-lactam.

Bactericidal.
Combination between L-cysteine and D-valine  resemble D-Ala-D-Ala terminus.
Acylate active site of transpeptidase (enzyme recognizes -lactam)  inactive.
Bacteria with -lactamase will cleave acylation.
Autolysins (murein hydrolyases) nick cell wall.
Good for gram+ cocci and bacilli. Extended spectrum: also for gram- bacilli.
Actively secreted by proximal tubule  short half-life.
Add probenecid to block active renal secretion (competitive inhibitor).
Toxicity:
Anaphylactic/allergic response via IgE  bronchospasm, urticaria, shock, rash.
Diarrhea via destroying natural GI flora.
Group I: penicillin G (benzylpenicillin), penicillin V (phenoxymethylpenicillin).
Narrow spec, penicillinase-sensitive.
Penicillin G has two depot forms for deep IM injection: procaine, benzathine
suspensions. Crystalline form increases half-life.
Lowest MIC so drug of choice for G+c, G+b, G-c.
-lactam ring is acid labile  need parenteral.
Inhibits GABA-gated chloride ion flux.
Penicillin V more stable at acid pH. Good for oral administration.
Penicillins Group II: methicillin, oxacillin, cloxacillin, dicloxacillin, nafcillin.
Narrow spec, penicillinase-resistant, “antistaphylococcal,” bulky side-chains.
Methicillin, nafcillin, oxacillin: IV.
Oxacillin acid stable.
Cloxacillin, dicloxacillin: oral. Used for gram+ only (S. aureus).
Methicillin causes nephrotoxicity  no longer used.
MRSA bacteria overcome penicillinase-resistant drugs  use vancomycin.
Bacterial: Nafcillin is drug of choice for S. aureus: cellulitis, endocarditis, sepsis.
Cell wall Group III: ampicillin, amoxicillin (aminopenicillins).
synthesis Broad spec, penicillinase-sensitive.
Good for Proteus, Haemophilus, Salmonella, E. coli, Enterobacteriaceae, H. pylori.
One of the few drugs for gram+ enterococcus.
Good for URI infections from S. pyogenes, S. pneumoniae, H. influenzae.
Ampicillin is acid-stable but absorption is affected by food intake  variable.
Often give with gentamicin: “Amp-gent.” Gives broader spec.
Amoxicillin is acid stable, absorbed by GI tract. Spectrum extended to G-b.
Drug of choice for Listeria.
Group IV
Carboxypenicllins: carbenicillin (prototype), carbenicillin indanyl, ticarcillin.
Carbenicillin high dose  high soium load, plately dysfunction, hypokalemia.
Ureidopenicillins: piperacillin, azlocillin, mezlocillin.
“Antipsedumonal,” penicillinase-sensitive.
Good for P. aeruginosa, Enterobacteriaceae, Bacteroids.
-lactam.
Irreversibly bind to and inhibit class A, C, D -lactamases (plasmid encoded).
Inactive against chromosomal (class B) -lactamases.
Weak intrinsic activity so use with penicillin’s.
Covers -lactamases of G+ and G- bacteria. Most active for plasmid-encoded,
inactive against chromosomal and inducible.
-lactamase Clavulanic acid.
inhibitors Augmentin = clavulanic + amoxicillin. Oral. Clavulanate is at max dose.
Timentin = clavulanic + ticarcillin.
Cannot inhibit class B -lactamases.
Sulbactam.
Unasyn = sulbactam + ampicillin.
Tazobactam.
Zosyn = tazobactam + piperacillin. Broadest spectrum of penicillins.
 -lactam.
Bactericidal.
Shouldn’t be used first: expensive, can cause superinfections.
Broad-spectrum: gram+ cocci and gram- bacilli.
Later generations gain G- but lose G+ activity. Same strep activity.
Ceftazidine, cefoperzone, cefepime are only ones for P. aeruginosa.
Toxicities:
IgE-mediated immune reaction with rash.
Synergistic nephropathy with aminoglycosides.
Inhibit platelet aggregation.
Intolerant to alcohol.
Prolong prothrombin time due to MTT group.
Resistance: cephalosporinases, MRSA, enterococci.
Don’t give to patients with reactions to penicillin: cross-reactivity.
First generation: cephalothin, cefazolin, cephalexin, cefadroxil, cephapirin,
cephradine.
Narrow spec.
Cephalosporins Good for S. aureus, Streptococci.
(Class of Cephalexin and cefradoxil: effective orally.
Penicillin) Cephalothin: deacetylated by liver esterases to less active metabolites.
Second generation: cefamandole, cefuroxime, cefaclor, cefoxitin, cefotetan,
cefmetazole, cefonicid, cefprozil, loracarbef, cefdinir.
Intermediate spec.
Good for G-r: E. coli, Klebsiella, Proteus, Hemophilus.
Cefuroxime: sinusitis and otitis media (from H. influenza, M. catarrhalis).
Use with community-acquired bacterial pneumonia if you don’t know cause.
Cefotetan, cefoxitin, cefmetazole have anaerobic coverage: B. fragilis.
Bacterial:
Ceflacor: oral administration.
Cell wall
Third generation: cefotaxime, ceftriaxone, ceftazidim, ceftizoxime, ceftibuten,
synthesis
cefixime, cefoperazone, cefpodoxime.
Broad spec., good for G- organisms but not as much for G+ organisms.
Good for Pseudomonas, Enterobacter, Klebsiella, Serratia.
Treatment of pyelonephritis from UTI, meningitis, community pneumonia.
