Pharmacology Exam 5

What is a narrow spectrum antibiotic?

drug efficacy is limited to a few selective microorganisms

What is a broad spectrum antibiotic?

drug efficacy extends to a wide range of microorganisms; potency of drugs may differ

What does it mean if an antibiotic is bacteriostatic?

inhibit bacterial cell replication, allowing host defenses to contain the infection and cause bacterial cell death

What does it mean if an antibiotic is bactericidal?

result in bacterial cell death and lysis- lethal to bacteria

What does it mean if an antibiotic is concentration dependent?

rate and extent of bactericidal activity increases with increasing drug concentrations

What does it mean if an antibiotic is time dependent?

-bactericidal activity does not increase with increasing concentrations above the MIC?
-bactericidal activity continues as long as serum concentrations are > MIC?

What is the post antibiotic effect?

persistent suppression of bacterial growth after limited exposure to an antibacterial agent; most likely represents an extension of the lag phase of bacterial growth

What is synergy in reference to antibiotics?

combination of 2 agents produce a decrease in colony counts that is 100 fold lower than when either agent is tested alone

What is antagonism in reference to antibiotics?

effect of combination is less than the added effects from the 2 individual drugs

What is emperic therapy?

"Best guess" based on most likely organism causing the infection- aimed at organisms suspected

What are the 3 signs/symptoms of microbial infection?

fever
leukocytosis
pain/inflammation

How are WBC's altered in a bacterial infection?

-elevated granulocytes (neutrophils and basophils) with increased bands (Left shift in peripheral blood smears
-a low neutrophil count in a bacterial infection has poor prognosis

How are WBC's altered in fungal or viral infections?

relative lymphocytosis, with normal to increased WBC counts

What are the 5 major reasons for using combination antimicrobial drug therapy?

-broad-spectrum empirical therapy in seriously ill patients
-polymicrobial infections involving both aerobic and anaerobic organisms
-decrease emergence of resistant strains
-allows dose reduction of one or more agents to decrease dose-related toxicity
-enhanced activity (synergism)

What are 2 major disadvantages of combination therapy?

additive nephrotoxic effects and antagonism

Why should bactericidal and bacteriostatic agents not be used for the same infection?

-inhibition of bacterial growth by the static agent prevents the presence of actively dividing bacteria required for activity of some bactericidal agents
-inhibition of active uptake of some bactericidal agents

What is the basis for selective toxicity for cell wall synthesis inhibitors?

absence of cell wall in eukaryotes

What is the basis for selective toxicity for bacterial protein synthesis inhibitors?

differences in ribosomal composition and size

What is the basis for selective toxicity for sulfonamides?

-mammalian cells utilize preformed folic acid and have specialized transport mechanisms for its absorption
-bacterial cells do not have these transport mechanisms the must synthesize folic acid intracellularly

What is the basis for selective toxicity for trimethoprim?

has 50,000-fold greater affinity for bacterial DHFR

What is the basis for selective toxicity for rifampin?

only targets bacterial RNA polymerase

What is the basis for selective toxicity for fluoroquinolones?

needs very high concentrations of drug required to inhibit eukaryotic DNA synthesis

What is the MOA of penicillins and cephalosporins?

Inhibit bacterial cell wall synthesis by covalent binding to cell wall precursors preventing transpeptidase cross linking

Are penicillins and cephalosporins bactericidal or bacteriostatic?

bactericidal

Are penicillins and cephalosporins concentration or time dependent?

time dependent - concentration independent

Which bacteria do penicillins and cephalosporins cover?

mostly g+, some g-

What is the MOA of imipenem/cilastatin?

bind to 1 or more PBPs (transpeptidase that makes up cell wall)

What is the role of cilastatin in imipenem/cilastatin?

Cilastatin protects imipenem from degradation, prolonging its antibacterial effect in the kidney by inhibition of renal dehydropeptidase

What is the MOA of vancomycin?

acts on the second stage of cell wall synthesis by inhibiting utilization of lipid intermediates in peptidoglycan synthesis

Is vancomycin bactericidal or bacteriostatic?

bactericidal but bacteriostatic for enterococci

Is vancomycin concentration or time dependent?

time dependent- concentration independent

What is the MOA of bacitracin?

inhibits bacterial cell wall synthesis by inhibiting dephosphorylation step in synthesis by preventing regeneration of the lipid carrier

Which bacteria does bacitracin cover?

g+

Is bacitracin bactericidal or bacteriostatic?

bactericidal

What is the MOA of polymyxins?

