Antibacterials Pt. 1 Flashcards
Selection of Appropriate Antibacterial Drug(s) (4):
-
Selective Toxicity
- risk vs. benefit
-
Type of organism
- identification and susceptibility
- empirical treatment: initial drug often chosen before culture results are known
- Anatomical location of organism within human host
-
Host Status
- age, allergies, renal/hepatic function, pregnancy, host defenses
Definitions:
- Bactericidal vs. Bacteriostatic
- MIC vs. MBC
-
bactericidal (kills the bacteria) vs. bacteriostatic (stops the active growth of the bacteria but they remain viable)
- host defenses are also important
- MIC (Minimal Inhibitory Concentration) vs. MBC (Minimal Bactericidal Concentration — kills 99.9%+ of bacteria)
time-dependent killing:
% of total time above MIC
- best clinical effect when remain 4-fold
above the MIC for >50% of total time - β-lactams
![](https://s3.amazonaws.com/brainscape-prod/system/cm/096/739/812/a_image_thumb.png?1659424819)
Concentration-dependent killing:
Maximize the peak concentration (Cmax)
- Cmax/MIC ratio ≥8 is best
-
Aminoglycosides
- Have persistent effect even when levels fall below MIC
![](https://s3.amazonaws.com/brainscape-prod/system/cm/096/740/986/a_image_thumb.png?1659424819)
Killing dependent on concentration x time:
Area under the curve
- AUC24hr/MIC expressed in hrs
- Quinolones (also Cmax)
![](https://s3.amazonaws.com/brainscape-prod/system/cm/096/741/399/a_image_thumb.png?1659424820)
Describe the Classes of Resistance Mechanisms (4):
-
Intrinsic Resistance
-
fundamental properties of a given microbe
- e.g. cell wall structure
-
fundamental properties of a given microbe
- Non-inherited Resistance
- cells not actively replicating
- Mutations
- mutations that alter cells’ susceptibility to antimicrobial agent
- Plasmid-mediated Resistance
- extrachromosomal genes that encode resistance mechanism
- potentially transferred to other microbes
- multiple-resistance
- extrachromosomal genes that encode resistance mechanism
List the Antibacterials that Target the Cell Wall (8):
-
ß-lactams
- Penicillins
- Cephalosporins
- Carbapenems
- Monobactams
- ß-lactamase inhibitors
- Vancomycin
- Fosfomycin
- Bacitracin
β-Lactams:
General Properties
-
Bactericidal
- bacteriostatic under some conditions
- Effective against gram-pos. and -negative bacteria
- Activity is maximal on actively growing bacteria
β-Lactams:
Mechanism
-
Inhibit transpeptidases (penicillin-binding proteins or PBPs) which catalyze cell wall crosslinks
- β-lactam covalently binds to PBPs
- competitive, irreversible
- β-lactam ring is a 3-d analog of D-Ala-D-Ala linkage in peptidoglycan side chain
- Bacterial lytic enzymes enhance breakdown of
crosslinks, accelerate cell lysis- Rapid bacterial lysis can cause symptoms due to release of bacterial components
- chills, fever, aching
Resistance to ß-lactams:
-
β-lactamase:
- most prevelant
- cleaves β-lactam ring
-
extracellular activity:
- β-lactamase can protect other bacteria in the vicinity
-
Altered PBP(s):
- will not bind β-lactam effectively
- methicillin-resistant Staph.; penicillin-resistant
Strep. pneumoniae
-
β-lactam agent cannot reach PBPs:
- intrinsic resistance of some gram-negatives
β-Lactams are ____ _________ killers:
time-dependent
- Keep the drug 4-fold above the MIC for >50% of total treatment time
- Since β-lactams have short t1/2 ⇒ shorter dosing intervals
Penicillins:
Common Properties
-
well distributed to most areas of the body
- low penetration into CSF, but this increases during meningitis
- some may be given orally, otherwise via IV or IM
-
short half-lives
- 30 min to a few hours
- renal elimination - anion transport
List of Penicillins (7):
- **penicillin G **
- penicillin V
- oxacillin
- amoxicillin
- ampicillin
- ticarcillin
- piperacillin
penicillin G & V:
- Route:
- Spectrum:
- **Route: **Oral (pen V) vs. IV/IM (pen G)
- **Spectrum: **(V is more acid stable than G)
-
for gram-pos. and gram-neg. cocci
- non ß-lactamase producing
-
gram-pos. anaerobes
- Clostridium, Peptococcus, Peptostreptococcus, Veillonella, Actinomyces
- not Bacteriodes fragilis
- Streptococcus pneumoniae (20-30% resistance)
- most other Strep.
