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These next three classes of drugs affect nucleic acid synthesis. The first is Fluoroquinolones. What is the MOA?

Only class of antimicrobial agents that are direct inhibitors of bacterial DNA synthesis
--inhibit two bacterial enzymes, DNA gyrase (topoisomerase II) and topoisomerase IV
-results in damage to bacterial DNA and bacterial cell death


What is the resistance in fluoroquinolones?

Emerged rapidly esp in C. jejuni, gonococci and gram positive coci, P. aeruginosa and Serratia. Mechanisms behind the resistance include mutations in chromosomal genes that:
--encode the subunits of DNA gyrase and topoisomerase IV
--regulate the expression of cytoplasmic membrane efflux pumps
Cross resistance between the fluoroquinolones does exist


What is the spectrum of activity and clinical application of fluoroquinolones?

Activity against gram negative aerobic bacteria
Limited activity against gram positive bacteria


Just like in cephalosporins drugs there are different generations based off gram + and negative activity. Each card will go through each generation. The first generation drug is Nalidixic Acid, what are some feature?

Mainly gram negative organisms
Bactericidal concentrations can only be achieved in urine so main use in uncomplicated urinary tract infections


The second generation Fluoroquinolone is Ciprofloxacin, what are some feature?

Gram negative bacteria
Some gram positive activity
Synergistic with the beta lactam antibiotics
tx of travelers diarrhea, pseudomonas aeruginosa infections (cystic fibrosis patients) and as an alternative to ceftriaxone and rifampin for prophylaxis against meningococcal infection


The third generation Fluroquinolone is Levofloxacin. What are some features?

Less active than cipro against gram - bacteria
Greater activity against gram + cocci (s. pneumoniae and strains of enterococci and MRSA)
--tx of prostatitis caused by E. coli infections, STDs, skin infections, acute sinusitis and chronic bronchitis and tuberculosis
--activity against organisms associated with community acquired pneumonia (s. pneumoniae, chlamydiae, mycoplasma, and legionella)


The fourth generation Fluroquinolone is Moxifloxacin and Gemifloxacin. What are some features?

Broadest spectrum, enhanced activity against anaerobes and atypical pneumonia agents
Tx: Respiratory fluoroquinolones -- used in tx of pneumonia, when first line has failed or if patient is inpatient


In general what are the pharmacokinetics for Fluoroquinolones?

Good oral bioavailability
Penetrate most body tissues
Divalent or trivalent cations interfere with oral absorption and bioavailability
Dose adjustments are needed in renal dysfunction except for moxifloxacin which is eliminated by hepatic metabolism and biliary excretion


What are the adverse effects of Fluoroquinolones?

GI distress: N/V/D
Connective Tissue Problems: tendinitis and tendon rupture
QT prolongation: due to inhibition of potassium channels
Superinfections: C. diff, C. albicans and strep
Other adverse effects: CNS effects, rash, photosensitivity


What are drug interactions with Fluoroquinolones?

NSAIDs and corticosteriods
--enhance toxicity of fluoroquinolones
Levo, Mox and Gem all raise serum levels of warfarin, caffeine and cyclosporine


What are the contrainidications of Fluoroquinolones?

Prego and Nursing: absence of data
Children under 18: due to development of arthropathy with erosions of the cartilage in weight bearing joints


Next set of drugs that affect nucleic acid synthesis are the Sulfonamides (Sulfamethoxazole, Sulfadiazine, Sulfasalazine). What is their MOA?

Analogues of p-aminobenzoic acid (PABA)
--competitive inhibitors (and substrates) of dihydropterote synthase and thus folate production
Combo of a sulfa with an inhibitor of dihydrofolate reductase (trimethoprim) provides synergistic activity due to inhibition of folate synthesis


What are the reasons for sulfa resistance?

--cause overproduction of PABA
--alter affinity of drugs for dihydropteroate synthase
--decrease cellular permeability
--decrease intracellular drug accumulation


What is the spectrum of activity and clinical applications of sulfa drugs?

Bacteriostatic active against gram + and gram - organisms
Poor against anaerobes
Not used as single agents due to resistance
Still used as topical agents to treat ocular or burn infections
Oral agents for the tx of simple UTIs


What is sulfasalazine specifically used for?

Oral, nonabsorable agent that is widely used in the tx of ulcerative colitis, enteritis, and other inflammatory bowel diseases


What are the pharmacokinetics for sulfa drugs?

Oral and absorbable
Oral and non-absorbable
Renal failure: dosage of oral, absorbable agents must be reduced


What are the adverse effects of sulfa drugs?

All are considered to be partially cross allergenic
1. Common: fever, skin rashes, photosensitivity, urticaria, nausea, vomiting and diarrhea
2. Crystalluria/nephrotoxicity: precipitate in urine, esp at neutral or acid pH
3. Hematopoietic disturbances: cause hemolytic or aplastic anemia
4. Kernicterus: taken near end of pregnancy increases the risk of kernicterus in newborns.


What are the drug interactions of sulfa drugs?

Competition with warfarin, phenytoin, and methotrexate for plasma binding can increase the plasma levels of these drugs


What are the contraindications of sulfa drugs?

Newborns and infants less than two months (due to risk of kernicterus)


The next drug under the nucleic acid synthesis drugs is a DHFR inhibitor called Trimethoprim. What is the MOA?

Inhibits bacterial dyhydrofolic acid reductase (Converts dihydrofolic acid to tetrahydrofolic acid)
--leads to inhibition of bacterial purine, pyrimidine and amino acid synthesis


Resistance to trimethoprim can result from?

1. Reduced cell permeability
2. Overproduction of dihydrofolate reductase
3. Production of an altered reductase with reduced drug binding


What is the spectrum of activity and clinical applications of trimethoprim?

20-50 times more potent than sulfa drugs
Main use:
--tx of UTIs, bacterial prostatitis and vaginitis


What are the pharmacokinetics for trimethoprim?

Weak base trapped in acidic environments
--reaches high concentrations in prostatic and vaginal fluids


What are the adverse effects for trimethoprim?

Antifolate effects: megaloblastic anemia, leucopenia and granulocytosis can usually be ameliorated by supplementary folic acid


The last drug under nucleic acid synthesis inhibitor is Cotrimoxazole. What is the MOA and resistance?

Combo of trimethoprim and sulfa drug (sulfa + DHFR inhibitor)(dihydropteroate synthase and dihydrofolate reductase)
--antimicrobial synergy results from the sequential blockade of folate synthesis
Bactericidal against susceptible organisms


What is the spectrum of activity for Cotrimoxazole?

Effective orally in the tx of UTIs and in resp, ear and sinus infections caused by H. influenzae and M. catarrhalis
--drug of choice for uncomplicated UTIs


In the immunocompromised patient, Cotrimoxazole is used for infections due to what?

Aeromonas Hydrophilia and is the drug of choice for prevention and tx of pneumocystic pneumonia (PCP)


Cotrimoxazole is also the drug of choice for what?

Nocardiosis and an alternative tx in toxoplasmosis (DOC= pyrimethamine + sulfadiazine + leucovorin)


What are the pharmacokinetics for Cotrimoxazole?

Given orally but an IV preparation is available for patients unable to take the drug by mouth
--well distributed including CSF


What are the adverse effects of Cotrimoxazole?

May cause adverse effects associated with sulfa drugs
AIDS patient have a higher incidence of adverse effects (fever, rashes,diarrhea)

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