agent
Some pathogens have predictable susceptibility
patterns to certain anticiotics, however, …
Unpredictable susceptibility patterns show:
•Gram-negative bacilli
•Enterococci
•Staphylococci
Antibiotics diffuse out from
antibiotic-containing disks and
inhibit growth of S. aureus
resulting in a zone of inhibition
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Specimen collection
Empiric
therapy
TREATMENT
Antimicrobial
susceptibility testing
Diagnosis
Empiric therapy
For critically ill patients drugs should be
administrated without waiting for the diagnostic report.
Criteria of drug selection:
•Site of infection
•Patient’s history
•Clinical knowledge
Broad-spectrum antibiotic should be prefered initially. Antibiotic
therapy can be modified after antimicrobial susceptibility testing
is done.
Empiric therapy
Pneumonia
1. the nature of the pneumonia:
•
Sudden onset (within a few houres)
Str. pneumoniae, H. influenzae
•
Intermediate onset (within a few days)
Mycoplasma pneumoniae, Chlamydiae, viruses
•
Prolonged onset (within a few weeks)
Mycobacterium tuberculosis, fungi
A chest X-ray showing a very
prominent wedge shaped
pneumonia in the right lung.
2. the place of the infection
•
Community-acquired
Str. pneumoniae, Mycoplasma pneumoniae, H. influenzae, influenza viruses
•
Hospital-acquired
E. coli, Pseudomonas aeruginosa
3. the local geografic area
4. the immune status
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Site and severity of the infection
Antibiotic must
reach the site of
infection
•Central nervous system
•Prostatic tissue
•Vitreous body of the eye
Blood-Brain Barrier
BBB
•Bone tissue
•Saliva
Blood--brain barrier
Blood
Single layer of tile-like
endothelial cells
– poor permeability
Only
•small
•lipophillic
•unbond with plasma proteins
agents can be transfered
Part of a network of capillaries
supplying brain cells
Route of administration
Oral (p.o.)
•Mild infections
•Economic conditions
Intravenous (i.v.)
•Serious infections (switch to oral agent as soon
as possible)
•Antibiotis i.v. administrated only (vancomycin,
aminoglicosides)
Topical
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Bacteriostatic or bactericidal?
bactericidal?
Bactericidal
Bacteriostatic
Seriously ill patients,
Immunocompromised,
+
–
Eldery patients
Single or combinated agent?
Single:
1. Reduces the possibility of superinfection
2. Decreases the emergence of resistant organisms
3. Minimizes toxicity
Combined:
1. Synergism (cidal+cidal, static+static only)
2. Infection of unknown origin
3. to support the traetment (tuberculosis)
Patient factors
Immune system
•Higher-than-usual doses
•Bacetricidal agents
•Longer courses
should be administrated to immunocompromised patiens (alcoholic,
diabetic, HIV, malnutritioned, taking immunosupresing therapy)
Kidneys
Renal disfunction can cause drug accumulation..
Liver
Antibiotic excreted via renal route should be preffered.
Circulation
Poor perfusion to distant part of body (diabetic patiens) can cause
the therapy being ineffective.
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Patient factors
Age
Methabolism and elimination is poorly developed in newborns.
Children are vulnerable to some drugs accumulating in growing
tissues.
Pregnancy
Antibiotics cross the placenta.
Adverse effects can be possible.
Lactation
Drugs may enter the nursing infant via the breast milk.
Safety of the agent
•Some antibiotics are among the least toxic of all drugs
(interfere with the unique site of bacteria cell)
•Some are reserved for life-threatening infections or
applied topically because of their toxicity.
Cost of therapy
Ambulatory care
Hospital care
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II.
ANTIMICROBIAL
AGENTS
GROUPS
1. Inhibitors of cell
wall synthesis
Classification
Inhibitors of cell wall synthesis:
1. β-lactam antibiotics
Penicillins
Cephalosporins
Carbapenems
Monobactams
2. Other antibiotics
Glycopeptides
Fosfomycin
Bacitracin
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β-lactam antibiotics
A. Penicillins
Natural penicillins:
Penicillin G (benzylpenicillin)
Penicillium chrysogenum
Procaine benzylpenicillin
Benzathine benzylpenicillin
Penicillin V (phenoxymethylpenicillin)
6-aminopenicillanic acid
Semisynthethic:
1. Antistaphylococcal
2. Extended-spectrum
3. Antipseudomonal
Isoxasoliles
Aminopenicillins
Carboxypenicillins
Ureidopenicillins
Amidopenicillins
β-lactamase inhibitors
Mechanism of action
Require proliferating cells:
1. Binding to PBP
2. Inhibition of
transpeptidase
3. Activation of autolysins
BACTERICIDIAL
Cross-linking peptide
PEP side chains
Peptidoglycan:
NAM (N-acetylmuramic acid)
NAG (N-acetylglucosamine acid)
Penicillinbinding
protein (PBP)
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Antibacterial spectrum
Gram-positive – susceptible
Gram-negative – resistant
Resistance widely occurs
(penicillinases)
Natural penicillins:
1. Streptococcus pneumoniae (major cause of
bacterial pneumonia), Streptococcus ssp.
G+
2. Bacillus anthracis (antrax), Cotynebacterium
diphtheriae (diphtheria)
