Infectious Disease Flashcards
Minimum inhibitory concentration (MIC)
Lowest antimicrobial concentration that prevents visible growth of an organism after ~24 hours of incubation in a specified growth medium
Minimum Bactericidal Concentration (MBC)
Lowest concentration of drug that kills 99.9% of the total initially viable cells or greater reduction in the starting inoculum)
Post-antibiotic Effect (PAE)
- Persistent suppression of an organism’s growth after a brief exposure to an antibiotic
- Primary clinical application - allow for less frequent administration of antimicrobials while still maintaining adequate antibacterial activity (e.g., extended-interval aminoglycoside administration)
Synergy
Using combination of antibiotics that result in activity that is greater than the activity of either agent alone
Antibiogram
Local antimicrobial susceptibility data gathered from recent cultures obtained from patient at that institution
Culture Reports:
- S = “susceptible”
- I = “intermediate or indeterminate”
- R = “resistant”
PROPHYLACTIC THERAPY
- Treating patients who are not yet infected or have not yet developed disease.
- Goal: prevent infection in some patients or to prevent development of a potentially dangerous disease in those who already have evidence of infection
PRE-EMPTIVE THERAPY
- Early, targeted therapy in high-risk patients who already have a laboratory or other test indicating that an asymptomatic patient has become infected
- Goal: Delivery of therapy prior to development of symptoms
EMPIRICAL THERAPY IN THE SYMPTOMATIC PATIENT
Before consideration is given in selecting an antimicrobial agent, is to determine if the drug is indicated
DEFINITIVE THERAPY WITH KNOWN PATHOGEN
- Once a pathogen has been isolated and susceptibilities results are available, therapy should be streamlined to a narrow targeted antibiotic.
- Goal: Maximize efficacy and minimize toxicity
POST-TREATMENT SUPPRESSIVE THERAPY
- In some patients, after the initial disease is controlled by the antimicrobial agent, therapy is continued at a lower dose if the infection is not completely eradicated and the immunological or anatomical defect that led to the original infection is still present.
- For example, in HIV and post-transplant patients as a secondary prophylaxis
Mechanism of Resistance
Emergence of Resistance is associated with:
- Evolution
- Clinical/environmental practices
Resistance may develop because of:
- Reduced entry of antibiotic into pathogen
- Enhanced export of antibiotic by efflux pumps
- Release of microbial enzymes that destroy the antibiotic
- Alteration of microbial proteins that transform prodrugs to the effective moieties
- Alteration of target proteins
- Development of alternative pathways to those inhibited by the antibiotic
Mechanism of Action:
Cell Wall Inhibitors
Cell Wall Inhibitors:
Beta-lactams
- Inhibits peptidoglycan synthesis; peptidoglycan is a component of the cell wall that provides rigid mechanical stability
Glycopeptides (Vancomycin)
- Inhibit cell wall synthesis by binding with high affinity to the D-alanyl-D-alanine terminus of cell wall precursor units
Lipopeptides (Daptomycin)
- Binds to bacterial membranes, resulting in depolarization, loss of membrane potential, and cell death
MoA:
Protein Synthesis Inhibitors (50S)
Protein Synthesis Inhibitors
Lincosamides (Clindamycin)
- Inhibits protein synthesis by binding to 50S ribosomal subunit
Macrolides
- Inhibits protein synthesis by binding reversibly to 50S ribosomal subunits
Oxazolidinones (Linezolid)
- Inhibits protein synthesis by binding to the P site of 50S ribosomal subunit and preventing formation of the larger ribosomal-fMet-tRNA complex that initiates protein synthesis
Chloramphenicol
- Inhibits protein synthesis by binding reversibly to 50S ribosomal subunits and inhibits peptide bond formation
MoA:
Protein Synthesis Inhibitors (30S)
Protein Synthesis Inhibitors
Tetracyclines
- Inhibits protein synthesis by reversibly binding to 30S ribosomal subunit and preventing access of aminoacyl tRNA to the acceptor (A) site on the mRNA-ribosome complex
Aminoglycosides
- Inhibits protein synthesis by irreversibly binding to 30S ribosomal subunit and leads to cell death; protein synthesis is inhibited by the following:
- Interference with protein synthesis initiation
- Causing misreading of the mRNA template and incorporation of incorrect amino acids into the growing polypeptide chains
- Breakup of polysomes into nonfunctional monosomes
MoA:
Antifolate Antibiotics
Antifolate Antibiotics
Sulfonamides
- Competitive inhibitors of dihydropteroate synthase, the bacterial enzyme responsible for incorporation of PABA into dihydropteroic acid, the immediate precursor of folic acid
