Exam 1 Flashcards
(37 cards)
What is the role of fever in the diagnosis of an infection? What are some reasons for the absence of a fever in the presence of infection (and vice versa)?
Fever is the hallmark of infection (Oral temp is > 38ºC)
*rectal temp is ~0.6º C higher, axillary temp is ~0.6º lower
Non-infectious causes of fever: (false-pos)
- Malignancy, autoimmune disease
- Drug fever (ex. β-lactams, amphotericin, anticonvulsants, hydralazine, etc.)
- Blood transfusions
Absence of fever w/ s/sx of infeciton: (false-neg)
- Antipyretics
- Corticosteroid therapy
- Antimicrobial therapy
- Overwhleming infection (may be hypothermic)
What are the typical signs and symptoms, lab tests, and radiologic findings that may be utilized to identify the presence of an infection? What changes in white count and differential are indicative of an infection caused by various pathogens?
Systemic S/Sx of infection:
- Fever (>38º or <36ºC)
- Increased WBC count (normal WBC is 4,500-10,500/mm^3, normal bands is 0-5%)
- Decreased WBC count (may be a sign of overwhelming infection)
- Chills, rigors
- Tachycardia (>90bpm)
- Tachypnea (>20breaths/min)
- Hypotension (SBP <90mmHg or MAP <70)
- Malaise
- Mental status changes
- Lymphocytosis (increased lymphocytes associated w/ viral, tuberculosis, or fungal infections)
Localized s/sx:
- pain/inflammation (ex. flank pain -> pyelonephritis (E. coli) most common
Tests:
- WBC differential (shows granulocytes & agranulocytes)
- ESR and CRP (elevated in inflammatory process, but doesn’t confirm presence of infection; can be helpful to see response to treatment)
- Procalcitonin (PCT): more specific, when elevated, suggestive of infection
- X-rays, CTs, MRI, nuclear imaging, EKG
What are common factors that can predispose a person to develop an infection?
- Alteration in normal flora
- Disruption of natural barriers (skin/mucus membranes, cilia of respiratory tract, pH, motility, integrity of GI tract)
- Age (very young & very old people)
- Immunosuppression (malnutrition, underlying diseases, hormones, drugs)
What do sensitivity and specificity mean in the context of antibody/antigen detection?
Antibody and/or antigen detection: (ex. immunofluorescence, ELISA)
- Sensitivity: pos. test in the presence of disease (chance of false negative)
- Specificity: neg. test in the absence of disease (chance of false pos.
What is the difference between empiric and directed antimicrobial therapy?
Empiric - Initiation of broad-spectrum antimicrobial therapy before we identify the pathogen and susceptibility results are known. It usually involves multiple antibiotics.
- Use an antibiogram to decide treatment. It’s a summary of susceptibility for organisms at an institution.
Direct/Targeted therapy - Used after the pathogen and susceptibility results are known. Now, we will de-escalate to the agent(s) with the narrowest effective spectrum of activity. We will also try to move from IV to PO.
What is the difference between bactericidal and bacteriostatic?
Bactericidal - Kills the organism by acting on the cell wall, cell membrane, or bacterial DNA, etc.
Bacteriostatic - Inhibit bacterial replication without killing the organism by inhibiting protein synthesis. So you need the host defenses to kill the organism.
Why may combo antimicrobial therapy be utilized (3) and what are the potential disadvantages (4) of combo therapy?
- Broaden spectrum coverage for empiric therapy if the organism isn’t adequately covered by a single agent
- Achieve synergistic bactericidal activity against a pathogen to improve the outcome
- Prevent emergence of resistance (TB, HIV)
Disadvantages: Increased cost, greater risk of drug toxicity, superinfection with resistant bacteria, antagonism
What are some drug-specific and host factors to be evaluated when choosing antimicrobial therapy? (9 main groups)
Host factors:
- Drug allergy/hx of ADR
- Pt age, weight, sex
- Pregnancy, lactation
- Genetic/metabolic abnormalities
- Renal/hepatic dysfunction
- Site of infection
- Concomitant drug therapy/nutritional supplements
- Concomitant disease states (CF, HIV, cancer)
- Prior antibiotic exposure (inc. risk of resistance)
How can you design a monitoring plan to assess the clinical response of a patient with an infection after initiation of antimicrobial therapy? What is the criteria to switch to PO therapy?
- “How’s the patient doing?”