3. Neisseria gonorrhoeae (gonorrhea), N.
meningitidis
G-
4. Treponema pallidum (syphyllis)
5. Clodtridium perfringens
Anaerobes
Antistaphylococcal penicillins:
Methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin –
penicillinase-resistant penicillins
G+
MRSA – methicillin-resistant Staphylococcus aureus
•responsible for more than 18,000 hospital stay-related deaths
in the United States in 2005 (more deaths than AIDS)
•susceptible to vancomycin, teicoplanin
and rarely to ciprofloxacin
MRSA
Extended-spectrum penicillins:
•Spectrum similar to natural penicillin
•More effective against gram-negative bacilli
Ampicillin
•Drug of choice for Listeria monocytogenes
G+
Listeriosis – relatively rare bacterial infection of children,
eldery, immunocompromised patients and pregnant women
(flu-like symptoms, meningitis)
•IV or IM route of administration
Ampicillin
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Amoxicillin
•Widely used for treatment of respiratory, GU system infections
•Prophylaxis in dentistry, conservative dentistry:
1. Good penetration to inflamed tissues
2. Active against periodontal pathogens: Actinobacillus
actinomycetemcomitans, Fusobacterium nucleatum, anaerobic cocci,
not against Bacteroides
•Helicobacter pylori (peptic ulcer disease)
G-
•PO route of administration possible
•Eschterichia coli, Haemophilus influenzae – frequently resistant
Amoxicillin
Antipseudomonal penicillins:
Pseudomonas aeruginosa
G-
•Gram-negative bacilli
•Does not have water-filled channels (porins) in the
lipopolysaccharide layer
Piperacillin, ticarcillin, carbenicillin
- Klebsiella – resistant (constiutive penicillinase)
G-
Resistance
Natural
1. Lack of peptidoglycan cell wall (Mycoplasma)
2. Cell wall impermeable
Acquired – Plasmid transfer
1. β-lactamase activity (usually acquired),
enzyme can be secreted extracellularly
2. Decreased permeability to the drug –
cleavage
prevents from reaching the target PBPs
3. Altered PBPs – lower affinity for β-lactams
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β-lactamase inhibitors
extend antimicrobial spectrum while added to
penicillin
Clavulanic acid (Streptomyces clavuligerus)
Clavulanic acid
Tazobactam
Sulbactam (parenteral preparations only)
β-lactamase inhibitors
•Have very little antimicrobial activity themselves
•Not all β-lactamase are ihibited
Pharmacokinetics
Routes of administration
PO: penicillin V, amoxicillin (almost completely absorbed)
Depot forms of IM: procaine penicillin G, benzathine penicillin G
Absorption
Oral administration - without food (gastric emptying time can be
lengthened)
Distribution
Well into body fluids
Insufficient to: CSF, bone, prostate (unless inflamed)
Biotransformation
Insignificant
Excretion
Urinary route (kidney): most of penicillins
•Contraindication: renal impaired patients
Biliary route (liver): nafcillin
Breast milk, saliva
Penicillins act
synergistically with:
Aminoglicosides
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Adverse reactions
Penicillins are among the most safety known drugs
Hypersensitivity (5% of patients)
From rash to angioedema, anaphylaxis (0,1%)
Penicillins and their metabolites serve as a hapten
Diarrhea
Nephritis
Neurotoxicity
Haematologic toxicity
Cation toxicity (Na+, K+ - added to penicillin compound to form salt)
Pregnancy – category B
B. Cephalosporins
•Originally derived from Acremonium
•The same mode of action as
penicillins
•The same resistance mechanisms as
penicillins
more resistant to penicillinases but still
susceptible to extended-spectrum
penicillinases
Core structure of
the cephalosporins
Generations
I
II
III
IV
Cephalosporins
Cefadroxil
Cefazolin
Cephalexin
Cephalothin
Cefaclor
Cefamandole
Cefprozil
Cefuroxime
Cefotetan
Cefoxitin
Cefdinir
Cefixime
Cefoperazone
Cefotaxime
Ceftazimide
Ceftibuten
Ceftizoxime
Ceftriaxone
Cefepime
Susceptibility
patterns
as penicillin G
+
•Proteus mirabilis
•E. coli
•Klebsiella
pneumoniae
as I-generation
+
•H. influenzae
•Enterobacter
aerogenes
•Neisseria ssp
Gram-negative
(II-generation)
+
•Serratia
marcescens
Methicillinsusceptible
•Streptococci
•Staphylococci
Weaker activity
against G+
Cefotetan
Cefoxitin
•Bacteroides
fragilis
Note: more useful drugs shown in bold
Ceftriaxone
Cefotaxime
-Drus of choice
for meningitis
Gram-negative:
•E. coli
•K. pneumoniae
•P. mirabilis
•P. aeruginosa
Ceftriaxone
Penicillin-resist.
N. gonorrhoeae
Ceftazidime
•Pseudomonas
aeruginosa
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Pharmacokinetics
Routes of administration
PO: I-gen.: Cefadroxil, Cephalexin, II-gen.: Cefaclor,
Cefuroxime axetil, III-gen.: Cefdinir, Cefixime, Ceftibuten
Distribution
Very well into body fluids
Into CSF: III-generation only (cefotaxime)
Into bone: Cefazolin (bone surgery, longer duration of action)
Cross placenta
Biotransformation
Insignificant
Excretion
Urinary route (kidney): most of cephalosporins
Biliary route (liver): cefoperazone, ceftriaxone
Adverse reactions
Allergic reaction (1-2% of patiens without history of allergic
reaction to penicillins)
•Patients who have had anaphylactic response to penicillins should
not receive cephalosporins
•5-15% of cross-sensitivity to penicillins
A disulfiram-like effect – accumulation of acetaldehyde – avoid
alcohol products
Bleeding
Methylthiotetrazole side chain (MTT) – anti-vitamin K effect –
cefamandole, cefotetan, cefoperazone
Pregnancy – category: B
C. Carbapenems
Synthetic antimicrobial drugs:
1. Imipenem/cilastatin
2. Meropenem
To protect from the
biotransformation by renal
dehydropeptidase to the toxic
metabolite (nephrotoxic)
Externalised
sulphur
Antimicrobial spectrum:
Very broad, (used in empiric therapy) within:
•Penicillinase-producting organisms (except for metallo-β-lactamases)
•anaerobes
•P. aeruginosa (resistant srains have been reported)
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Pharmacokinetics
Routes of administration
IV only
Distribution
Well into body tissues
Into CSF (when the meninges are inflamed)
Biotransformation
Imipenem – protected by cilastatin
Meropenem – insignificant
Excretion
Urinary route (kidney)
Adverse reactions
Nausea
Vomiting
Diarrhea
Eosinophilia, neutropenia – less common than
with other β-lactams
D. Monobactams
Aztreonam
Antimicrobial spectrum:
Narrow
•Enterobacteriacae
•Aerobic gram-negative rods
Pseudomonas aeruginosa
Aztreonam
– beta-lactam ring is not
fused to another ring
Resistant to beta-lactamase action (!)