Inhibit cell membrane function- alters cytoplasmic membrane permeability by binding to a negatively charged site in the lipopolysaccharide layer which has an electrostatic attraction for the positively charged amino groups in the cyclic peptide portion--> fatty acid portion dissolves in hydrophobic region of membrane and disrupts membrane integrity --> leakage of cellular molecules, inhibition of cellular respiration-->binds and inactivates endotoxin

Are polymyxins bactericidal or bacteriostatic?

bactericidal

Which bacteria do polymyxins cover?

g-

What is the MOA of daptomycin?

Inhibition of cell membrane function- binds to bacterial membranes and causes rapid depolarization of the cell membrane; loss of membrane potential leads to inhibition of protein, RNA, and DNA synthesis, resulting in cell death

Is daptomycin bactericidal or bacteriostatic?

bactericidal

Is daptomycin concentration or time dependent?

rapid concentration dependent

Which bacteria does daptomycin cover?

aerobic g+

What is the MOA of aminoglycosides?

interacts with 30S subunit receptor protein and alters its conformation blocking ribosomal movement along mRNA "frozen" in initiation phase

Are aminoglycosides bactericidal or bacteriostatic?

bactericidal

Are aminoglycosides time or concentration dependent?

rapid concentration dependent

What is the MOA of tetracyclines?

bind to *30S* subunit receptor and block binding of aa-tRNA to mRNA- ribosomal complex at the A site *preventing chain elongation*

Are tetracyclines bactericidal or bacteriostatic?

bacteriostatic

What is the MOA of chloramphenicol?

binds to *50S* at the propanediol portion of the molecule- interferes with binding of aa-tRNA to 50S subunit at the P site and inhibits peptidyl transferase --> *prevents chain elongation*

Is chloramphenicol bactericidal or bacteriostatic?

bacteriostatic

What is the MOA of macrolides?

binds reversibly to the *50S* subunit P site- binding site is 23S rRNA- inhibits translocation by preventing proper association of the peptidyl-tRNA chain with its binding site after peptide bond formation--> prevents chain elongation

Are macrolides bactericidal or bacteriostatic?

bacteriostatic

Macrolides interfere with binding of which other antibiotics?

Interferes with binding of *chloramphenicol and clindamycin* at the 50S site but erythromycin is not inhibited by the 2 drugs

What is the MOA of clindamycin?

binds to *50S* subunit- inhibits peptidyl transferase rxn by interfering with the binding of the aa-tRNA to the A site--> *prevents chain elongation*

Is clindamycin bactericidal or bacteriostatic?

bacteriostatic usually but bactericidal against highly susceptible organisms

Clindamycin is antagonized by which other antibiotics?

erythromycin and chloramphenicol

What is the MOA of sulfonamides?

structural analog of para-aminobenzoic acid (PABA) which is required in the bacterial cell for synthesis of folic acid

Are sulfonamides bactericidal or bacteriostatic?

bacteriostatic

What is the MOA of trimethoprim?

Competative inhibitor of bacterial dihydrofolate reductase (DHFR)

Is trimethoprim bactericidal or bacteriostatic?

bacteriostatic

What is the MOA of rifampin?

Inhibits bacterial DNA-dependent RNA polymerase (beta subunit) by altering conformation and inhibiting RNA synthesis

Is rifampin bactericidal or bacteriostatic?

bactericidal

What is the MOA of fluoroquinolones?

Inhibit DNA gyrase (topoisomerase II) and topoisomerase IV- inhibiting DNA replication

Are fluoroquinolones bactericidal or bacteriostatic?

bactericidal

Are fluoroquinolones time or concentration dependent?

concentration dependent

What is the MOA of nitrofurantoin?

enzymatic reduction and cause DNA strand breakage by either direct reaction or by generation of O2 radicals

Is nitrofurantoin bactericidal or bacteriostatic?

bactericidal or bacteriostatic depending on concentration

What is the MOA of metronidazole?

nitro group reduced by bacterial enzymes to reactive intermediates which covalently bind DNA causing lethality

Is metronidazole bactericidal or bacteriostatic?

bactericidal

Which bacteria does metronidazole cover?

anaerobic

What are the mechanisms for resistance for beta lactams?

-beta lactamases
-altered affinity for PBPs
-altered porins (in g-)

What 3 factors determine the efficacy of beta-lactams for gram-negative bacteria?

- ability to penetrate outer membrane
- beta-lactamase sensitivity (note location in periplasmic spaces)
- intrinsic ability to bind to PBP

What is beta lactamase?

A bacterial enzyme that catalyzes the hydrolysis of the lactam ring --> inactivating beta lactams

Which drugs inactivate beta lactamase?

