Antibiotics! Flashcards
What are the characteristics of an antibiotic?
Substances produced by a micro-organism, typically a fungus or a bacteria, that inhibits growth of some other microorganism. Many antibacterials based on naturally occurring compound but chemically modified to improve potency and pharmacokinetics.
What are general types of adverse events that can occur with antibiotics?
Allergic reactions: hypersensitivity to drug (ex. beta-lactams)
Toxic effects: drug specific (ex. Gentamycin nephrotoxic)
Suppression of normal flora: a reason to use narrow-spectrum antibiotics
What is the therapeutic index for an antibiotic?
TI- lowest dose that is toxic to patient divided by dose used to typically treat patient.
Ratio of toxic dose/therapeutic dose.
Larger TI is better!
What is the difference between a disinfectant and an antibiotic?
Disinfectants (detergent/peroxide) have a nonspecific mechanism of action and are broadly active, not tolerated by host. Need a higher concentration than antibiotics due to lack of specificity.
What are the major mechanisms by which antibiotics kill bacteria or inhibit bacterial growth?
- Inhibit cell wall synthesis
- Inhibit protein synthesis
- Inhibit nucleic acid function or production
- Disrupt metabolic pathways, like folate metabolism
- Disrupt the cell membrane
What are the bases for antibiotic selective toxicity?
- Absence of target from host- mammalian cells do not have a cell wall, antibiotics targeting cell wall are selective and well tolerated. High TI (>100).
- Permeability differences- antibiotics taken up by bacteria, but poorly by our cells. Results in selectivity but means that drug needs to be given IV, not oral.
- Structural differences in the target- bacterial ribosomes sufficiently different from our ribosomes, prokaryotic ribosomes are a bit smaller.
What is a bacteriostatic antibiotic?
Reversibly inhibits bacterial growth. Drugs that target metabolic processes typically fall into this category- competitive inhibitors with normal metabolites. Growth resumes when drug is removed.
What is a bactericidal antibiotic?
Antibiotic that kills bacteria. For a bactericidal effect, bacteria typically need to be growing actively. Generally drugs that target bacterial cell wall or membrane are bactericidal. Beneficial for situations where you need to treat aggressively (i.e. endocarditis).
What is the minimum inhibitory concentration?
The lowest concentration of an antibiotic that effectively inhibits growth of bacteria. Determined by susceptibility testing.
Describe the tube dilution assay for antibiotic sensitivities.
Bacteria grown in small cultures in presence of different concentrations of antibiotics, tells you sensitivities of given bacterial isolate to range of drug concentrations.
Describe the disc diffusion method.
Bacterial isolate spread over a plate agar. Over time will grow to form cloudy bacterial lawn. Small antibiotic discs placed on the agar and drug diffuses into agar. If bacterial isolate not sensitive to antibiotic, will continue to grow and will see cloudy area around disc. IF strain is sensitive, will see a clear area around disc. Width of clear area is related to MIC (minimum inhibitory concentration). Does not tell you if drug is bacteriostatic or bactericidal.
What situations warrant combined antibiotic therapy?
Chronic infections: using 2 or more drugs may limit emergence of drug resistance
Emergencies: gravely ill patient to treat, can’t wait for culture results or drug sensitivities
Mixed infections: wounds/abdominal infections can be caused by mixed pathogens
Drug synergies: certain drugs more effective in combination
Describe possible drug interactions.
Indifference: two drugs have no effect on each other
Additive response: response is the sum of two drugs used individually
Synergy: response is greater than the sum of the two drugs used individually
Antagonism: response is less than the sum of the two drugs used individually (rare)
What are some factors that limit successful antimicrobial therapy?
Location: cannot penetrate blood-brain barrier or eukaryotic cells
Abscess formation/necrosis: decreased circulation in area of abscess limits drug concentrations, low nutrient levels may slow bacterial growth making some antibiotics less effective
ex. necrotizing pneumonia with abscess formation
Presence of foreign bodies/obstructions: biofilms on artificial surfaces, foreign body granulomas
Emergence of drug resistance
What are the general mechanisms of drug resistance?
- Enzymatic inactivation of antibiotic- beta lactamase
- Inadequate/decreased uptake of drug into microbe- mutate porin proteins
- Increased efflux of antibiotic out of microbe- efflux systems
- Alteration of drug target- mutations in PBPs
- Altered metabolic pathways- new enzymes expressed that utilize alternative metabolic pathways
How do beta-lactam antibiotics work?
Bind to transpeptidase (PBP) and inhibit formation of new cross-links in the cell wall. Competitive inhibitors. In general, more effective against Gram-positive bacteria because cell wall is exposed. Beta-lactams are bactericidal but work most effectively against rapidly growing bacteria.
What are the three major classes of penicillins?