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Pharmacokinetics
IV or IM route of administration
Excreted via urine
Adverse reactions
Relatively nontoxic
•Skin rash
•abnormal liver function occasionally
•low immunogenic potential
•Little cross-sensitivity to allergic reaction after taking penicillins
Pregnancy – category: B
Other inhibitors of
cell wall synthesis
Glycopeptides
Vancomycin (Amycolatopsis orientalis)
Teicoplanin (Actinoplanes teichomyceticus)
Vancomycin
Teicoplanin
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Mechanism of action
Binds to D-Ala-D-Ala
side chain of precursor
pentapeptide
Inhibits
transglycosylation
step in peptidoglycan
polimerisation
Inhibits synthesis
of bacterial cell wall
phospholipids
Interferes with
peptidoglycan
polimerisation
Antimicrobial spectrum
1. Methicilin-resistant Staphylococcus aureus (MRSA)
2. Methicilin-resistant Staphylococcus epidermidis (MRSE)
3. Enterococci (some vancomycin-resistant strains have been
reported – VRE):
G+
E. faecalis, E. faecium
4. Clostridium ssp.
Anaerobes
5. Actinomyces
Reserved only for serious life-threatening infections of:
•beta-lactam-resistant Staphylococcus ssp.
•Metronidazole-resistant Clostridium difficile
•Serious allergy to β-lactams
!!!
Resistance
Resistance can be due to
•plasmid-mediated changesi n permeability to the drug
•Decreased binding of a drug to receptor molecules
Cross-resistance of glycopeptides occurs
(quinopristine/dalfopristin and linezolid are the only drugs
available for the treatment of glycopeptides-resistant bacteria)
Vancomycin and teicoplanin should be used wisely
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Pharmacokinetics
Route of administration
Slow IV infusion – systemic infections
PO – vancomycin ca be taken oraly to treat antibiotic-associated colitis
Teicoplanin can be administrated once-daily
Vancomycin – every 12 houres
Absorption
Do not absorbe from GI tract
Distribution
Into CSF – when mininges are inflamed
Biotransformation
Glicopeptides act
synergistically with:
Insignificant
Excretion
Urinary route
•Contraindication:
renal impaired
patiens
Aminoglicosides (adverse effects)
for enterococcal endocarditis
Ceftriaxone to treat CNS infections
Adverse effects
Serious problems with vancomycin:
1. Fever, chills, flushing
2. Phlebitis at the infusion site
3. Dose-related ototoxicity and nephrotoxicity (more common if
administrated with aminoglycosides)
Teicoplanin can give the same adverse effects but it is less common
Pregnancy – category: C
Fosfomycin
Derived from Streptomyces
Mechanism of action:
Antimetabolite of phosphoenolpyruvate in the
enzymatic synthesis of N-acetylmuramic acid
(the component of cell wall)
Broad-spectrum antibiotic
Treatment of urinary tract infections (UTIs)
Administrated as an oral single megadose
Widespread resistance – limited use
Pregnancy – category B
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Bacitracin::
Bacitracin
Mixture of natural polypeptides (Bacillus subtilis)
Inhibits the cell wall synthesis
Active against gram-positive bacteria
Topical application only because of its potential nefrotoxicity
2. Protein synthesis
inhibitors
Classification
A.
B.
C.
D.
E.
Tetracyclines
Aminoglycosides
Macrolides
Lincosamides
Others:
Chloramfenicol
Streptogramins
Oxazolidinones
Fusidic acid
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A. Tetracyclines
Originally derived from
Streptomyces ssp.:
Natural-occuring
Chlortetracycline
Oxytetracycline
Tetracycline
Demeclocycline
Semi-synthetic:
Doxycycline*
Lymecycline
Minocycline*
The 4 rings of the basic
tetracycline structure
* - long-acting antibiotics
Mechanism of action
Entry to bacterial cell:
1. Passive diffusion
2. Energy-dependent transport
1. Drug binds reversibly to the
30S subunit of the bacterial
ribosome
2. Blocks access of the
aminoacyl-tRNA to the
mRNA-ribosome complex
3. Inhibits matrix
metalloproteinases
BACTERIOSTATIC
anti-inflamatory effect - treating acne and
various types of neoplasms – synthetic
incyclinide has non-antibiotic properties
Antibacterial spectrum
Very broad spectrum:
1. Bacillus anthracis (anthrax) - doxycycline
G+
G-
2. Vibrio chlerae (cholera), Brucella ssp. (+gentamycin), Yersinia pestis
3. Clostridium ssp.
Anaerobes
4. Borrelia burgdorferi (Lyme disease = borreliosis – transmitted by
the bite of infected ticks – leading to meningoenceophalitis)
5. Mycoplasma pneumoniae (pneumonia among young adults)
6. Chlamydia ssp.
7. Rickettsia rickettsii (rocky mountain spotted fever – fever, chills,
aches in bones and joints)
8. Propionibacterium acnes – acne – lymecycline (+ antiinflamatory
effect, contraindication: retinoids)
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Doxycycline
•Good penetration to saliva
•Active against some periodontal pathogens
Drug resistance
Widespread resistance
– limits tetracyclines clinical use
1. Inability of bacterial to accumulate the drug
2. Mg2+-dependent active efflux – plasmid encoded resistance
3. Enzymatic innactivation
Cross-resistance among tetracyclines
Penicillinase-producting Staphylococci – resistant to tetracyclines
Pharmacokinetics
Absorption
PO – all tetracyclines are adequatelly but incompletelly absorbed
(lymecycline – completelly absorbed – active intestinal transport as
carbohydrates)
Note: nonabsorbable chelates are form with di- and trivalent cations!