- Lab tests: culture/susceptibility results, WBC/differential, therapeutic drug monitoring, ESR/CRP/PCT
Criteria to switch to PO therapy: overall clinical improvement, resolution of fever for 8-24 hours, decreasing WBC count, functioning GI tract, acceptable oral agent w/ good bioavailability
What factors should be assessed when a patient fails to clinically respond to antimicrobial therapy?
Patient should be better after 2-3 days.
If not:
- Incorrect diagnosis?
- Wrong abx selection?
- Host factors: immunosuppression, foreign bodies, abscess needing drainage, source control
- Due to microorganism: resistance, mixed infection (polymicrobial)
- Lab errors?
What is the structure of bacteria? Where are β-lactamases in gram pos. and gram neg. bacteria? (bacterial DNA, plasmids, cytoplasmic membrane, cell wall, outer membrane, porins, periplasmic space)
Bacterial DNA - single circular, double-stranded chromosome.
Plasmids - some bacteria have plasmids (mainly gram neg.). This is extrachromosomal, double-stranded DNA that encodes for genes whose products are not essential for cell survival, but offer certain benefits. These are transferable to other bacteria.
Cytoplasmic membrane - Acts as selective permeability barrier.
Cell wall - Gram pos. has thick cell wall, gram neg. has a thin cell wall. The cell wall acts as a permeability barrier for large molecules.
Outer membrane - In gram neg. bacteria. This contains lipopolysaccharide (LPS, endotoxin), which is an important mediator in gram neg. sepsis
Porins - In gram neg. bacteria, the outer membrane has porins. These are hydrophilic channels that permit the diffusion of essential nutrients and other small hydrophilic molecules.
Periplasmic space - In between the cytoplasmic membrane and the outer membrane of gram neg. bacteria. This is where β-lactamases are in gram neg. bacteria.
What are penicillin-binding proteins? What are their roles in bacterial replication, porins, and periplasmic space?
Penicillin-binding proteins (PBPs) - enzymes that are vital for cell wall synthesis, cell shape, and structural integrity. Inhibiting this enzyme will cause the cell to lyse.
- ex. transpeptidases (most important), carboxypeptidases, endopeptidases
If PBP is altered, there will be decreased binding affinity. This is what causes Methicillin resistance in S. aureus and penicillin and cephalosporin resistance in S. pneumoniae. In S. aureus, the mecA gene produces a new PBP (PBP2a or 2’), which aids in its resistance to methicillin.
- In this scenario, adding a β-lactamase inhibitor won’t do anything.
What is the difference between intrinsic resistance and acquired resistance?
Intrinsic resistance - Organisms are always resistance to a given antibiotic. This happens if theres an absence of target site, bacterial cell impermeability, etc.
- Ex. β-lactams vs. mycoplasma (doesn’t have a cell wall, which is the target of β-lactams)
Acquired resistance - Organisms initially susceptible to a drug become resistant. This happens when there is a change in bacterial DNA or acquisition of new DNA.
- Ex. fluoroquinoloes vs. P. aeruginosa
What are the 3 ways of transferring genetic information? What are the 3 specific mechanisms of resistance?
Ways to transfer genetic info:
- Conjugation - direct contact or mating via sex pili
- Transduction - genes are transferred between bacteria by bacteriophage
- Transformation - transfer or uptake of “free-floating” DNA from the environment; then DNA is integrated into the host DNA
Specific mechanisms of resistance:
1. Enzymatic inactivation (most common): β-lactamases, aminoglycoside-modiyfing enzymes
2. Alteration of target site: PBPs, cell wall precursors, ribosomes, DNA gyrase/topoisomerase
3. Altered permeability of bacterial cell: efflux pumps, porin changes
What are the major mechanisms of resistance for specific bacterial pathogens to the HECK-YES Ma’aM organisms?
These are all cephalosporinases (AmpC)
Enterobacter cloacae
Citrobacter freundii
Klebsiella aerogenes
Serratia marcescens
Morganella species
- Induction of β-lactamase production. At first, the gene for β-lactamase production is repressed, then it’s induced, then the gene is derepressed, then there is increased β-lactamase production
- Cefoxitin is a strong, labile inducer of β-lactamases
Due to this, these are not inhibited by the other β-lactamase inhibitors. But they ARE inhibited by the newer β-lactamase inhibitors.
How can resistance occur to third generation cephalosporins by selection of stably derepressed mutants and what is the clinical significance of this phenomenon? What do we treat them with then?