- Natural Penicillins: Penicillin G- inactivated by low pH (IV)
Penicillin V- acid stable, taken PO - Penicillinase-resistant penicillins: Methicillin, Oxacillin, Naficillin, Cloxacillin, Dicloxacillin. Resistant to beta-lactamases due to steric hindrance of R group attached to beta-lactam ring.
- Extended spectrum penicillins: Ampicillin, Amoxicillin, Carbenicllin, Pipericillin. Improved against gram-negatives, less effective against gram positives. Often combined with beta lactamase inhibitors.
What are the side effects of penicillins?
Hypersensitivity reactions. Can be severe and cause anaphylaxis, can become more severe if a person exposed to drugs multiple times. Reactions can include hives or a maculopapular skin rash, itchy skin, wheezing, swollen lips that can occur quickly or develop over a day or two. Anaphylactic reactions to penicillin occur immediately and include difficulty breathing, decreased blood pressure, swelling of throat/tongue.
What are the 3 mechanisms of beta-lactam resistance?
- Beta lactamases (penicillinases) produced to destroy drug
- Transpeptidase (main PBP) acquires mutation that prevents drug binding
- Gram negatives have membrane pumps to remove drug from periplasmic space
What are beta lactamase inhibitors?
Drugs that have no antimicrobial activity on their own, but can make beta lactam antibiotics more effective by binding or inactivating beta lactamases.
Clavulanate, sulbactam, tazolbactram
What are some common combinations of beta lactamase inhibitors and penicillins?
Augmentin: Amoxicillin-clavulanate
Ampicillin-sulbactam
Zosyn: Piperacillin-tazolbactam
What are the typical uses of natural penicillins?
Drug of choice for community-acquired Streptococcus, pneumococcus, meningococcus, syphilis (Penicillin G). Not effective against Staph due to drug resistance.
What are the typical uses of penicillinase-resistant penicillins?
Resistant to beta lactamases produced by Staph, very narrow spectrum with no gram negative coverage. Many strains of Staph now resistant to these. MRSA- Methicillin resistant Staph aureus. Now Oxacillin used to treat Staph.
What is the use of extended spectrum penicillins?
Similar to natural penicillins but can cross membranes of some gram negatives and inactivate transpeptidase enzymes. Used for uncomplicated UTIs, otitis media, community acquired pneumonia, H. flu, Listeria. Not as effective for gram + and sensitive to beta lactamases.
What is the mechanism of action of cephalosporins?
Like penicillins, contain a beta-lactam ring and inhibit peptidoglycan synthesis via PBPs. Wider antibacterial spectrum, resistance to many beta-lactamases, improved pharmacokinetics. Bactericidal. Adjoining ring differs from penicillins. Different R groups alter characteristics.
What are the general properties of cephalosporins?
Generally resistant to beta-lactamases produced by Staph and common Gram-negatives.
Do NOT cover enterococci- internally resistant.
Newer generations have better gram-negative coverage and poorer gram-positive coverage.
Induce hypersensitivity like penicillins.
5% of patients with penicillin reactions, react to cephalosporins as well.
1st Generation Cephalosporins?
Cefazolin, Cefadroxil, Cephalexin
Very active against gram positives including staph (but not MRSA)
Moderate against some gram negatives (E. coli)
Used for community acquired UTIs and respiratory infections
Cefazolin used for surgical prophylaxis
2nd generation Cephalosporins?
Cefuroxime
Used for otitis media in children
Increased activity against gram negatives including H. influenzae.
Respiratory infections, UTIs
3rd generation Cephalosporins?
Ceftriaxone, ceftazidime, cefixime, cefotaxime
Less Gram+ activity. More Gram- coverage.
Management of hospital-acquired gram- bacteremia, inpatient pneumonia, and UTIs. Some can penetrate CNS.
4th generation cephalosporins?
Cefipime only licensed 4th generation cephalosporin in the US.
Enhanced activity against hospital-acquired gram-negative bacteremia (Enterobacter) when resistance to 3rd generation drug.
Side effects of cephalosporins?
Hypersensitivity reactions just like penicillin. Cross-allergy between penicillins and cephalosporins approx 5%. Patients with significant PCN allergies should not be given cephalosporins, if mild reactions, can risk it. Greater incidence of GI problems/C. diff infections due to better gram negative coverage.
What is the mechanism of action of Carbapenems?
Same mechanism of action as penicillins. Inhibit PBPs that form links in the bacterial cell wall. Carbapenems have wider antibacterial spectrums than other beta lactams. Highly active against Gram+, Gram-, aerobic, and anaerobic bacteria. Resistance to beta-lactamases. Improved pharmacokinetics. Bactericidal and usually given IV. Often used as empiric therapy for critically ill patients, last resort for E. coli and Klebsiella infections.