Fourth generation: cefepime, cefpirome.
Same spec as third generation but some -lactamase resistance, good for G+.
Cefpirome not in U.S.

-lactam.
Resistant to -lactamases.
Acyl-enzyme isomerizes from eneamine to imine  slower to hydrolyze.
Second ring has C instead of S (penicillin has S).
Thienamycin: chemically unstable. Other two are byproducts of it.
Imipenem.
Binds PBP’s, bactericidal. Broadest spectrum of all Abx.
Very resistant to most -lactamases.
Good for P. aeruginosa, Enterococcus.
Carbapenems Hydrolyzed by dehydropeptidase-1 in kidney brush border  short half-life.
Hydrolysis product is a toxic metabolite.
Administer with cilastatin—inhibits dehydropeptidase-1, block nephrotoxicity.
Nausea, vomiting, seizures.
Meropenem.
Resistant to dehydropeptidase-1.
Similar power as imipenem, but less potential to cause seizures.
Ertapenem.
Drug of choice for diabetic foot infections.
Once-daily IV injection.
 -lactam.
Resistant to -lactamases.
Single-ring structure: only binds to transpeptidase of G-.
Aztreonam.
Monobactams
Binds PBP’s  make long filamentous structures in bacteria.
Good for G-R but inactive for G+ bacteria and anaerobes (magic bullet for G-).
Good to use for patients allergic to penicillins and cephalosporins.
Use as a combo if you also are treating G+: add vancomycin or clindamycin.
Bind to D-ala-D-ala terminus of peptidoglycan.
Resistant bacteria have D-ala-D-lac instead (i.e. Lactobacilli).
Resistant acquired: chromosomal or plasmid, from conjugation.
vanA: catalyze formation of D-ala-D-lac.
Good for all G+ bacteria. Inactive against G- bacteria.
Reserved for MRSA, MRSE, patients allergic to -lactams.
Orally not absorbed  use for S. enterocolitis, C. difficile colitis, GI superinfection.
Vancomycin Use IV. IM causes intense pain.
Excreted renally by filtration, usually unmetabolized.
Toxicity:
Rapid infusion causes histamine release, urticaria, flushing (“red man/neck”),
tachycardia, hypotension.
Thrombophlebitis and pain at site of IV injection.
Ototoxicity (partial hearing loss at high frequencies) if excessive in serum.
Bacterial:
Nephrotoxic: decrease renal function if not excreted by kidney (toxic cycle).
Cell wall
Bind to D-ala-D-ala terminus of peptidoglycan.
synthesis
Good for G+ bacteria.
Teicoplanin
Can be given IM.
Available in Europe but not in U.S.
Analog of phosphoenolpyruvate.
Forms covalent adduct to transporter used in formation of muramic acid.
Fosfomycin Good for G+ and G- bacteria, UTI’s (concentrated in urine).
(Phosphonomycin) Bacterial resistance: shut down transferase and use glutathione transferase.
Oral and parenteral.
Only oral used in U.S. Oral bioavailability = 40%.
Inhibit dephosphorylation of bactoprenyl diphosphate (used to transfer NAG-NAM-
pentapeptide subunits across cell membrane to cell wall).
Good for G+ bacteria, Neisseria.
Bacitracin Systemic toxicity: nephrotoxicity  proteinuria, hematuria, nitrogen retention.
Topical use only (external wounds).
Neosporin: bacitracin + neomycin (aminoglycoside, G-) + polymixin B (detergent
for G- outer membranes).
Inhibit alanine racemase (convert L-ala to D-ala) and D-ala-D-ala ligase.
Structure resembles D-ala.
Good for G+ and G- bacteria.
Cycloserine
Used almost exclusively for T.B.
Dose-dependent toxicity: peripheral neuropathy, CNS dysfunction (depression,
psychoses)  use as second choice for T.B.
Cyclic lipopeptide.
Rapidly bactericidal.
Bacterial:
Good for G+ bacteria, including MRSA and VRE.
Cell
Daptomycin Alters membrane electrical charge and transport.
membrane
Renally cleared.
function
Effects blocked by pulmonary surfactant.
Toxicity: myotoxicity.
 Bacteriostatic (can be bactericidal at higher concentrations).
Binds 50S  can’t form peptide bonds, ribosomes frozen in place (polysomes).
Antagonist with macrolides, clindamycin.
Broad-spectrum.
Good for G+, G-, anaerobes.
Well-absorbed from GI.
Gets to brain and CSF, crosses placenta.
Can use for bacterial meningitis when cause is unknown.
Use for RMSF of young children and pregnant women (tetracycline toxic).
Resistance:
Mostly enzymatic acetylation.
Sometimes reduce cell permeability or affinity of 50S binding site.
Two asymmetric centers; only one isomer is active.
Free hydroxyl groups needed for activity.
Toxicity (rare but severe):
Bone marrow depression: due to mitochondrial protein inhibition.
Chloramphenicol Reversible type is dose-related.
Bacterial: Irreversible type wipes out bone marrow  aplastic anemia.
Reversibly Serious and fatal dyscrasias  reserve use for meningitis, typhus, typhoid fever.
inhibit Aplastic anemia: 70% of dyscrasias. May be genetically linked.
protein Irreversible, usually delayed in onset, not dose-related.
synthesis Binds to mammalian cell ribosomes, erythropoietic cells very sensitive.
via 30S or Gray baby syndrome: insufficient glucuronyl transferase  don’t clear.