IV and IM administration possible
Distribution
•Well into body fluids and tissues, binds to tissues undergoing
calcification (teeth, bones, high calcium content tumors)
•Into CSF – minocycline only (but not effective for CNS infections)
•Cross placenta
Biotransformation
Liver glucuronisation
Excretion
Urine route (after being reabsorbed via the enterohepatic circulation)
Contraindication: renal compromised patients
Bile route – doxycycline only
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Adverse effects
Gastric discomfort
(drugs can be taken with food except from diary products,
do not use cation antacids to relieve the problem)
Calcified tissues (discoloration and hypoplasia) – deposition in
bones and primary dentition
Contraindication: growing children (under 8), pregnant women
Hepatotoxicity
Phototoxicity (avoid sun and UV rays)
Vestibular effects (dizziness, nausea, vomiting)
Benign, intracranial hypertension (headache, blurred vision)
Superinfections (because of their broad-spectrum – Candida,
Staphylococci, C. difficile)
Pregnancy – category: D
B. Aminoglycosides
Derived from Streptomyces:
-mycin suffixes:
Glycosidic linkage
Neomycin
Tobramycin
Streptomycin
Derived from Micromonospora:
-micin suffixes:
Amino sugars
Gentamicin
Netilmicin
Amikacin
Streptomycin
Policationic nature –
highly water-soluble
Mechanism of action
Aminoglycosides
work synergistically
with β-lactams and
glycopeptides
1. Diffuses through porin channels (outer
membrane in gram-negative)
2. Oxygen-dependent transport across
the cell membrane
3. Binds to 30S ribosom subunit prior to
ribosome formation
4. Wrong assembly of functional
ribosome apparatus
5. Misreading of genetic code
6. Prevents from the
elongation of the
polypeptide chain.
BACTERICIDAL
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Drug spectrum
1. Aerobic gram-negative bacilli – empiric therapy (strict anaerobes
do not have oxygen-requiring transport system)
GPseudomonas aeruginosa (tobramycin often + antipseudomonal
penicillin)
2. Francisella tularensis (tularemia – hunters skinning infected
rabbits: pneumonic tularemia - gentamycin)
3. Enterococci (often resistant - requires two synergistic antibiotics:
gentamycin) G+
4. Streptomycin – reserved for antimicobacterial therapy
Replaced to some extent by safer anibiotics:
•III-generation cefalosporins
•Fluoroquinolones
•Carbapenems
Drug resistance
1. Decreased uptake of the drug – lack of
• Porins in the outer membrane
• Oxygen-dependent transport system
2. Altered 30S ribosome subunit – decreased affinity for the drug
3. Plasmid-associated enzymatic inactivation (cross-resistance
does not occur in enzymatic inactivation:
•
Amikacin
•
Netilmicin – are less vulnerable
Pharmacokinetics
Absoption
•PO – inadequate absorption
Neomycin - to sterilize GI tract prior to surgical procedures – can be
abrobed if intestines are inflamed – nephrotoxic effect (no IM or IV)
•IV, IM – post-antibiotic effect, concentration-dependent killing effect –
once-daily bolus infusion (q8h administration – pregnancy, neonatal
infections, endocarditis
Distribution
Variable penetration to body fluids
Not into CSF
High levels in renal cortex tissue and inner ear fluids: toxicity!
Cross the placenta
Biotransformation
Insignificant
Excretion
Urine route (renally compromised patients require dose modification)
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2010-04-10
Adverse effects
Plasma levels should be monitored to avoid over-concentration
Factors predisposing to adverse reaction:
•
Old age
•
Liver diseases
•
Previous exposure to aminoglycosides
•
Taking ototoxic drugs (furosemide, cisplatin)
Ototoxicity – drugs accumulate in the endolymph and perilymph of
the inner ear – destroy hair cells in the organ of Corti – deafness may
be irreversible and can affect fetus in utero
Nephrotoxicity – retention in proximal tubular cells
Neuromuscular paralysis – decreased ACh transmition
calcium gluconate
neostygmine – can reverse the block
Allergic reaction – while applied topically
Pregnancy – category: D
C. Macrolides
Erythromycin
Cyclic carbonate of erythromycin
(esterified form)
•Resistant to stomach juice
•Less toxic
•Longer-acting
14, 15, 16membered
macrocylic
lacton
Clarithromycin
Azithromycin
Roxithromycin
Telithromycin
Spiramycin
•Ketolides – used to kill macrolideresistant bacteria
Erythromycin
Tacrolimus
– non-actibiotic macrolide
used as immunosuppressant
Mechanism of action
1. Binds to 50S ribosomal subunit
2. Inhibits translocation – stops protein synthesis
Ketolides act on
macrolides-resistant
bacteria
BACTERIOSTATIC
CIDAL – at higher concentration
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2010-04-10
Antibacterial spectrum
Broad-spectrum antibiotics
Erythromycin
– similar to penicillin G (for patients allergic to penicillins)
Other microlides
– like erythromycin +
1. H. influenzae,
G-
2. Legionella (roxithromycin)
5. Helicobacter pylori (peptic ulcer disease)
intracellular
3. Chlamydia (azithromycin – alternative to tetracyclines)
4. Moraxella, Ureaplasma ssp., Mycoplasma pneumoniae,
6. Toxoplasma gondii (toxoplasmosis in pregnant women) –
spiromycin
Drug resistance
Resistance to erythromycin:
Most hospital isolated strains of Staphylococci
1. Decreased permeability of bacteria cell
2. Increased efflux
3. Decreaced affinity to 50S subunit
4. Plasmid-associated erythromycin esterase
Cross-resistance in macrolides group
Ketolides (telithromycin, spiramycin)
– no cross-resistance
Pharmacokinetics
Administration
PO: erythromycin – only esterified form, other macrolides – OK.
(food interferes a little with the absorbtion)
IV – azithromycin, spiramycin
post-antibiotic effect – spiramycin
Distribution
not into CSF, penetrates well into prostatic fluid, accumulates in
macrofages (azithromycin)
Biotransformation
extensively metabolized – inhibit CYP450 system,
except for azithromycin (and roxithromycin, spiramycin)
Excretion
Biliary route – erythromycin, azithromycin, spiramycin
Urinary route - clarithromycin
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2010-04-10
Adverse effects
Epigastric distress (especially erythromycin)
Cholestatic jaundice (high bilirubil level – after esolate form
of erythromycin)
Ototoxicity – transcient after erythromycin
Myastenia gravis – can be worsen after telithromycin
Pregnancy – category: B/C
Contraindications:
Avoid take CYP450-inhibiting macrolides with:
1. Antihistaminics: astemizole, terfenadine
2. Antiepileptics: carbamazepine, valproate
3. Bronchial relaxings: theophyline
4. Immunosuppressants: cyclosporine
5. Anticoagulants: warfarin
6. Others (digoxin etc.)
D. Lincosamides
Lincomycin (Streptomyces
lincolnensis)
-OH group in
lincomycin
Clindamycin
Mechanism of action:
Very similar to macrolides’:
1. Binds to 23S portion of the 50S
ribosomal subunit
Clindamycin
2. Premature dissociation of the
peptidyl-tRNA from the ribosome
BACTERIOSTATIC
Antibacterial spectrum
Extended-spectrum antibiotics
1. Bacteroides fragilis (abdominal infections associated with
trauma) – other gram-negative bacteria resitant Anaerobes
2. Staphylococci, Streptococci (many MRSA strains still susceptible)
– not Enterococci
G+
no cross-resistance with erithromycin
3. Plasmodium falciparum (malaria) - given with chloroquine or
quinine
4. Toxoplasma gondii (toxoplasmosis – for people infected with
HIV)
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2010-04-10
Pharmacokinetics
Absoption
PO: well absorbed
IV forms available, topical forms (treatment of acne – with benzoyl
peroxide)
Distribution
Well into body fluids, bones and bone marrow, macrophages,
polymorphonuclear leucocytes – inflamation site
Not into CSF
Biotransformation
Extensive oxydation
Excretion
Urinary and biliary route
Clindamycin – dentistry:
•Excelent pharmacokinetics and
antimicrobial spectrum
•NOT against: Actinobacillus
actinomycetemcomitans
•Synergism with β-lactams and
quinolones
Adverse reactions
Hipersensitivity- skin rashes
Pseudomembranous colitis (Clostridium difficile)
1) Metronidazole
2) Vancomycin
Impaired liver function
Pregnancy – category: B
E. Others
Others::
Chloramfenicol
Streptogramins
Oxazolidinones
Fusidic acid
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2010-04-10
Chloramfenicol
Mechanism of action:
- as lincosamides
BACTERIOSTATIC/CIDAL
- depends on the organism
Broad-spectrum antibiotic:
1. Anaerobes
2. Rickettsiae
3. Salmonella typhi (typhoid – most strains are now multi-drug
resistant)
4. Vibrio cholerae (tetracycline-resistant cholera)
5. Enterococcus faecium (also VRE)
not Pseudomonas
Restricted to serious, life-threatening infections – toxicity
Pharmacokinetics
Absorption
PO, IV: well absorbed
Topical use
Distribution
Well into body tissues, very well into CSF (meningitis)
Biotransformation
Glucuronisation – unchanged drug can interfere with the function
of mitochondrial ribosomes
Excretion
Urine route
Adverse effects
Affects human mitochondrial ribosomes
Anemias
Hemolytic anemia – low levels of Glucose-6-phosphate dehydrogenase
Reversible anemia – dosrelated
Aplastic anemia – non dose-related, may occur after therapy is ceased
Gray baby syndrome
Neonates (biotransformation mechanisms are not developed) – if the
dose is not properly adjusted: cyanosis – poor feeding, depressed
breathing, cardiovascular collapse, death
Bone marrow suppression
Leukemia
Pregnancy – category: C
Interactions:
Blocks biotransformation of:
•Warfarin
•Phenytoin
•Tolbutamide, etc.
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Streptogramins
Quinupristin/dalfopristin
Quinupristin/
Streptogramins:
weight-to-weight ratio:
Quinupristin 30%
Dalfopristin 70%
Mechanism of action:
•Dalfopristin – binds to 23S portion of 50S bacterial
ribosome subunit and changes ribosome
conformation – enhances binding of quinupristin
Quinupristine
•Quinupristin – binds nearby, prevents elongation
of the polypeptide
Act synergistically: BACTERICIDAL
Antibacterial spectrum
Gram-positive cocci:
•Methicilin-resistant Staphylococcus aureus (MRSA)
•Vancomycin-resistanat Staphylococcus aureus (VRSA)
•Vancomycin-resistant Enterococci (VRE) – Enterococcus faecium
Enterococcus faecalis - resistant
Resistance
1. Ribosomal enzyme – methylates the target for quinupristin
2. Plasmid-associated acetyl transferase – inactivates dalfopristin
3. Active efflux pump
Resistance mechanisms do not affect antibiotic action completely.
Pharmacokinetics
Absorption
IV administration only
Distribution
To macrophages, polymorphonucleocytes (VRE are intracellular)
Not to CSF
Biotransformation
Extensive metabolism, inhibits CYP450
Excretion
Via the bile
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2010-04-10
Adverse effects
Venous irritation (at the site of infusion)
Arthralgia, myalgia
Hyperbilirubinemia
Interactions:
CYP3A4 inhibition – following drugs level can increase:
1. Antiviral: indinavir, ritonavir
2. Ca-chanells blockers: verapamil, diltiazem, nifedipin
3. Antiepileptics: carbamazepine
4. Immunosuppressants: cyclosporine
5. Others (digoxin etc.)
Oxazolidinones
Oxazolidinones group:
Linezolid
Synthetic antimirobial agent
Mechanism of action:
Inhibits formation of 70S
complex of bacterial ribosome
Cross-resistance with other antibiotics does not occur
QUINUPRISTIN/
DALFOPRISTIN
LINEZOLID
Action towards
Enterococcus faecalis
–
+
Additional spectrum:
Corynebacterium ssp.
Listeria monocytogenes
Clostridium perfringens
–
+
CIDAL
STATIC
IV
IV, PO
(well absorbed)
Antimicrobial agent
Antibacterial action
Route of administration
Inhibition of CYP450
Excretion
+
–
VIA THE BILE
VIA THE URINE
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2010-04-10
Adverse effects of linezolid:
Generally well-tolerated
Gastrointestinal upset – nausea, diarrhea
Headache
Rash
Trombocytopenia
Interactions
Are unlikely, but patients have to be careful with:
•Thyramine-containing food (MAO-I)
•Dopaminergic, serotonergic agents
Fusidic acid
Mechanism of action:
preventing the turnover of elongation
factor from the ribosome
Antimicrobial spectrum:
like penicillin G:
•more active against Staphylococci
(even those penicillinases-producting),
•Enterococcus faecium
- severe staphylococcal infections
(patients allergic to penicillins) –
synergistic with β-lactams
Steroid structure
Administration:
PO, topically
Distribution
Well into bones
3. Inhibitors of
nucleic acid function
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2010-04-10
A. Quinolones
Synthetic chemotherapeutics
Nalidixic acid – the prototype of
Nalidixic acid
quinolones – was invented accidentally
during the synthesis of chloroquine –
the agent used to treat malaria
Fluoroquinolones
Mechanism of action
Passive diffusion through:
• porins in outer membrane (G-)
• peptidoglican cell wall (G+)
Interfering with the action of
Drug target is
bacteriospecific,
gyrase
(topoisomerase II)
however, host’s
topoisomerase IV
mitochondrial DNA
•
•
DNA cleavage
cell death
•
•
can be demaged
DNA replication
cell division
G-
G+
BACTERICIDAL
Generation
I
Chemical
group
quinolones
Agents
Nalidixic acid
Pipemidic acid
Antimicrobial
spectrum
G-
Additional
informations
Urinary tract
infections
(UTIs)
II
III
IV
fluoroquinolones
Ciprofloxacin
Norfloxacin
Ofloxacin
G-
G+
+
Mycoplasma
pneumoniae,
Chlamydia
pneumoniae
Gatifloxacin
Levofloxacin
Sparfloxacin
G- G+
as II-gen.