-clavulanic acid
-sulbactam
-tazobactam

What is the major mechanism for resistance of MRSA?

MRSA contained a mutated PBP2 (PBP2A) with no affinity for beta-lactams

What is the major mechanism of transmission of MRSA?

dissemination through an infected or colonized health care worker; typically, transmitted on the hands of a health care worker after contact with an infected patient; prevention of spread is critical

What are the mechanisms for resistance for vancomycin

-resistance genes code for enzymes that produce a modified peptidoglycan side chain to which vancomycin cannot bind
-the terminal D-ala-D-ala in the peptidoglycan is changed to D-ala-D-lactate to which vancomycin cannot bind

What is the DOC for MRSA bacteremia?

IV vancomycin or IV daptomycin

What is the DOC for MRSA infective endocarditis?

IV vancomycin or IV daptomycin

What is the DOC for MRSA pneumonia?

IV vancomycin
-alternative: IV or PO linezolid or clindamycin

What is the DOC for MRSA meningitis?

IV vancomycin

What are the risk factors for vancomycin-intermediate resistant S. aureus (VISA)?

- renal failure requiring dialysis, and multiple other medical problems

- peritoneal catheters or other indwelling devices

- MRSA infections treated with repetitive or prolonged courses of vancomycin (6-18 weeks) which ultimately failed, with other antibacterials being used successfully

- diabetes

What is the DOC for vancomycin-intermediate resistant S. aureus (VISA)?

linezolid or daptomycin

What are the 2 major enterococcal pathogens in humans?

Enterococcus faecalis and enterococcus faecium

What serious infections can enterococci cause in humans?

-endocarditis
-intra-abdominal infections
-UTI's
-bacteriemias

What is the DOC for beta-lactam resistant enterococci or in beta-lactam allergy?

vancomycin

How did enterococci develop resistance to vancomycin?

- production of two distinct membrane-bound bacterial enzymes which cause alterations in the normal peptidoglycan assembly pathway, resulting in the loss of the normal vancomycin binding site on cell wall components
-genes coding for these abnormal proteins are termed "vanA" and "vanB"
-the terminal D-ala-D-ala portion of the peptidoglycan side chain where cross-linking occurs is replaced by D-ala-D-lactate

What are risk factor for VRE?

- previous vancomycin use (IV or po) resulting in GI colonization with VRE
- previous use of broad-spectrum antibacterials
- immunosuppression, increasing number of neutropenic patients, antineoplastic therapy
- prolonged hospital stay
- abdominal surgery
- use of indwelling urinary or central venous catheters

How is VRE prevented and managed in hospitals?

-reserve for treatment of infections in which there is high suspicion or documentation of beta-lactam-resistant g+ organisms (MRSA, MRSE, ampicillin-resistant enterococci)
-strongly discourage routine use for surgical prophylaxis, or any use for nonsurgical prophylaxis
-reserve po vancomycin only for antibiotic-associated pseudomembranous colitis (AAPMC) in patients not responsive to two courses of metronidazole or in life-threatening colitis; recurrence or relapse of C. difficile colitis is not an indication for po vancomycin

What is the DOC for nonVRE enterococci infections?

Penicillin or ampicillin

What is the DOC for nonVRE bacteremia?

penicillin or ampicillin + an aminoglycoside

What is the MOA for VRE bacteremia with high PCN resistance?

linezolid or daptomycin

What is the mechanism of resistance for penicillin-resistance S. pneumonia (PRSP)?

mechanism appears to be alteration of PBP in cell wall and reduced affinity for 3 or more PBPs

What is the DOC for initial management of PRSP in acute otitis media?

Amoxicillin high dose or Augmentin with specific 14:1 ratio

What is the DOC for initial management of PRSP in acute otitis media in patients with beta-lactam allergy?

If no anaphylaxis: cefdinir, cefuroxime, cefodoxime, or ceftriaxone
If anaphylaxis: consider cephalosporins- or macrolides or clindamycin

What is the DOC for community acquired pneumonia in an adult outpatients with no comorbidities?

-amoxicillin or doxycycline or macrolide

What is the DOC for community acquired pneumonia in an adult outpatients with comorbidities?

-Augmentin or cephalosporin *+* a macrolide or doxycycline

What is the DOC for community acquired pneumonia in an adult inpatients with nonsevere disease?

-beta lactam + macrolide
-OR fluoroquinolone monotherapy

What is the DOC for community acquired pneumonia in an adult inpatients with severe disease?

-beta lactam + macrolide OR -beta lactam + fluoroquinolone