Selection - Some organisms have the AmpC gene derepressed all the time. This is really rare, but it happens. Using a 3rd gen cephalosporin may kill 99.9% of the organisms, but then that 0.1% will replicate. This is associated with increased mortality.
Treatment:
- Cefepime (4th gen cephalosporin)
- Carbapenem (meropenem, imipenem, ertapenem)
- Non-β-lactam antibiotics
What is the clinical significance of extended-spectrum β-lactamases? What are risk factors for infections caused by these β-lactamases? What is the appropriate treatment of infections caused by organisms producing these enzymes?
ESBL - the enzyme has changed so that it has expanded the drugs that it can hydrolyze.
- Ex. CTX-M-15
Risk factors: prolonged hospital/ICU/neonatal ICU stay, residency in long-term care facility, exposure to 3rd gen cephalosporin, exposure to ciprofloxacin, etc.
Treatment: carbapenems (meropenem, imipenem, dorpenem, ertapenem
- careful if they are on valproic acid, since it increased the metabolism of valproic acid
What are the examples of narrow-spectrum β-lactamases, ESBL, serine carbapenemases, metallo-β-lactamases, and cephalosporinases?
Narrow-spectrum: staphylococcal penicillinase
ESBL: CTX-M-15
Serine carbapenemases: KPC-1, KPC-2, KPC-3
Metallo-β-lactamases: VIM-1, IMP-1, NDM-1
Cephalosporinases: AmpC
What is the mechanism of vancomycin resistance in enterococci? What is the importance of the vanA phenotype?
Vancomycin inhibits cell wall synthesis by binding to the D-alanine-D-alanine terminus of the pentapeptide. If the D-alanine-D-alanine terminus is changed, vanc will have significantly less binding affinity to the sequence.
- Treatment is daptomycin or linezolid
We can test for VanA and VanB. These cause a high level of vancomycin resistance AND they are on a plasmid (highly transferable).
What is the preferred treatment options for organisms with serine carbapenemases (KPC), metallo-β-lactamases (NDM, VIM, IMP), or OXA-type in CRAB?
Serine carbapenemases (KPC)
- ceftaidime/avibactam
- meropenem/vaborbactam
- imipenem/cilastatin/relebactam
- Cefiderocol (Fetroja)
Metallo-β-lactamases (NDM, VIM, IMP)
- aztreonam + ceftazidime/avibactam
-Cefiderocol
OXA-type in carbapenem-resistant Acinetobacter baumannii (CRAB)
- High dose sulbactam
- Sulbactam/durlobactam
- Cefiderocol
- Minocycline
What are the 3 mechanisms of resistance for aminoglycoside-modifying enzymes?
- Acetylation
- Nucleotidylation
- Phosphorylation
These modify aminoglycoside structure by transferring a chemical group to a specific side chain. This impairs uptake and/or binding to the bacterial ribosome.
Which drugs are the biggest sustrates of the efflux pumps?
Ciprofloxacin
Levofloxacin
(quinolones)
What are the usual methods used in antimicrobial susceptibility testing and how do we use information from these to make clinical decisions?
Broth dilution - Gold standard where there are two-fold dilutions of drug concentration in liquid media (no protein) [ex. 1mcg/mL, 2, 4, 6, 16mcg/mL]. Then, add the organism and incubate for ~24 hours. From this we can determin the MIC.
Agar dilution - two-fold dilutions of antibiotic incorporated into molten agar that’s poured into petri dishes and allowed to solidify. Then we let the bacteria inoculate over time. The MIC would be the agar plate with the lowest concentration of drug to prevent growth.
Disc diffusion - A fixed amount of antibiotic is impregnated into a disc. We put the organism on the surface of the agar, then incubate it. We can observe the zone of inhibition from this. The only results are S, I or R (not MIC).
Etest - (Epsilometer test) These are rectangular strips that have a concentration gradient of the antibiotic. We take the organism and streak it across the plate, incubate it, then see where the growth stops. The MIC is the conc on the strip where the bacterial growth intersects that strip.
We use these to determine the MIC, which we can use to decide treatment
What is MIC and MBC?
MIC - Minimum inhibitory concentration. lowest drug concentration that prevents visible growth (unaided eye)
MBC - Minimum bactericidal concentration. Lowest drug concentration resulting in ≥99.9% decrease in initial bacterial inoculum. We don’t do this clinically.