+
Streptococcus
pneumoniae
Trovafloxacin
Moxifloxacin
G-
G+
anaerobes
+
prophylaxis
before
transurethral
surgery
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2010-04-10
Ciprofloxacin II
II--generation
Antibacterial spectrum and clinical use:
1. Bacillus antracis (drug of first choice – antrax, alternate is
doxycycline)
2. Neisseria gonorrhoeae (gonorrhea – also for penicilinaseproducting strains)
3. Pseudomonas aeruginosa
4. Enterobacteriaceae (E. coli, Klebsiella pneumoniae, Proteus
mirabilis, Serratia marcescens, Shigella)
• GI tract: acute diarrheal illnesses, traveler’s diarrhea
• UTIs (similar to co-trimoxazole)
• Respiratory infections (unresponsive to β-lactams) – but is
not the drug of first choice - week activity against Strept.
pneumoniae
• Systemic infections (except for MRSA, enterococci,
pneumococci)
5. Mycobacterium tuberculosis (tuberculosis – second-line drug)
Norfloxacin II
II--generation
Antibacterial spectrum and clinical use:
1. gram-negative (including Pseudomonas aeruginosa) and grampositive UTIs, prostatisis
2. Not for systemic infections (binds to plasma proteins)
Levofloxacin III
III--generation
Clinical use:
1. Prostatisis (E. coli)
2. Sexually transmited diseases (except for syphilis) – alternative
therapy for gonorrhea
3. Respiratory infections (Streptococcus pneumoniae)
Long half-life: once-daily dosing
Trovafloxacin, Moxifloxacin
Trovafloxacin,
IV
IV--generation
Antibacterial spectrum and clinical use:
1. Streptococcus pneumoniae and others gram-positive bacteria
2. Anaerobes (Bacteroides fragilis)
3. Poor activity against Pseudomonas aeruginosa
Long half-life: once-daily dosing
Trovafloxacin – only IV preparations
Life-threatenings infections
Gatifloxacin IV
IV--generation
Antibacterial spectrum and clinical use:
Streptococcus pneumoniae – excellent activity – respitratoty
infections
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2010-04-10
Resistance
No cross-resistance with other antimicrobial agents (except
for multi-drug resistant organisms)
Cross-resistance among the quinolones
1. Altered targets – mutation in bacterial DNA topoisomerases
2. Decreased number of porins in the outer membrane
3. Energy-dependent efflux
Pharmacokinetics
Absobtion
PO: available for most fluoroquinolones
Note: sucralfate, di- and trivalent cations (antacids, dietary
suplements) – decrease oral absorption!
Distribution
Well into body tissues (bone, urine, kidney, prostatic tissue)
into CSF – ofloxacin only
Accumulate in macrophages, polymorphonuclear leukocytes –
intracellular organisms
Biotransformation
Insignificant (ciprofloxacin and ofloxacin interfere with CYP450 –
may increase theophyline, warfarine, cyclosporine, etc. level)
Excretion
Via urine
Adverse effects
Gastrointestinal (nausea, vomiting, diarrhea)
CNS problems (headaches, dizziness, light-headedness (caution:
epileptic patients)
Phototoxicity
Liver toxicity (especially trovafloxacin: reserved for life-threatening
infections)
Cartilage erosion (arthropathy) – contraindicated for pregnant and
nursing mothers, children under 18-year-old
Prolonged the QT interval – predispositions to arrhythmias
Pregnancy – category C
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2010-04-10
B. Nitroimidazoles
Mechanism of action:
Metronidazole
selectively absorbed
by anaerobes and
susceptible protozoa
Metronidazole
[H] - anaerobes
Unstable complex
with DNA
Toxic metabolites
Antimicrobial action
and clinical use
1. Bacteroides fragilis, Fusobacterium spp, etc. (anaerobes
infections)
2. Clostridium difficile (pseudomembranous colitis - monotherapy)
3. Helicobacter pylori (peptic ulcer disease)
4. Gardenella (bacterial vaginitis)
5. Giardia lamblia (protozoal infection – gardiasis)
Pharmacokinetics
Absorption
PO (well absorbed) – strict rules of q8h of administration must be
complied, IV, topically
Biotransformation
Insignificant
Excretion
Urinary route
Metronidazole:
Penetrates to bones
Active against anaerobes
Metronidazole + β-lactams
Metronidazole + quinolones
NOT: pregnant women
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2010-04-10
Adverse reactions
Gastrointestinal (nausea, vomiting, metalic taste, stomatitis)
Hypersensitivity (rash, flushing, fever) – also after topical use
Leukopenia, neutropenia
Peripheral neutropathy
Potential human carcinogen (experiments on animals)
Interactions with:
•Alcohol – disulfiram-like reaction
•SSRI/SNRI – serotonine syndrome (potentially life-threatening
adverse drug reaction)
4. Inhibitors of
methabolism
Folic acid antagonists
A. Sulfonamides
B. Trimethoprim
C. Co
Co--trimoxazole
BACTERIOSTATIC
Bacteria cells:
impermeable to FOLIC ACID
Human cells:
trimethoprim has significantly lower
affinity to human DH-folate reductase
Human DH-folate reductase is affected by
methotrexate – used in cancer chemotherapy
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2010-04-10
Sulfonamides:
A. Sulfonamides
(sulfa drugs
drugs)
)
•Sulfadiazine
•Sulfacetamide
•Sulfasalazine
Synthetic antimicrobial drugs
•Silver sulfadiazine
•Sulfamethoxazole
Others:
Diuretics (furosemid, hydrochlorothiazid)
Ophtalmics (dorzolamide – carbonic anhydrase inhibitor – glaucoma)
Antiinflamatory drug (celecoxib – COX-2 inhibitor)
Migraine headaches drug (sumatriptan – 5HT-receptors agonist)
Etc.
