L1: Introduction to Antimicrobial Therapy Flashcards
Inevitable consequence of widespread use:
- Emergence of antibiotic-resistant pathogens
- Increasing need for new drugs
- Rising costs of medical care
Agents that inhibit synthesis of bacterial cell walls
a. Penicillins, cephalosporins
b. Cycloserine
c. Vancomycin
d. Bacitracin
e. Azole antifungal agents
Agents that act directly on the cell membrane of the microorganism, affecting
permeability leading to leakage of intracellular compounds
a. Polymixin
b. Polyene antifungal agents
Agents that affect the function of 30 S or 50 S ribosomal subunits to cause a
reversible inhibition of protein synthesis (bacteriostatic)
a. Chloramphenicol
b. Tetracyclines
c. Erythromycin
d. Clindamycin
Agents that bind to the 30 S ribosomal subunit & alter protein synthesis which
eventually leads to cell death (bactericidal)
a. Aminoglycosides
Agents that affect bacterial nucleic acid metabolism
a. Rifamycins – inhibit RNA polymerase
b. Quinolones – inhibit topoisomerases
Antimetabolites which block essential enzymes of folate metabolism
a. Trimethoprim
b. Sulfonamides
For an antibiotic to be effective, it must:
- Reach its target
- Bind to its target
- Interfere with its target’s function
0 Outer membrane of gram-negative bacteria is a permeability barrier
that excludes large polar molecules from entering the cell
0 Small polar molecules, including many antibiotics, enter the cell
through channels made up of proteins called porins
0 Absence of, mutation in or loss of the appropriate porin channel can
slow the rate of drug entry into the cell or prevent entry altogether,
reducing the effective drug concentration at the target site
0 For intracellular targets of drugs that require active transport across the
cell membrane, a mutation or environmental condition that shuts down
the transport mechanism confers resistance
The drug does not reach its target
0 2nd general MOR
0 Production of inactivating enzymes
b-lactamases
aminoglycoside-modifying enzymes
0 Variation: failure of the bacterial cell to convert an inactive drug to its
active metabolite
Isoniazid resistance among M. tuberculosis
The drug is not active
0 May be due to:
Mutation of the natural target – fluoroquinolone resistance
Target modification – ribosomal protein type of resistance to
macrolides & tetracylcines
Substitution with a resistant alternative to the native,
susceptible target – methicillin resistance in staphylococci
v Reduced binding of drug by the critical target substitution
of a new target that does not bind the drug for the native
target
The target is altered
§ Molecular basis for resistance to streptomycin (ribosomal mutation),
quinolones (gyrase gene mutation) & rifampin (RNA polymerase gene
mutation)
§ Underlies the drug resistance of M. tuberculosis to anti-tuberculous drugs
§ May occur in the gene encoding:
· The target protein, altering its structure so that it no longer binds the drug
· A protein involved in drug transport
· A protein important fro drug activation
· In a regulatory gene or promoter affecting expression of the target, a transport
protein or an inactivating enzyme
Mutations & antibiotic selection
0 Acquisition of bacterial DNA from a bacteriophage (a virus that
propagates on bacteria) that has incorporated DNA from a previous
host bacterium within its outer protein coat
0 Important in the transfer of antibiotic resistance among strains of
Staphylococcus aureus, where some phages can carry plasmids
(autonomously replicating pieces of extrachromosomal DNA) that code
for penicillinase, while other transfer genes encoding resistance for
erythromycin, tetracycline or chloramphenicol
Transduction
0 Involves uptake & incorporation of DNA that is free in the environment
into the host genome by homologous recombination
0 Molecular basis of penicillin resistance in pneumococci & Neisseria
Transformation
0 Passage of genes from cell to cell by direct contact through a sex pilus
or bridge
0 Extremely important mechanism fro spread of antibiotic resistance
since DNA that codes fro resistance to multiple drugs may be
transferred
0 First recognized in Japan in 1959 after an outbreak of bacillary
dysentery caused by Shigella flexneri that was resistant to 4 different
classes of antibiotics
0 Transferable genetic material consists of 2 different sets of plasmidencoded
genes:
i. A gene that encodes for the actual resistance
ii.A gene that encodes genes necessary for bacterial conjugation
0 Common among gram-negative bacilli
Conjugation
Factors that determine the susceptibility & resistance of microorganisms to
antimicrobial agents:
- The concentration of antibiotic at the site of infection
Ø Must be sufficient to inhibit growth of the offending microorganism
Ø Must remain below the level that is toxic to human cells - Host factors
Ø Host defenses
§ If intact & active, a minimum inhibitory effect (bacteriostatic agents)
may be sufficient
§ If impaired, antibiotic-mediated killing (bactericidal effect) may be
required to eradicate the infection
Ø Age
Ø Genetic factors
Ø Pregnancy
Ø Drug allergy
Ø Kidney function - Local factors
Ø Low pH
Ø High protein concentration
Ø Blood flow - Pharmacokinetic factors
Ø In vitro activity is only a guide as to whether or not an antibiotic is likely to be
effective in an infection
Ø Successful therapy also depends upon achieving a drug concentration that is
sufficient to inhibit or kill the bacteria at the site of the infection without
harming the host
§ May to a large extent, dictate the route of administration
§ Access to sites of infection depends on multiple factors
· CSF – drug must pass the blood-brain barrier
Location of the infection
§ Oral administration is preferable whenever possible
§ Parenteral administration considered in seriously ill patients
Route of administration
Antibiotics are used in 3 different ways:
- Empirical therapy
- Definitive therapy
- Prophylactic or preventive therapy
§ Requires knowledge of the most likely infecting microorganism
& their susceptibilities to antimicrobial drugs
· Gram’s stain of appropriate specimens
§ Must “cover” all of the likely pathogens since the infecting
organism has not been identified
§ “Broad-spectrum” antibiotics
§ Monotherapy or combination therapy
Empirical therapy
§ Culture of appropriate specimens
§ “Narrow-spectrum”, low-toxicity regimen against the identified
pathogen
Definitive therapy
§ Highly effective in some clinical settings & in others, is totally
without value & may be deleterious
§ May be used to protect healthy persons from acquisition of or
invasion by specific microorganisms to which they are exposed
§ Used to prevent a variety of infections in patients undergoing
organ transplantation or receiving cancer chemotherapy
§ Recommended for patients with valvular or structural lesions of
the heart predisposing to endocarditis who are undergoing
dental, surgical or other procedures that produce a high
incidence of bacteremia
§ Used to prevent wound infections after various surgical
procedures
Prophylactic or preventive therapy
Ø Requires an understanding of the potential for interaction between agents
which may affect either the microorganism or the patient
Ø Antimicrobial agents acting at different targets may enhance or impair overall
antimicrobial activity
Ø May result in:
· Additive effects
· Antagonism
· Synergism
Ø Indications:
· Empirical therapy of severe infections in which a cause is unknown
· Treatment of polymicrobial infections
· Enhancement of antibacterial activity in the treatment of specific infections
Therapy with combined antimicrobial agents
Misuses of antibiotics
- Treatment of untreatable infections
- Therapy of fever of unknown origin
- Improper dosage
- Inappropriate reliance on chemotherapy alone
- Lack of adequate bacteriological information