50S Abdominal distention, vomiting, cyanosis, irregular resp, hypothermia,
vasomotor collapse (can be fatal).
Blurred vision, digital parasthesias, mild GI disturbances.
Inhibits P450.
Metabolized via conjugation with glucoronic acid in liver (not toxic but inactive).
Hepatic insufficiency  increased half-life.
Glucoronide conjugate and hydrolysis products excreted via tubular secretion.
Parent compound cleared by glomerular filtration (10%).
Try not to use that much, stop if you see leucopenia.
Only for hospitalized patients.
Binds 50S  block initiation via blocking ribosomal assembly.
Good for Gram+, aerobes.
Used mainly for MRSA, VRE.
Oxazolidinones Faster onset than vancomycin.
(Linezolid) High oral bioavailability  good for outpatient use. Can also give via IV.
Toxicity:
Thrombocytopenia, anemia, neutropenia.
Heaches, GI irritation are common.
 Bacteriostatic.
Binds 30S (16s rRNA)  block tRNA binding to A site.
Broad-spectrum: gram+ cocci and gram- bacilli.
Used for Chlamydia, walking M. pneumoniae, Brucella, Rickettsia, acne.
Resistance:
P. aeruginosa, Proteus.
G+ bacteria have lower MIC but develop resistance quicker.
Resistance frequent  usually don’t use for G+ cocci infections.
Upregulation of efflux pump TetA, and/or downregulation of influx.
Genes for resistance carried on plasmid (inducible).
Decreased access to ribosome: ribosome protection proteins.
Can have induced bacterial degradation of tetracyclines.
Four fused rings with electron-negative O for chelating Ca, Mg, Al, Fe.
Usually adequately absorbed in GI.
Less from milk, Al-, Ca- antacid, PeptoBismal, iron supplements.
Less from di- or tri- valent metals (Ca2+, Mg2+, Fe3+, Al3+): chelation.
Gets to all tissues and fluids, CSF, placenta.
Decomposes in solution  dissolve just before use.
Administer as sodium or HCl salts: more water soluble.
Excreted via bile and feces (accumulates in liver), glomerular filtration.
Toxicity:
Tetracyclines
Fanconi syndrome: renal dysfunction due to outdated preparations.
Can inhibit mammalian protein synthesis, but have selective toxicity:
Bacterial ribosomes have higher affinity, transport for uptake.
Bacterial:
Deposited in bones  40% depression of growth in premature infants.
Reversibly
Permanent staining of growing teeth (pregnant women and children).
inhibit
Superinfection due to broad-spec  oral thrush, yeast infections.
protein
Liver dysfunction: lethargy, jaundice from large doses.
synthesis
Photosensitivity: less time to develop sunburn.
via 30S or
GI irritation from oral administration.
50S
Thrombophlebitis from IV administration.
Short-acting: tetracycline, chlortetracycline, oxytetracycline.
Chlortetracycline: basis for deriving tetracycline. Rarely used.
Intermediate-acting: demeclocycline, methacycline.
Methacycline not in U.S.
Long-acting: doxycycline, minocycline.
Minocycline and doxycycline most active by weight.
Doxycycline chelates cations poorly  absorbed better with food.
Tigecycline: derivative of tetracycline; glycycline class.
Used in complicated skin and soft tissue infections, intra-abdominal infections.
Active against MRSA and VRE.
Common GI upset.
Binds 50S.
Good for Gram+, aerobes. Used for MRSA, VRE (faecium only, not faecalis).
Toxicity (nasty drug—use only when necessary):
Hyperbilirubinemia (3-35%).
Pain at infusion site (40%).
Arthralgia/myalgia (40%).
Streptogramins
Group A: dalfopristin.
Large polyunsaturated non-peptide ring.
Distort ribosome  no tRNA binding.
Group B: quinipristin.
Cyclic peptides.
Block translocation of elongating peptide.
 Bacteriostatic.
Binds 50S (antagonist to macrolides, chloramphenicol).
Good for Gram+, anaerobes.
Strains resistant to clindamycin often resistant to macrolides, vice versa.
Superior to macrolides for anaerobes, B. fragilis, P. carini, T. gondii.
Gets to bone and fibrous CT  used for staph osteomyelitis.
Also use for infections of female genital tract (i.e. septic abortions).
Toxicity:
Diarrhea (2-20%).
Pseudomembranous colitis (0.01-10%) from C. difficile toxin. Can be lethal.
Lincosamides
Abdominal pain, diarrhea, fever, mucoid/bloody stools.
(Clindamycin)
White/yellow plaques on mucosa of colon: fibrinoid, PMNs, no pathogens.
Can detect using barium enema and air contrast enema.
Discontinue drugs and treat with metronidazole or vancomycin. Can relapse.
Opioids (and others that inhibit peristalsis) prolongs condition.
Skin rashes (10%, more common with HIV).
Resistance: cross-resistance with macrolides due to ribosomal methylation by erm.
Doesn’t get to CSF and CNS.
Clearance mostly by N-demethylation and conversion to sulfoxide.
10% excreted unmetabolized.
Lincomycin (no longer used).
Bacteriostatic. Can be bactericidal in high concentrations.
Macrocyclic lactone ring of 12-16 atoms.
Bacterial: Binds 50S (23S rRNA site, E tunnel)  inhibit translocation.