What are the carbapenems?
Meropenem, Imipenem, Ertapenem, Doripenem.
Powerful drugs. Need ID approval to use at Penn. Very broad spectrum and BAD if resistance develops.
What is the mechanism of action of Vancomycin?
Glycopeptide antibiotic. Interacts with the D-ala-D-ala termini of the pentapeptide side chains, interfering with formation of bridges btw peptidoglycan chains. Works a step BEFORE beta-lactams in preventing transpeptidation. Inhibits cell wall synthesis, but no cross-resistance with beta lactams.
What are the typical uses of Vancomycin?
Excellent Gram+ coverage (Staph and Strep). NO Gram- coverage b/c a glycopeptide too big to pass through porins in Gram- membranes. Inferior to Oxacillin if MSSA. Used for MRSA and other beta-lactam resistant Gram+s. Oral form used for C. difficile colitis. Usually given IV due to poor absorption from intestinal tract (unless treating GI infection). Peptides generally not PO bc/ degraded or poorly absorbed.
What reaction can Vancomycin cause?
Vancomycin can cause hypersensitivity reaction. Occasionally can be very severe and cause Red Man Syndrome- a red rash on face, neck, and trunk.
What is the mechanism of action of Bacitracin?
Bacitracin is a mixture of cyclic peptides. Inhibits cell wall synthesis by preventing the transport of peptidoglycan precursors across bacterial membrane. ONLY used topically. Most effective against Gram+. Common ingredient in non-prescription first-aid ointments.
What are the drugs that target protein synthesis?
C(L)Ean TAG:
Chloramphenicol, [Linezolid not learning!] and Erythromycin (all macrolides) bind to 50S subunit of prokaryotic ribosomes. Tetracycline and AminoGlycosides bind to 30S subunit.
What is the mechanism of action of Daptomycin?
Daptomycin is a lipophilic peptide that disrupts membranes of Gram+. Can be given IV. Approved for Gram+ skin infections. Also S. aureus bacteremia. Active against MRSA.
What is the mechanism of action of the macrolides?
Reversibly bind to the 50S ribosome and prevent protein elongation. Bacteriostatic. Broad activity against Gram+ and Gram- organisms.
What are the macrolides used for?
Erythromycin, Azithromycin (Z-Pak), Clarithromycin.
Broad activity against Gram+ and some Gram-. Erythromycin replaced by Azithromycin. Community acquired pneumonia. Upper respiratory tract infections. Atypical pathogens (Legionella, Chlamydia, Mycoplasma). Drug of choice for patients allergic to penicillin. Well-tolerated drugs.
What is the mechanism of action for the aminoglycosides?
Bind IRREVERSIBLY to the smaller 30S subunit of prokaryotic ribosome, and are thus BACTERICIDAL. Causes distortion and malfunction of ribosome. Blocks initiation translation–> misreading of mRNA. Can be used in conjunction with a beta-lactam drug, damages cell wall and makes it easier for aminoglycoside to enter cell. SYNERGY.
Transport through the bacterial cell membrane requires ATP hydrolysis (energy) and therefore are NOT effective against anaerobes.
What are the aminoglycosides?
GNATS- Gentamycin, Neomycin, Amikacin, Tobramycin, Streptomycin
Neomycin only used topically.
How are the aminoglycosides used?
Good coverage against gram negatives, particularly Pseudomonas. Toxicity issues, need to be monitored (nephrotoxicity, ototoxicity). Must be delivered IV or IM (not absorbed from gut). Tend to be administered for SERIOUS gram negative infections: complicated UTIs, pneumonia, pseudomonas. Gentamycin frequently administered with beta lactam at HUP.
What are common resistance mechanisms for aminoglycosides?
Most common resistance mechanism is modification of the drug. Enzyme responsible for this is plasmid associated and can spread rather easily. Delivery of drug-inactivating enzyme to a bacterium is high-level drug resistance. Reduced uptake and altered drug binding site also described but afford intermediate levels of resistance as neither uptake nor binding completely prevented.
What are the common resistance mechanisms to macrolides?
Resistance can either entail change in drug-binding site, hydrolysis of drug, or enhanced efflux of drug.
What are the side effects of aminoglycosides?
- Nephrotoxicity: quite common, associated with high trough levels, generally reversible, monitor drug levels and renal function.
- Ototoxicity: irreversible, associated with overly high peak levels, can cause tinnitus as well as hearing loss.
What is the mechanism of action of tetracyclines?
Bind reversibly to the 30S subunit, prevent attachment of tRNA, block protein synthesis. Bacteriostatic.
What are tetracyclines normally used for?
Old drug class commonly used for unusual agents: mycoplasma, chlamydia, Lyme disease. Newer drugs (Doxycycline, minocycline) have better pharmacokinetics which allows for less frequent dosing. Commonly used for Acne.