Antibacterial spectrum
and clinical use
Narrow-spectrum chemotherapeutics
Enterobacteriaceae, Nocardia – UTIs
Sulfadiazine
In combination with pyrimethamine (dihydrofoliate reductase inhibitor
– as trimetoprim) – Toxoplasma gondii (toxoplasmosis – other
drugs: spiramycin, clindamycin) – Plasmodium falciparum
(chloroquine-resistant malaria)
Sulfacetamide
10% topical lotion, eye drops (antiinflamatory effect)
Sulfasalazine
Does not absorb after PO administration – Chronic inflamatory
bowel diseases (Crohn disease, ulcerative colitis): sulfapyridine +
+ 5-aminosalicylate
Silver sulfadiazine
Reduces burn-associated sepsis (does not absorbe) –
superinfections of resistant pathogens may occur
Sulfamathoxazole
with trimetoprim
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2010-04-10
Resistance
Bacteria that do not synthesize FOLIC ACID
are naturally resistant
Acquired resistance:
1. Altered dihydropteroate synthetase
2. Decreased celluler permeability
3. Enhanced production of PABA (substrate)
Pharmacokinetics
Absorption
PO: most sulfas well absobed (except for sulfasalazine)
IV: also available
Topical use: risk of sensitization (except for silver sufadiazine)
Distribution
Well into CSF
Cross the placenta
Biotransformation
Liver acetylation (products may precipitate in kidneys at pH≤7)
Excretion
Via urine
Adverse effects
Crystalluria (kidney damage) – to protect: hydration, alkalinization
newer agents metabolites are more soluble: sulfisoxazole,
sulfamethoxazole
Hypersensitivity (rashes, angioedema, Stevens-Johnson syndrom)
Hemopoietic disturbance (glucose-6-phosphate dehydrogenase
deficiency – hemolytic anemia)
Kernicterus (increased level of free bilirubin) – avoid in newbornes
(under 2 months) and pregnant women (category B)
Interactions:
•Increased hypoglycemic effect of tolbutamide
•Anticoagulant effect of warfarin
•Level of methotrexate (displacement from binding sites on serum
albumine)
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2010-04-10
B. Trimethoprim
Antimicrobial spectrum
and clinical use:
Spectrum similar to that of
sulfamethoxazole (trimethoprim is 20-50fold more potent)
Synthetic
antimicrobial drug
Treatment of acute UTIs, bacterial
prostatitis (fluoroquinolones preferred),
vaginitis
Resistance
1. Altered dihydrofolate reductase – gram-negative bacteria
2. Overproduction of the enzyme
No cross-resistance with sulfonamides
Pharmacokinetics
Absorption
PO, IV
Distribution
Into relatively acidic fluids: prostatic, vaginal
Into CSF
Biotransformation
O-demethylation
Half-life time similar to that of sulfamethoxazole
Excretion
Via urine
46
2010-04-10
Adverse effects
Folic acid deficiency (megaloblastic anemia, leukopenia,
granulocytopenia) – especially int hose having poor diet and
pregnant
can be reversed by FOLIC ACID supplementation
C. Co
Co--trimoxazole
Sulfamethoxazole Trimethoprim -
1 part (16,7%)
5 parts (83,3%)
Plasma levels:
Sulfamethoxazole Trimethoprim -
20 parts
1 part (20-50-fold more potent)
The same activity, half-life
Antimicrobial spectrum
and clinical use
1. Enterobacteriacaeae – E. coli, Proteus mirabilis (UTIs), Salmonella
typhi, Shigella (shigellosis, nontyphoid salmonella,
chloramfenicol – second-line drug)
2. Haemophilus influenzae, Legionella pneumophilia (respiratory
infections) – for Legionella – alternative treatment; drug of choice
is azithromycin
3. Listeria monocytogenes (septicemia and meningitis – first-line:
ampicilin)
4. Pneumocystis carinii (Pneumocystis jiroveci pneumonia) –
common opportunistic infection complicating AIDS – prophylaxis
for ≤200 CD4+ cells/ml patients
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2010-04-10
Pharmacokinetics
Absorbtion
PO,IV (severe P. jiroveci pneumonia)
Distribution
Into relatively acidic fluids: prostatic, vaginal
Excretion
Via urine
Adverse effects
Dermatologic (skin rash – may be severe in the eldery)
Gastrointestinal (nausea, vomiting, stomatitis)
Hematologic (trimethoprim: megoplastic anemia – folic acid
supplementation; sulfamethoxazole: hemolytic anemia – patinets
with G6PD deficiency)
HIV patients with P. jeroveci: drug-induced fever, rashes,
diarrhea, pancytopenia
Interactions:
•Increased anticoagulant effect of warfarin
•Increased level of methotrexate (displacement from binding sites on
serum albumine)
•Increased level of phenytoin – due to metabolism inhibition
Other antimicrobial agents
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2010-04-10
Urinary tract antiseptics
Echerichia coli
Klebsiella pneumoniae
Proteus mirabilis
Staphylococcus saprophyticus
Methenamine
Nitrofurantoin
Concentrate high level in urine,
not in circulation
Methenamine
pH ≤5,5
Methenamine
Formaldehyde
Administration: PO
Kills bacteria
Adverse effects:
•Gastrointestinal
•Albuminuria, hematuria
•Rashes
Contraindications:
•Hepatic insufficiency (ammonium cumulation)
•Sulfonamides administration (react with formaldehyde
Nitrofurantoin
Nitrofurantoin
[H] – bacterial reduction
Active agents
•Inhibit various enzymes
•Damage DNA
•Narrow antimicrobial spectrum (E. coli)
•Toxicity (gastrointestinal, pneuminitis,
neurologic)
less commonly used
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2010-04-10
Fusafungine
•Antibacterial (Staphylococci, Streptococci, H. influenzae,
Chlamydia, Mycoplasma, Legionella, Candida albicans)
•Antiinflamatory
•Immunostimulants
Applied topically (aerosol) does not penetrate into tissues
-nasal and throat infections
No cross-resistance with other antibiotics
Antimycobacterial
drugs
A. Tuberculosis
Tuberculosis (TB = Tubercle Bacillus)
Infectious disease cauced by mycobacteria
(usually Mycobacterium tuberculosis)
Attacs usually the lungs (75%) – chest pain, productive, prolonged
cough, fever, weight loss, etc.
