Synthetic Antibacterials TBL

sulfonamide

sulfasalazine

Trimethoprim

Fluroroquinolones

sulfones

metrodinazole

nalidixic acid

phosphoymcin

methenamine/hexamine

microdantin/nitrofurantoin

sulfonamides

Synthetic antimicrobials containing a sulfonamide function as a common functional group

bacteriostatic antimetabolites

sulfonamide mode of action

dihydropteroate synthase

sulfonamide mechanism of action: interfere with nucleic acid synthesis by inhibiting _____________________

dihydrofolic acid

in some bacteria, the sulfonamides also block the biosynthesis of ________________________ by acting as false metabolites

dihydropteroate synthase

sulfonamide false metabolites are converted by __________________________________ to different intermediates (inactive analogs of dihydropteroic acid), which cannot continue down the normal pathway

folic acid

Humans do not have the necessary enzymes to biosynthesize ______________ so they are immune to the antimetabolites effect of sulfonamides

resistant

bacteria capable of taking up preformed folic are intrinsically resistant to sulfonamides

acidic

the more _____________ the sulfonamide N-H group, the better the inhibition and the more water soluble the drug at physiological pH

sulfoxazole

Is sulfonamide or sulfoxazole more water soluble at physiological pH?

resonance

______________ stabilizes the conjugate base upon ionization, making sulfonamides more soluble and causing less crystal deposits in the kidneys

sulfonamides

Spectrum includes:

-uncomplicated UTIs (E. coli)

-Pneumocystis carinii (jirovecii) fungal infections for immunocompromised patients

-second or third choice for other susceptible bacteria

-topical treatment for gardnerella vaginalis

oral

sulfonamide bioavailability

sulfonamide metabolism

deactivated in the liver N-4 acetylation (mainly) hydroxylamine formation and glucuronidation (phase I and II)

intermediate

sulfonamide protein binding is _____________ (30-70%)

plasmids

sulfonamide resistance involves having altered dihydropteroate synthase, which is most commonly transmitted by ______________

rash

most common adverse reaction to sulfonamides

haptens

Sulfonamides form ______________ but are not cross-allergenic with B-lactam antibiotics

stevens-johnson syndrome

rare and severe sulfonamide allergy characterized by ulceration of mucous membranes of eye, mouth, and urethra (aka Erythema multiforme major)

sulfonamide adverse effects

-Allergy: most common adverse effect = rash; also photosensitivity, sore throat, drug fever

-Crystalluria: causes nephritis

-Liver and kidney damage, and hemolytic anemia are less common

-Stevens-Johnson syndrome

Sulfasalazine (Azulfidine)

Prodrug to treat both ulcerative colitis and Cron's disease (anti-inflammatory); NOT an antimicrobial agent

5-ASA (m-aminosalicylic acid)

the active anti-inflammatory component for treating both ulcerative colitis and Chron's disease; metabolized from sulfasalazine because it would be irritating to the

dihydrofolate reductase (DHFR)

bacterial enzyme that trimethoprim acts on; also in mammals but is far less sensitive to inhibition by trimethoprim

1:5

Synergistic with sulfonamides: the combination of trimethoprim/sulfamethoxazole (Bactrim) is used clinically as a ratio of __________

trimethoprim-sulfamethoxazole spectrum

used primarily against UTIs but also finds significant use against:

-shigellosis, otitis media, traveler’s diarrhea, bronchitis

-Pneumocystis carinii infections in AIDS patients, MRSA infections, pneumococci, enterobacteria, E. coli, Klebsiella, Pneumoniae, Proteus mirabilis and Proteus vulgaris, Salmonella typhi, Serratia marcescens, Shigella, Yersinia, Aeromonas, Bordetella, Brucella, Haemophilus, Legionella, Vibrio cholerae, non-aeruginosa pseudomonas

DHFR

trimethoprim resistance is developing fast via alterations in the structure of ___________

trimethoprim adverse effects

-Rash, nausea, and vomiting most common

-Rarer: blood dyscrasias and pseudomembranous colitis due to superinfection by C. diff