What is the common resistance mechanism for tetracyclines?
Increased efflux from cells.
What are the side effects of tetracyclines?
Discolored teeth in children. Do NOT give to children or pregnant women. GI upset. Phototoxic dermatitis.
What is the mechanism of action of Chloramphenicol?
Binds to the 50S ribosomal subunit. Prevents peptide bonds from forming, thus blocking protein synthesis. Effective against a very wide variety of organisms, but has rare/deadly side effects. Bacteriostatic?
What are the side effects of Chloramphenicol?
Aplastic anemia. Bone marrow wiped out. Fatal. Very rare (1/20,000- 1/40,000). Neonates cannot metabolize drug, resulting in very high levels of drug and vasomotor collapse.
What are the uses of Chloramphenicol?
Drug of last resort in life-threatening infections. Used for meningitis if organism unknown and patient has penicillin allergy. Used in young children/pregnant women with Rocky Mountain Spotted Fever b/c cannot be treated with tetracycline. Used frequently in underdeveloped countries b/c of broad spectrum utility and very low cost.
What are the drugs that inhibit nucleic acid synthesis?
QFRM: Quite Fancy Racing Medal!
Quinolones/Fluroquinolones, Rifampin, Metronidazole
What is the mechanism of action of the quinolones/fluroquinolones?
Quinolones target DNA gyrase, thus inhibiting DNA replication. [DNA gyrase normally relieves tension as DNA unwinds for replication.] Bacteriostatic?
What are the quinolones/fluoroquinolones?
Levofloxacin, norfloxacin, ciprofloxacin, ‘Cipro’
What are the quinolones/fluroquinolones used for?
Used for Gram negatives: GNR including multi-drug resistant Pseudomonas, Enterics (if necessary/severe- E. coli, salmonella, shigella, campylobacter), complicated UTIs (usually gram-).
Not good for Gram positives or anaerobes. Levofloxacin active against many penicillin-resistant pneumococci.
What are the benefits and drawbacks of quinolones?
Safe, good PO, good tissue absorption. Can disrupt normal gut flora, increasing chances of getting C. difficile.
How does resistance to quinolones/fluroquinolones occur?
Resistance due to mutations in drug binding site of gyrase.
What is the mechanism of action of Metronidazole/Flagyl?
Enters a bacterium as a prodrug, nitro group reduced, making drug active. Disrupts DNA structure, leading to double-strand breaks and mutations, inhibits DNA replication. BACTERICIDAL.
What is metronidazole used for?
Anti-parasitic drug. Used for protozoans such as Trichomonas, Giardia, Amoebic infections. Only active against ANAEROBES. One of the most reliable anti-anaerobic agents. Used for C. difficile if Vancomycin doesn’t work. [What do we do? Use Flagyl to, get rida ya, Clostridya!]
What drugs are the antimetabolites?
Sulfa drugs= Sulfonamides. Only significant drugs that target bacterial metabolites. Target folic acid synthesis. Historically the first antibiotics developed.
How do sulfonamides work?
Inhibit the growth of Gram+ and Gram- organisms by competitively inhibiting an enzyme in the production of folic acid. Sulfonamides are structurally similar to para-aminobenzoic acid, which is a substrate (metabolite) in the folic acid synthesis pathway. Human cells lack the specific enzyme in the folic acid pathway, which is the basis for selective toxicity. Folic acid is necessary for nucleotide synthesis.
How do bacteria acquire resistance to the sulfonamides?
They acquire resistance through a plasmid that codes for an enzyme with lower affinity to the drug.
How does Trimethoprim function?
Inhibits folic acid production by interfering with the activity of the enzyme following the enzyme inhibited by sulfonamides in the folic acid synthesis pathway. Often used synergistically with sulfonamide.
How do bacteria acquire resistance to Trimethoprim?
Most commonly, bacteria acquire resistance through a plasmid that encodes for an alternative enzyme with lower affinity to the drug. Often genes encoding resistance to sulfonamide and trimethoprim are carried on the same plasmid.
What is Bactrim used for?
Bactrim is Trimethoprim/Sulfamethoxazole. No coverage of anaerobes. Good for Streptococcus and H. influenzae (otitis media, sinusitis, bronchitis). Covers diarrheagenic gram negatives (shigella, salmonella, E. coli). Good for pneumocystis in AIDS patients.
What are the side effects of Bactrim?
Hypersensitivity reaction. Don’t give to patients on Warfarin (blood thinner) as it increases warfarin levels and can lead to bleeding.
What is the mechanism of action of Rifampin/Rifabutin?
Inhibits DNA-dependent RNA polymerase, inhibiting RNA replication and is BACTERICIDAL.