10%
Most TB are
asymptomatic
Progress to
untreated
active disease
(contagious)
death rate – 50%
World-wide problem:
Age-standarised death from tuberculosis
per 100,000 inhabitants in 2004:
Red - more than 2000
Yellow - less than 50
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2010-04-10
Mycobacterium tuberculosis
1. Aerobic gram-positive bacillus
2. Unusual cell-wall: rich in lipids (mycolic
acid) - withstands weak disinfectants,
survives in a dry state
3. Devides every 15-20 houres (other
bacteria – every 1 hour) – difficult to be
cultured and treated
Mycobacterium tuberculosis –
scanning electron micrograph
Intracellular
infection
Granulomatous
reaction (tubercles)
Tissue
destruction
Carswells' illustration of tubercle, 1838
Treatment
First-line drugs
Second-line drugs
Isoniazid
Aminosalicylic acid
Capreomycin
Cycloserine
Ethionamide
Fluoroquinolones
Macrolides
Rifabutin
Rifapentine
Rifampin
Pyrazinamide
Ethambutol
Streptomycin
•Good efficiency
•Acceptable toxicity
For multi-drug resistant
Mycobacteria tuberculosis
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2010-04-10
Intensive phase
Continuation phase
3-4 drugs in combined therapy
2 drugs in combined therapy
Hospital treatment
Ambulatory treatment
2 months
4 months
Combined treatment only:
Resistance grows rapidly if
only one drug is emloyed
Mycobacterium tuberculosis
(stained red) in sputum
1. Isoniazid
Mechanism of action:
1. Prodrug activated by mycobacterial enzymes
2. Inhibition of the unique fatty acid synthetase
3. Decreased production of mycolic acid (cell
wall synthesis)
Isoniazid
– the analog of pirydoxine
(vitamin B6)
Antibacterial spectrum:
•
Mycobacterium tuberculosis
•
Mycobacterium kansasi (causes 3% of TB)
Resistance:
No cross-resistance between isoniazid and other antitubercular drugs
Pharmacokinetics
Absorption
PO: highly absorbed – carbohydrates and aluminium-containing
antacids decrease oral absorption
Distribution
Well into body fluids, cells and tubercles
Biotransformation
N-acetylation (drug accumulation in slow acetylators, patiens with
chronic liver diseases)
Excretion
Via urine
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2010-04-10
Adverse effects
Periphral neuritis (paresthesia) – relative pyridoxine deficiency vitamin B6 supplementation needed
Hepatitis (the most severe side effect)
Drug interaction:
Increased phenytoin level
(isoniazide decreases phenytoin metabolism)
2. Rifampin
Mechanism of action:
Inhibition of transcription (bacterial
not human RNA polymerase inhibition)
Antimicrobial spectrum:
•Mycobacterium tuberculosis, M. kansasii
•Other bacteria: Neisseria meningitidis (meningitis), Haemophilus
influenzae
Pharmacokinetics
Absorption
PO: highly absorbed
Distribution
Well into body fluids and CSF
Biotransformation
Induction of CYP450 enzymes while metabolised – decreases level of
coadministrated drugs
Excretion
Via urine and bile – orange-red color – patients should be warned
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2010-04-10
Adverse effects
Gastric problems (nausea, vomiting)
Jaundice (hepatotoxicity)
In patiens receivig drugs metabolised by CYP450 (e.g. AIDS patients):
Rifampin
Rifabutin
•less effective against tuberculosis
•no CYP450 induction
3. Pyrazinamide
Synthetic prodrug (must be enzymatically activated)
Bactericidal to Mycobacterium tuberculosis
PO administrated
Adverse effects:
•
Liver disfunction
•
Urate retention (uric acid accumulation and gouty attack)
Narrow therapeutic margin
4. Ethambutol
Mechanism of action:
Arabinosyl transferase inhibition –
mycobacterial cell wall synthesis
PO administrated
Adverse effects:
•Optic neuritis (blurred vision)
•Red-green color blindness – sight should be periodically examined
•Urate retention (uric acid accumulation and gouty attack)
Narrow therapeutic margin
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2010-04-10
5. Streptomycin
Aminoglycoside anibiotic:
Protein inhibitor
Extended spectrum antibiotic (reserved to TB
treatment)
Adverse effects:
Ototoxicity, nephrotoxicity
Narrow therapeutic margin
streptomycin-resistant mycobacteria can be treated with amikacin
Second--line drugs
Second
For multi-drug resistant strains of mycobacteria:
1. Fluoroquinolones – important place
2. Macrolides – treatment of infections by Mycobacterium aviumintracellulare complex (azithromycin – preffered for HIV-patients –
does not interfere with coadministrating drugs metabolism)
3. Capreomycin – IV administration, ototoxicity, nephrotoxicity
4. Cycloserine – CNS disturbance, seizures
5. Ethionamide – hepatotoxicity, optic neuritis
6. Aminosalicylic acid – used infrequently (poorly tolerated)
B. Leprosy
Leprosy = Hansen disease: granulomatous disease affecting:
•peripheral nerves
•mucosa of the upper respiratory tract
skin lesions are the primary external sign
Mycobacterium leprae
Worldwide problem:
World distribution of leprosy, 2003:
red, rosy color – more than 1/10.000 – 1/1.000 people
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2010-04-10
Treatment
Multi Drug Therapy (MDT):
1. Dapsone
(acts as a PABA antagonist – similar to sulfonamides,
PO administrated, adverse effects: hemolysis,
peripheral neuropathy, skin complications)
2. Clofazimine
(interferes with DNA function and generate cytotoxic
oxygen radicals, PO administrated, adverse effects: redbrown skin discoloration, eosinophilic enteritis)
3. Rifampin
MDT patient packs and blisters
56