-Discontinue drug if severe diarrhea occurs

first generation fluoroquinolones

Norfloxacin, Lomefloxacin, Ciprofloxacin, Ofloxacin (racemic)/levofloxacin (1-S)

second generation fluoroquinolones

moxifloxacin, gatifloxacin

bacteriostatic

trimethoprim mode of action

oral

trimethoprim bioavailability

bactericidal

fluoroquinolone mode of action

fluoroquinolones

MOA: inhibit bacterial DNA gyrase and topoisomerase IV (both are subtypes of topoisomerase II) but not mammalian DNA topoisomerase II (which is similar in function)

topoisomerase

relieve the tension of supercoiled DNA before replication by breaking and reconnecting DNA strands at specific locations

Decreased uptake

topoisomerase

bacterial fluoroquinolone resistance is due to _________________ and altered _________________

oral

fluoroquinolone bioavailability

fluoroquinolones

should not be taken with dairy, antacids, hematinics, and tonics due to chelation with metal ions

6-fluoro

fluoroquinolone modification that broadens spectrum to include gram-positives

7-piperazinyl

fluoroquinolone modification that has antipseudomonal activity, reduces metabolism of other drugs, and may increase CNS adverse effects

8-methoxy (in 2nd gen)

fluoroquinolone modification that enhances activity against gram-positives and reduces CYP450 metabolism of FQs

fluoroquinolone adverse effects

-CNS: pro-convulsant, occasionally hallucinations, insomnia, visual

-Erosion of joints (not normally given before puberty or to sexually active females of child-bearing age)

-GIT: diarrhea, vomiting, abdominal pain, anorexia

-Other: photosensitivity, liver damage, prolongation of QT interval; bad/metallic taste

CYP-450

drugs metabolized by ______________ may be affected by fluoroquinolone therapy due to inhibition of these enzymes

fluoroquinolone spectrum

-Broad spectrum and used for many infections

-UTI (due to enterobacteria, enterococci); lower RTI, prostatitis, SSSI, GI infections due to S. aureus, MRSA, PPNG, gonococcus, campylobacter, E. coli, Klebsiella, Proteus, Providencia, Salmonella typhi, Serratia, Shigella, Yersinia, Acinetobacter, Aeromonas, Legionella, Pseudomonas (except moxifloxacin), Vibrio cholerae, TB, Chlamydia, rickettsia, cat scratch fever, Haemophilus, etc.

target, uptake

resistance to fluoroquinolones is developed through alteration _____________ enzymes and changes in __________ mechanisms

sulfones

differ from sulfonamides in that the central sulfur is attached to two carbons; MOA is not clearly understood but thought to be the same as sulfonamides

sulfones

have special utility in treating Hansen's disease (leprosy) caused by mycobacterium leprae; also in pneumocystis jirovecii pneumonia

oral

sulfones bioavailability

sulfones

treatment is required for a cure and the drug will not restore lost tissue

sulfone adverse effects

dose released hemolysis; methemoglobinemia, severe cutaneous adverse reactions (SCARS); orange yellow skin discoloration when topically applied with benzol peroxide

metranidazole

synthetic antimicrobial with a nitroimidazole ring used for infections, such as amoebal vaginitis, trichomoniasis, Giardiasis and Gardnerella vaginalis (Gram variable) infections of the vagina

metronidazole spectrum

treatment of anaerobic and microaerophilic infections including those by C. diff, Cl. Perfringens, Bacteroides, and H. pylori

metronidazole

MOA: bind with critical cysteine-containing enzymes or may directly react with DNA, causing death of anaerobic microorganisms and protozoa

metronidazole adverse effects

metallic taste and disulfiram-like effects (nausea and GI cramps after consumption of alcohol)

nitroimidazoles

metronidazole class

Nalidizic acid (Negram)

older analog (naphthyridinone) of the fluoroquinolones given orally for treatment of uncomplicated UTIs

bactericidal

Nalidixic acid mode of action

inhibits DNA synthesis

nalidixic acid MOA

phosphomycin

bactericidal agent that inhibits cell wall synthesis; primarily used against E. coli and enterobacter

methenamine/hexamine

depolarizes in acid to ammonia and formaldehyde; liberated formaldehyde is a non-specific bactericide; used for treatment of recurrent UTIs

macrodantin/nitrofurantoin

orally active; for treatment or prophylaxis; bactericidal - inhibits DNA and RNA functions; little resistance developed so far; nausea and vomiting due to rapid absorption