Reversibly Allows for 6-8 peptide tRNA build-up before elongation is blocked.
inhibit Antagonistic binding to chloramphenicol, clindamycin, puromycin.
protein Can inhibit mitochondrial ribosome, but doesn’t penetrate mitochondria  fine.
synthesis Good for gram+ cocci and bacilli (accumulates 100x more drug than Gram-).
via 30S or Most useful for M. pneumoniae, L. pneumophila. Also for Chlamydia pneumoniae.
50S Used as a substitute penicillin if allergic to -lactams.
Don’t use for S. aureus: concern of resistance.
Resistance: usually decreased binding affinity to 50S.
Toxicity (generally low):
GI: erythromycin stimulates motility  cramps, nausea, vomiting, diarrhea.
Dose-related, more common in children.
Cholestatic jaundice from extended treatment of estolate (reversible).
Erythromycin inhibits CYP450  inhibit metabolism of other drugs.
Macrolides
5x risk of cardiac death (long QT) if combined with another inhibitor of CYP3A.
IM administration  severe and persistent pain.
Unstable at acid pH.
Coat or give as salt (stearate), ester (ethylsuccinate), estolate (lauryl sulfonate or
propionyl ester).
Esters inactive until hydrolyzed in blood.
Food delays absorption.
Gets to everything except CNS, CSF, placenta.
Mostly excreted via bile and feces, unmetabolized.
Erythromycin (prototype), clarithromycin, azithromycin, telithromycin (ketolide).
Erythromycin has more side effects  not used as much as others.
Clarithromycin: first-pass metabolism to active metabolite.
Azithromycin: concentrated within cells (phagocytes).
Tissue fibroblasts are reservoir  half-life increased to 40-68 hours.
Marketed in “Z-pack.”
Telithromycin has activity against resistant S. pneumoniae.
 Bactericidal (concentration-dependent).
Postantibiotic effect: residual bactericidal activity below MIC  once-daily doses.
Two+ amino sugars connected to hexose core via glycosidic linkage.
Good for aerobic G- bacteria (most widely used).
Not in anaerobes: needs bacterial electron transport to move into cell.
Popular for nosocomials: P. aeruginosa, Enterococci.
Synergy with penicillins: break open cell wall so aminoglycoside can enter.
Resistance:
Usually via enzymatic modification and inactivation.
Bacteria can have plasmids encoding different inactivating enzymes.
Acetylation, phosphorylation, adenylation.
Amikacin is least susceptible to enzymatic modification.
Aminoglycosides lose affinity to ribosomes.
Decreased drug uptake from altering bacterial active transport system.
Several binding sites on 30S; may have some 50S sites as well.
Irreversibly inhibit protein synthesis. Possible mechanisms:
Block initiation  streptomycin monosomes.
Misread codons:
Block translation and prematurely terminate.
Make nonfunctional proteins, disrupt cell function  cell death.
Use IM or IV (no IV for streptomycin).
Don’t cross human cell membranes well  not orally absorbed.
Aminoglycosides are cationic  don’t use in IV solution with anions (penicillins).
Drug stays in extracellular space (VD). Cationic  don’t bind to serum proteins.
Concentrated in renal cortex, endolymph, perilymph of inner ear. Not in CNS.
Can get into CNS if the meninges is inflamed (meningitis).
Bacterial: Excreted via glomerular filtration (unmetabolized).
Alter Half-life 2-3 hours  50-100 hours in aphrenic patients.
protein Aminoglycosides Clearance varies  monitor blood levels to prevent toxicity.
synthesis Toxicity:
via 30S Nephrotoxicity is saturable, usually reversible.
Initially have excretion of brush border enzymes.
Acute tubular necrosis, proteinuria, isosthenuria, low GFR.
High plasma creatinine and BUN.
Neomycin: cells swell, vacuolize  myeloid bodies, necrosis, sloughing.
Gentamicin, amikacin have milder toxicity, reversible.
Ototoxicity: damage cochlear and vestibular hair cells.
Degeneration of hair cells, or fusion into giant hairs.
Irreversible with longer and higher doses (>7 days).
Get high-pitched tinnitus and hearing loss.
Later get vertigo, imbalance, drifting eyes at end of movement.
Mostly vestibular: streptomycin and gentamicin.
Streptomycin  8th nerve toxicity, dizziness (mostly vestibular).
Mostly auditory: amikacin, kanamycin, neomycin.
Neuromuscular block:
Block presynaptic Ca2+ channels (reversible).
Block postsynaptic nAChR (weaker effect, reversible).
Potency: neomycin > kanamycin > amikacin > gentamicin > tobramycin.
Synergistic with other neuromuscular blockers: d-tubocurarine, congeners.
Worse for patients with myasthenia gravis and Parkinson’s.
Treat via Ca2+ IV administration (calcium salt).
From streptomyces: streptomycin, kanamycin, tobramycin, neomycin, paromomycin.
Neomycin and kanamycin for topical use. Paromomycin in intestinal amebiasis.
From micromonospora: gentamicin, sisomicin, netilmicin, amikacin.
Gentamicin, tobramycin, amikacin most widely used.
Spectinomycin (really an aminocyclitol) has similar pharmacology.
Use for gonorrhoeae. IM. Rare side effects.
 Bactericidal.
Broad-spec. for G+ and G-.
Good for MRSA, P. aeruginosa, Chlamydia, Enterobacter, Salmonella, Shiggella, E.
coli, Mycobacterium.
Treat and prevent traveler’s diarrhea, UTI’s.
Gets into bone  use for osteomyelitis from S. aureus.
DNA gyrase and topoisomerase inhibitor.