- Neisseria meningitidis meningitis
- Syphillis
- good activity against:
- anthrax (Bacillus anthracis)
- Listeria, Actinomyces
-
for gram-pos. and gram-neg. cocci
- **Tidbit: **t1/2 can be extended if combined with procaine or benzathine
- IM pencillin G + benzathine for syphillis
What antibacterial drug would you use to treat ß-lactamase producing Staphylococci?
Oxacillin
- “methicillin”-type drug
- given IM or IV
- reasonable activity against most streptococci
- Staph. aureus that are sensitive to these drugs are
called MSSA (methicillin-sensitive Staph. aureus)
Ampicillin, Amoxicillin:
Spectrum
- various β-lactamase-negative gram-pos:
- Listeria, Streptococcus, etc.
- Enterococcus (e.g. urinary tract infections)
-
gram-neg:
- including Haemophilus, Neisseria, Escherichia, Salmonella
- High dose amoxicillin is the drug of choice for **otitis media **in otherwise healthy children
- Amoxicillin alternate choice for Lyme disease
Ampicillin vs. Amoxicillin:
- Amoxicillin: better absorbed after oral dose
- Ampicillin: available IV or oral
-
Ampicillin has 2 important uses that amoxicillin doesn’t:
-
Meningitis (e.g. Neisseria, Listeria):
- ampicillin available IV
- amoxicillin only orally
-
GI infections:
- esp. Shigella
- Less absorption of oral doses = more in GI tract
-
Meningitis (e.g. Neisseria, Listeria):
Penicillins with extended gram-negative spectrum (2):
- ticarcillin
- piperacillin
Ticarcillin:
-
broad gram-neg, effectiveness extended to include:
- Pseudomonas aeruginosa
- some Enterobacter and Proteus, E. coli
- susceptible to β-lactamases
- sometimes used with aminoglycoside
-
some anaerobes
- when combined with β-lactamase inhibitor
- ticarcillin + clavulanate
- Retain some gram-pos. activity
- given IM
Piperacillin:
-
broad gram-neg. spectrum including:
- some Pseudomonas and Klebsiella
- including those that are ticarcillin resistant
Excretion/metabolism of penicillins:
- mostly renal
- 20% glomerular filtration
- 80% tubular anionic excretion
- ≈ 30% hepatic metabolism
Adverse reactions of penicillins (7):
-
Allergic rxns can be VERY SEVERE, incl.:
- anaphylaxis (low incidence but VERY important)
- serum sickness, delayed hypersensitivity
- rash <8%
- Use of Pre-Pen can help with predicting an allergic rxn
- fever (4-8%)
- diarrhea (< 25%)
-
enterocolitis (~1%)
- NOTE: all antibacterials can cause enterocolitis!
-
elevated liver enzymes (1-4%)
- hepatotoxicity
- hemolytic anemia (low incidence)
- seizures
Administration of penicillins:
- some IV or IM only
- penicillin G, azlocillin, ticarcillin
- some oral
- ampicillin, amoxicillin, penicillin V, dicloxacillin
- generally well-distributed to most areas of the body
- generally short half-lives
- procaine and benzathine penicillin are slow-release IM forms ⇒ substantially increase the duration of action
- inflamed meninges ⇒ increased CNS distribution
β-Lactamase inhibitors:
-
clavulanic acid, tazobactam, sulbactam:
- β-lactam analogs that bind irreversibly to β-lactamase
- limit hydrolytic cleavage of β-lactams by some types of β-lactamases (Class A; some Class D)
-
given in conjunction with some β-lactams:
- ampicillin, amoxicillin, ticarcillin, piperacillin
Brand names of β-lactam/β-lactamase drug combinations:
- Augmentin®: amoxicillin + clavulanate (oral)
- Staph. (MSSA)
- E. coli, Klebsiella
- Haemophilus, Moraxella
- Proteus, Bacteroides (ampicillin/sulbactam)
- Unasyn®: ampicillin + sulbactam
- Timentin®: ticarcillin + clavulanate
- Zosyn®: **piperacillin + tazobactam **(IV)
- Staph. (MSSA)
- E. coli, Klebsiella, Acinetobacter
- Haemophilus
- Bacteroides
Cephalosporins:
Common Properties
-
well distributed to most areas of the body
- only some reach the CSF
-
majority require injection
- only some may be given orally
- short half-lives (at best only a few hours)
- mechanism: similar to other β-lactams
- resistance mechanisms are comparable to those of penicillins
List of Cephalosporins:
- 1st generation:
- 2nd generation:
- 3rd generation:
- 4th generation:
- 1st generation:
- **cefazolin **
- cephalexin
- 2nd generation:
- cefuroxime
- cefoxitin
- 3rd generation:
- ceftriaxone
- ceftazidime
- 4th generation:
- cefepime