- Sensitive microorganisms are those that must synthesize their own folic acid otherwise it won’t work
Trimethoprim
- Inhibits bacterial dihydrofolate reductase, an enzyme downstream from the one that sulfonamides inhibit in the same biosynthetic sequence
MoA:
DNA Gyrase Inhibitors
DNA Gyrase Inhibitors
Quinolones
- Block DNA synthesis by inhibiting Bacterial topoisomerase II (DNA gyrase) and topoisomerase IV preventing the relaxation of positively supercoiled DNA required for normal transcription and replication [broad spectrum, emerging resistance]
Beta-Lactam Antibiotics
Penicillins
Penicillin
- Penicillin G / VK; Penicillin G Benzathine; Penicillin G Procaine
- Susceptible to hydrolysis by β-lactamases
Anti-staphylococcal penicillin
- Nafcillin; Oxacillin; Dicloxacillin
- Resistant to staphylococcal β-lactamases
Extended-spectrum penicillin
- Ampicillin; Amoxicillin (Amoxil); Piperacillin; Ticarcillin
- Improved activity against Gram-negative rods
- Relatively susceptible to hydrolysis by β-lactamases
- Combined with β-lactamase inhibitors (clavulanate, tazobactam) to prevent resistance
Penicillins pharmacokinetics
Not well absorbed from the GI
- Except penicillin VK and amoxicillin – only oral
- Penicillin G is not acid stable, only parenteral (syphillis)
Primarily excreted in the urine in the unchanged form
Do not penetrate well into the cerebrospinal fluid (CSF) in the absence of meningeal inflammation
- Except Ampicillin – achieves therapeutic concentrations in most body fluids
Procaine or benzathine penicillin provide tissue depots (for IM)
- Procaine absorbed over several hours; benzathine over several days
Penicillins side effects
- Allergic reactions ~0.01 to 5% – skin rashes ranging from maculopapular eruptions to exfoliative dermatitis, urticaria, and reactions resembling serum sickness (chills, fever, edema, arthralgia)
- Higher rate of maculopapular rash with ampicillin
- Rare: Hematologic toxicity (anemia, leukopenia, thrombocytopenia)
- Sodium overload from parenteral (caution with renal impairment)
Anti-Staphylococcal Penicillin
- Oxacillin - May enhance anticoagulant effect of warfarin
- Nafcillin – Higher risk of drug interactions (nasty)
- Decrease opioid concentrations; may decrease anticoagulant effect of warfarin
- Predominantly excreted through biliary system - Caution with accumulation in jaundiced neonates
- Higher risk of extravasation
β-Lactamase Inhibitors
• Sulbactam, clavulanic acid, tazobactam
- Only used in combination with a penicillin
- Dosing always based on penicillin component
- Combination extends spectrum of activity to include β-lactamase producing organisms
• Clavulanic Acid – higher diarrhea and GI effects when administered orally with amoxicillin (augmentin). Can be ameliorated with probiotic use.
Cephalosporins
Beta-lactam Abx
Generations based on spectrum of activity
1st gen– higher gram+ coverage (skin flora, post-op)
2nd gen– some gram+ coverage, some gram-
3rd gen– coverage of gram+ varies, high gram- coverage
- drug of choice for Streptococcus pneumo;
- ceftaz – only 3rd gen with Pseudomonas coverage
4th gen– broad coverage including Pseudomonas
5th gen– unique cephalosporin with broad coverage
- including Enterococcus and MRSA (only cephalosporin with this coverage, but not first-line for MRSA)
Cephalosporins pharmacokinetics, side-effects
PK:
- Primarily excreted via kidneys mainly by glomerular filtration
- Adjust doses in patients with renal insufficiency
- CTX has significant biliary excretion
- Avoid in the 1st month of life due to kernicterus risk
- Most have good penetration into tissues & fluid compartments
- Optimal for CSF: cefotaxime, CTX, cefepime
SE:
- Skin Rashes (1-3%); Anaphylactic (0.1%); thrombocytopenia
AOM
Goals of Therapy
- Pain management is important!
- Acetaminophen or ibuprofen
- Prudent antibiotic usage – Identify need for antibiotics
- Prevention with vaccinations!
- No benefit in using decongestions or antihistamines
- Topical agents (benzocaine) – only brief benefit in those > 5 yrs.
Antibiotic therapy:
*Must evaluate antibiotic therapy after 48-72 hours*
- Verify if symptoms are resolved
- Evaluate if complications develop
First Line ABX for AOM
Clinda used in true PCN anaphylactic reactions
Amox –> augmentin –> other cephalosporin –> IM CTX –> Clinda –> Clinda + 3rd gen cephalosporin (would require cx)
ABRS ABX Therapy
Augmentin
SD: 45mg/kg/day BID
HD: 90mg/kg/day BID
Beta-lactam allergy**
Non-type I hypersensitivity
Type I hypersensitivity
Acute pharyngitis: therapy
- Prescribe antibiotics only for proven cases of GAS pharyngitis
CSF Penetration (therapeutic)