DNA gyrase targeted in G- bacteria. Binds to A subunit (DNA strand cutting).
Topoisomerase IV targeted in G+ bacteria (separate DNA into daughter cells).
Inhibit bacterial growth at much lower concentration than for eukaryotes.
Enhanced activity:
Fluorine substitution at C6  increased against G- bacteria, extend spec to G+.
Piperazine attached to C7  essential for P. aeruginosa.
Resistance: mutations in bacterial DNA gyrase subunits.
Most have very high oral bioavailability.
Most excreted renally. Goes through enterohepatic circulation.
Toxicity: well-tolerated.
Fluoroquinolones
GI upset (3-17%): nausea, vomiting, diarrhea.
(Quinolones)
CNS: headache, dizziness, insomnia.
Bacterial: Potentiated by NSAIDs  seizures, delirium.
Nucleic acid Ciprofloxacin increases seizures via inhibiting GABA.
metabolism Possible damage to growing cartilage + arthropathy  not for patients under 18.
Tendonitis and tendon rupture (ciprofloxacin).
Gatifloxacin: hypo- and hyper- glycemia.
May inhibit P450  drug interaction problems.
Nalidixic acid: oldest, least active.
Excreted very rapidly  use for UTIs.
Lomefloxacin, oflaxacin, levofloxacin, pefloxacin, ciprofloxacin, enoxacin.
Very good against G-, moderate to good for G+.
Ciprofloxacin good against Anthrax, S. aureus.
Clinafloxacin, sparfloxacin, gatifloxacin: better for G+.
Sparfloxacin: half renal and half fecal excretion.
Moxifloxin, trovafloxacin: better for G+, anaerobes.
Excreted non-renally  use for aphrenic patients.
Trovafloxacin: acute hepatitis and hepatic failure. Monitor liver function tests.
Rifampin (T.B. section)
Inhibits iso-leucyl-tRNA synthetase  can’t incorporate iso-leucyl into peptide.
Good for Gram+ aerobes.
Mupirocin
Rapidly degraded in plasma.
Use topically for Staph, Strep.
Folate reductase inhibitor (inhibit dihydrofolate reductase).
Structural analog of pteridine of folic acid.
50,000x higher affinity to bacterial than mammalian enzyme.
Synergistic with sulfonamides.
Bactrim: trimethoprim-sulfamethoxazole.
Good for G+ and G-. Respiratory, GI, GU, AIDS.
Bacterial:
S. pneumoniae, H. influenzae, Shigella, Salmonella, E. coli, E. coli, P. carinii.
Inter-
Paired together due to similar half-lives (9-11 hrs). Less resistance.
mediary Trimethoprim
Use 5x more sulfamethoxazole  eventually becomes 20:1 ratio (ideal).
metabolism
TMP lipid-soluble  goes everywhere. SMX only in extracellular space.
(Antifolate)
Both excreted in urine.
Toxicity: well-tolerated. GI upset, skin reactions.
May cause folate deficiency: megoblastic anemia, leucopenia, granulocytopenia.
Treat via co-administering folinic acid.
Rash and leucopenia in AIDS patients treating P. carinii.
Very bad for patients on warfarin: high risk of bleeding.
 Folate reductase inhibitor (inhibit dihydrofolate reductase).
Structural analog of pteridine of folic acid.
Pyrimethamine High affinity for plasmodial enzyme.
Synergistic with sulfonamides.
Mixed bactericidal/static.
Inhibit de novo synthesis of folic acid. Selective toxicity:
Mammals don’t make it—use dietary sources.
Bacteria don’t have transport system to uptake folic acid.
Effect delayed for several replication cycles after administration.
Time to deplete folate stores
Resemble PABA (p-aminobenzoic acid)—bound to pteridine and glutamate during
folate biosynthesis  make fake analogs of folate.
Dihydropteroate synthase normally catalyzes reaction (not in mammals).
Folate needed as cofactor to make thymidine, purine, A.A.’s  bacteriostatic.
Effects reversed by:
High concentrations of PABA.
Presence of thymidine, purines, methionines, serines (can be in pus).
Resistance (rapidly develops):
Increased intracellular PABA (less common).
Enzymes have reduced affinity for sulfonamides (via R-factors).
Lose permeability to sulfonamides or active efflux
Bacterial: Broad-spectrum: gram+ cocci and gram- bacilli.
Inter- Good for Actinomycetes, Clamydias, protozoal parasites.
mediary Toxicity:
metabolism Crystalluria: acetylated metabolites of sulfamethoxazole and sulfadiazine
(Antifolate) precipitate in kidney tubules. Reduce via sodium bicarbonate.
Sulfonamides
Hematopoietic acute hemolytic anemia, agranulocytosis, aplastic anemia.
Hypersensitivity: rashes, erythema, drug eruption, fever, malaise, pruritis.
Sulfisoxazole, sulfamethoxazole.
Sulfisoxazole short-acting; sulfamethoxazole intermediate-acting.
Treat UTIs: highest water solubility and excreted unmetabolized.
Sulfadiazine: crosses into CSF  bacterial meningitis.
Sulfadoxine: only long-acting still in use.
External uses:
Silvadine (silver sulfadiazine): pre vent and treat burns
Sulfacetamide: eye or ear drops
Sulfacetamide: lotion has drying agent for acne and other skin conditions
Trisulfapyrimidines: sulfadiazine, sulfamerazine, sulfamethazine (“Triple Sulfa”)
No longer available
Sulfasalazine
Sulfapyridine bonded to 5-ASA. Splits via intestinal flora.
5-ASA goes to colon  anti-inflammatory.
Sulfapyridine can be toxic  Olsalazine is dimer of 5-ASA instead.
Used for Chron’s disease, enteritis, IBS.
Sulfonamides with folate reductase inhibitors:
Bactrim: sulfamethoxazole + trimethoprim
Fansidar: sulfadoxine + pyrimethamine (for chloroquine-resistant malaria)
Sulfadiazine + pyrimethamine (for acute toxoplasmosis)
 All cause hepatotoxicity: mild elevation of liver enzymes (15-20%).
Absorbed orally.
Get into most tissues, including center of caseous granulomas.
Isoniazid (INH).
Bacteriocidal.
Interferes with biosynthesis of mycolic acid of cell wall.
Alcohol increases metabolism of INH  more hepatotoxicity.
Increases urinary excretion and depletion of Vitamin B6 (pyridoxine).
Leads to peripheral neuropathy and anemia.
Resistance developing.
Rifampin.
Inhibits DNA-dependent RNA polymerase.
Body fluids turn bright orange-red: urine, feces, sweat, saliva, tears.
Less hepatitis than INH.
Induces P450 system  decreased half-lives of others (i.e. oral contraceptives,
anti-convulsants, coumadin, hypoglycemics and corticosteroids).
Rifabutin similar in structure and activity.
Used primarily for MAI.
Anti-Tuberculosis Less induction of P450.
Pyrazinamide.
Unknown effect on fetus  don’t use in pregnancy.
Bacterial: Ethambutol.
Anti- Dose-depedent, reversible ocular toxicity: decreased acuity and color vision.
Mycobacter. Not used in children: can’t report changes in vision.
Streptomycin (aminoglycoside).
Avoid in pregnant women: congenital deafness.
Fixed-dose combinations:
Rifamate: isoniazid and rifampin.
Rifater: isoniazid, rifampin, pyrazinamide.
Second-line drugs for resistant T.B.:
Para-aminosalicylic acid.
Capreomycin sulfate.
Cycloserine.
Ethionamide.
Kanamycin.
Amikacin.
Quinolones (levofloxacin).
Dapsone.
Rifampin.
Clofazimine.
Anti-Leprosy Binds to DNA.
Anti-inflammatory.
Can color skin and conjunctiva red.
Lesions will turn tan to black.
 Fungicidal.
Broad-spec.
Water insoluble: large polyene ring with 36 atoms.
Use sodium deoxycholate or lipid vehicle to make liposomes for delivery.
Bind to ergosterol in cell membrane of fungi  pores  K+ leakage.
One side hydrophilic for aqueous pore; other side hydrophobic for membrane.
Doesn’t cross GI epithelium  need IV admin.
Doesn’t get to CNS: need intrathecal injection.
90% bound to serum proteins.
Slow urinary excretion: half-life of 15 days.
Used in induction therapy: replace with azole for maintenance therapy.
Toxicity:
Polyenes
Chills, fever, muscle spasm, vomiting, headache, hypotension after IV infusion.
(Amphotericin B)
Premedication with corticosteroids, antipyretics, meperidine, antihistamine
will help. Can also slow infusion rate, use test dose, use lower dose.
Inflammation of vein (phlebitis) at injection site.
Delayed toxicity: nephrotoxicity.
Renal tubular acidosis, K+ and Mg2+ wasting, azotemia.
Prerenal component: reversible, decreased renal perfusion.
Renal: irreversible, damage of tubular cells.
Hepatotoxicity and anemia from reduced erythropoietin (kidney damage).
Decrease via adding lipids:
Amphocil: Ampho B + cholesterol sulfate (colloidal dispersion: ABCD).
ABLC: Ampho B + lipid complex.
Ambisome: Ampho B + liposome.
Fungal:
Fungicidal.
Cell
Related to amphotericin B.
membrane
Nystatin Too toxic for systemic use: use for skin or mucous membranes.
function
Prevent and treat vaginal, oral, mucosal, esophageal, cutaneous candidaisis.
Not well absorbed in GI tract  use for GI candidiasis.
Fungicidal.
Broad-spec.
Inhibit P450 for synthesis of ergosterol  leaky cell membranes  death.
Higher affinity for fungal P450  selective toxicity.
Most selective: fluconazole > itraconazole > ketoconazole.
Toxicity of targeting human P450:
Elevation of serum transaminase.
Reduced synthesis of adrenal and gonadal steroid hormones.
Infertility, menstrual irregularities, gynecomastia.
Other drugs not metabolized by P450  toxic.
Least for fluconazole (most selective toxicity).
Azoles Well-absorbed from GI.
Doesn’t get to CNS, but fluconazole gets to CSF.
Metabolized by liver.
Imidazoles: ketoconazole, miconazole, clotrimazole.
Miconazole and clotrimazole older and less safe: restrict to topical use.
Ketoconazole toxicity:
GI: nausea, vomiting, anorexia.
Hepatotoxicity.
Triazoles: itraconazole, fluconazole, voriconazole, posaconazole, ravuconazole.
Fluconazole water-soluble  can give via IV.
Fluconazole excreted renally, unmetabolized  can use for UTI’s.
Safe for systemic use.
 Fungicidal.
Topical and oral for mucocutaneous, dermatophyte infections (i.e. onchomycosis).
Fungal:
Inhibit non-P450 squalene oxidase  accumulate squalene  death.
Cell Allylamines
Toxicity (rare):
membrane (Terbinafine)
GI upset, headache.
function
Severe hepatotoxicity.
Doesn’t inhibit P450  avoids drug-drug interactions.
Narrow spec.
Limited to C. neoformans, some Candida and Aspergillus.
5-FC converted to 5-FU  F-dUMP, F-dUDP, F-dUTP (inhibit DNA/RNA synthesis).
F-dUMP blocks thymidylate synthase (needed to convert dUMP to dTMP.
Human cells can’t deaminate 5-FC to F-FU  selective toxicity.
Fungal:
Resistance: use as an adjuct to amphotericin B or azoles.
Nucleic Acid Flucytosine (5-FC)
Well-absorbed by GI, gets everywhere (including CNS).
Metabolism
Serum binding 20%.
Excreted via kidney, mostly unmetabolized.
Toxicity:
Bone marrow depression (anemia, leucopenia, thrombocytopenia).
Nausea, vomiting, diarrhea (may damage DNA).
IV administration.
Fungal: Glucan Synthesis
Inhibit fungal cell wall synthesis: inhibit 1,3 D-glucan synthase.
Cell Wall Inhibitors
Capsofungin.
synthesis (Echinocandins)
Micafungin.
Fungistatic.
Fungal: Inhibits fungal growth via spindle disruption  prevent mitosis.
Griseofulvin
Cell division Toxicity (uncommon): headache, nausea, vomiting, photosensitivity, mental
confusion, bone marrow suppression (leucopenia, neutropenia).
 Good for asexual erythrocytic P. falciparum and P. vivax + gametocytes of P. vivax.
Can’t cure P. vivax or P. ovale; completely cures P. falciparum.
Inactive against liver-stage metabolites.
Selective toxicity for parasitized erythrocytes.
Drug of choice for non-falciparum and sensitive falciparum malaria.
Mechanism:
20X more concentrated in RBC than in plasma.
Protonated in food vacuole (pH 4.7).
Block polymerization of heme to hemozoin.
Intercalate DNA  inhibit nucleic acid synthesis.
Concentrate in lysosomes  inhibit acid hydrolases in plasmodial vacuoles.
Chloroquine-ferriprotoporphyrin IX complex from digesting Hg  lyse membrane.
Resistance:
4-Aminoquinolines R1: initial therapy works, but relapse 2-4 weeks later.
(Chloroquine) R2: initial improvement, relapses even sooner.
R3: no response to initial therapy. Induces or up-regulated P-gp for efflux.
Absorbed rapidly from GI.
Gets everywhere.
Excreted slowly:
70% renal, unmetabolized.
Concentrated in liver, spleen, kidney, lung.
Half-life 4 days  once-weekly prophylaxis.
Toxicities (reversible):
Headache, visual disturbances, GI upset, pruritis.
Lichenoid skin eruptions with prolonged treatment.
Hemolytic anemia with G6PD deficiency.
Anti- Contraindicated with psoriasis or porphyria.
Malarials Amodiquine: related but toxic; declining in use.
Doxycycline Doxycycline inhibits protein synthesis in malaria. Has delay: targets apicoplast.
(Tetracycline) Delay  good for prophylaxis but not treatment.
Schizontocidal for all species.
Chinese herbal antimalarial.
Heme degradation by parasite releases Fe  reduces peroxide bond in artemisinin
Artemisinin
 high-valent iron-oxo species  free radicals of oxygen.
Toxicity: potential neurotoxicity.
Artemether-lumefantrine: now in U.S.
Good for exo-erythrocytic P.vivax + all gametocytes.
Drug of choice for dormant liver forms of P. vivax and P. ovale.
Binds to DNA, enter plasmodial mt  swelling and vacuolization.
Rapidly absorbed and metabolized.
Gets everywhere.
Excreted in urine.
Toxicity: well-tolerated.
Large doses: cramps, epigastric disease, mild anemia, cyanosis, leukocytosis.
8-Aminoquinolines
Hemolytic anemia with G6PD deficiency.
(Primaquine)
Drug increases amount of oxidized glutathione (GSSG), which is toxic and can’t
be reduced when G6PD is low  cell is damaged.
Reductase to get rid of GSSG needs NADPH, which is made by G6PD.
Blacks have A- variant of gene  older erythrocytes hemolyzed.
Mediterranean and Asian B- variant  more erythrocytes destroyed.
Males more susceptible since G6PD is on X chromosome.
Fetuses are G6PD deficient  risk of hemolysis.
Test for G6PD deficiency before giving primaquine.
 Suppressive: good for erythrocytic forms but not liver stages.
Some gametocytocidal against P. vivax and P. malariae.
Drug of choice for resistant P. falciparum.
Orally effective: absorbed in upper GI.
Excreted in urine: metabolized by hydroxylation.
Quinoline Short half-life  take ever 8 hours.
methanols Toxicity:
(Quinine) Cinchonism: tinnitus, headache, nausea, dizziness, flushing, blurred vision.
Cardiac depressant, uterine contractions in 3rd trimester, insulin release 
hypoglycemia, hemolytic anemia (G6PD deficiency).
High doses: depresses respiration.
Quinidine also antiarrhythmic.
Mefloquine good for chloroquine-resistant falciparum; long half-life.
Good for erythrocytic forms of all.
Anti- Proguanil also good for hepatic forms.
Malarials Fansidar very good for chloroquine-resistant falciparum.
Inhibit DHFR (dihyrofolate reductase) in plasmodia.
Selective toxicity: preferential binding to parasites.
Resistance: elevated DHFR or altered binding affinity.
Well-absorbed from GI.
Pyrimethamine has long half-life (4 days)  once a week.
Proguanil half-life about 16 hours  daily.
Folate antagonists
Fansidar half-life about 170 hours.
Toxicity: well-tolerated.
Fansidar  rare but severe cutaneous reactions.
Erythema multiforms, Stevens-Johnson syndrome, toxic epidermal necrolysis.
No longer used for prophylaxis.
Pyrimethamine, proguanil (chloroguanide), fansidar.
Combination drugs: sequential inhibition, less resistance:
Fansidar: pyrimethamine + sulfadoxine.
Maloprim: dapsone + pyrimethamine.
 Not active against tissue trophozoites.
Diloxanide furoate.
Drug of choice for asymptomatic infections.
Supplement with metronidazole for all other amebiases.
Split into diloxanide and furoic acid in GI tract:
90% diloxanide absorbed  covert to glucoronide  excrete.
10% is active amebicide.
Common flatulence; no serious side-effects.
Not available in U.S.
Iodoquinol.
Luminal Alternative to diloxanide furoate for asymptomatic amebiases (not as safe).
amebicides Supplement with metronidazole for all other amebiases.
Administer orally for 20 days. 10% is absorbed.
Possible iodine problems:
Increase protein-bound serum iodine  less 131I  thyroid enlargement.
Iodine intoxication  dermatitis, urticaria, pruritis, fever.
Hypersensitivity with intolerance to iodine.
Infrequent GI toxicity, possibly from intake with meals.
Anti- Paromomycin sulfate (aminoglycoside).
Protozoals Administer orally. Not absorbed by GI tract.
Toxicity:
Occasional abdominal distress and diarrhea.
Accumulates in patients with renal insufficiency  renal toxicity.
Active against tissue trophozoites.
Systemic Dehydroemetine: severe amebic dysentery.
amebicides Dehydroemetine, chloroquine: for hepatic abscesses.
Usually don’t use unless others have failed.
Nifurtimox: T. cruzi. 50% failure rate. Possible mechanism of futile redox cycling.
Metronidazole. Protozoa and anaerobic bacteria.
Good for C. difficile (drug of choice), giardiasis, amebiasis.
Can be luminal and tissue, but strongly absorbed from GI  more systemic.
Administer with a luminal amebicide.
Nitro group is reduced to products disrupting DNA helix.
Mixed amebicides
Selective toxicity: prodrug needs reductive activation of nitro group by anaerobic
or microaerophilic pathogens  reactive radical anion kills DNA/membrane.
Aerobic cells of humans don’t do reductive activation.
Toxicity (not serious): nausea, headache, dry mouth, metallic taste in mouth.
Disulfiram-type interaction with ethanol.
 Niclosamide: cestodes/tapeworms.
Inhibit oxidative phosphorylation and stimulates ATPase  kill cestode.
Not in U.S.
Administered orally (without food), not absorbed by GI tract.
Potential for cystocercosis after drug treatment: avoid with purges.
Praziquantal: drug of choice for nearly all trematodes (not Fasciola hepatica).
Broad spec.
Also used against cestodes.
Mechanisms:
Rapid titanic contraction of worm musculature (spastic paralysis).
Vacuoles in apical tegument.
Worms detach and move to liver  immune system reacts.
Inhibit egg production at low doses.
Administer orally.
Absorbed and metabolized in liver by P450  cross-reactivity with P450 drugs.
Toxicity: nausea, epigastric pain, dizziness, headache, drowsiness.
Benzimidazoles: thiabendazole, mebendazole, albendazole.
Drug of choice for nearly all nematodes.
Albendazole treats cystocercosis of pork tapeworm at larval stage.
Mechanism:
Inhibition of phosphorylation  biochemical changes.
Inhibit microtubule polymerization via binding to b-tubulin.
Selective toxicity: human microtubules would need higher concentration.
Absorptions:
Thiabendazole: GI tract after oral administration (higher toxicity).
Mebendazole: poorly absorbed.
Albendazole: variably absorbed.
Anti-trematodes,
Anti- Toxicities from thiabendazole: anorexia, vomiting, nausea, dizziness.
cestodes,
Heminths Ivermectin.
nematodes
Drug of choice for Strongyloides and Onchocerciasis.
Tonic paralysis of parasite: activate GABA-gated Cl- channels.
Concentrated in liver and fat and stored  4 doses per year.
Lack of toxicity to humans.
Diethylcarbamazine.
Drug of choice for filariasis, Loa loa, tropical eosinophilia.
Mechanisms:
Immobilize microfilariae.
Enhance susceptibility to immune response.
Rapid absorption.
Gets to all tissues except fat.
Excreted in urine, unmetabolized or as N-oxide metabolite.
Enhanced by lower pH.
Vegetarian diets have alkaline urine  toxicity if dose is too high.
Toxicity:
Headache, weakness, malaise, nausea, vomiting.
Can have severe allergies to products of killed organisms (onchocerchiasis).
Low cost  used in developing countries.
Piperazine: treatment for ascariasis lumbricoides.
Agonist of GABA-gated chloride channels on nematode muscle.
Roundworms are paralyzed and expelled by rectum.
Ivermectin: single dose to prevent Onchocerca Volvulus.
Wolbachia antigen is released with drug  immune response.
Single annual dose is effective to prevent blindness.
Praziquantel: single dose to treat Schistosomiasis.
Increases calcium permeability.
Combine with anti-snail to prevent reinfection.