Sketchy Pharm - Linezolid (Police Line)

• Linezolid (Police line) • Binds 50S ribosomal subunit, preventing formation of initiation complex. Bacteriostatic (jammed typewriter) • Active against G+ including staph, strep, enterococcus (purple jewels in clusters & chains) o Treatment of serious G+ infections including nosocomial skin & soft tissue infections and PNA and VRE (lung shaped uniform on nurse; resisting arrest in police van; purple diplococcus drums) o MRSA coverage (“No Mercy” pharaoh sarcophagus) • Adverse effects o Thrombocytopenia (broken plates) o Prolonged courses have reported optic neuropathy (cut optic nerve camera wires) o Peripheral neuropathy, usually in glove & stocking sensory impairment (detective gear) o Weak inhibitor of MAO, so may lead to serotonin syndrome (smiley face) • Aminoglycosides inhibit ribosomes, halting translation (Kanji translators with tRNA hats). Bactericidal (dead translator). Irreversibly bind 30S ribosomal subunit, inhibiting formation of initiation complex, causing misreading mRNA (clock at 30 bound by sai-wielding assassin; smeared kanji; dead translator) • Used in treatment of aerobic G- bacilli (red bacilli bricks in wall). Aminoglycosides are actively transported across cell membrane via oxygen dependent process (bellows); to transport across cell wall, are usually coupled with cell wall active drugs to enhance ability to enter cell (e.g. β-lactams, vancomycin) (β-lactam bombs which look like the β-lactam planet). • Used especially when there is suspicion of sepsis or resistance. IV administration d/t poor oral absorption (ivy rope) • When coupled with wall agents, also effective against enterococcus. Useful in enterococcal endocarditis (diplococcus taiko drums). However, are intrinsically resistant to low to moderate levels of aminoglycosides, in part d/t acetylation enzyme that modifies aminoglycosides (drummer throwing stars at ninjas). • Resistance can develop with changes specific modifying enzymes, mutations to the ribosomal proteins, or mutations to the porins. • Neomycin (ninjutsu master) o Remains active in the GI tract when taken orally (colon-shaped pipe). o Useful in bowel prep before colorectal surgery (scalpel shuriken) • Paromomycin (pair of mice) o Remains active in the GI tract when taken orally (colon-shaped pipe). Useful in bowel prep before colorectal surgery o Luminal agent against parasites • Streptomycin (sai wielding wilderness specialist) o Effective in tularemia & plague Tx, spread by contact with ticks from rabbits (rabbit hoodie) and fleas from a variety of hosts (small woodland creature). • Gentamycin (judo master) o Used in treatment of nosocomial infections (red G- shogun). Include septicemia (red armor), complicated UTI (gold bladder pouch), intraabdominal infections (colonic armor plates), nosocomial RTI (lung patches), osteomyelitis (fish-bone shaped helmet) o Pseudomonas activity (Mona in the background) • Tobramycin (cobra ninja) o Similar spectrum to gentamycin. o Pseudomonas activity. • Amikacin (katana master) o Broadest spectrum, including resistant to enterococcal acetylation ( o Pseudomonas activity (Mona in the background) o Most expensive • Adverse effects o Ototoxicity – may result in vestibular or cochlear damage (gong looks like eardrum getting struck by sai). Often irreversible. o Nephrotoxicity (kidney shaped armor). More likely to be seen in renal insufficiency, and when co-administered with other nephrotoxic agents including loop diuretics ▪ d/t ATN (rusty downspout draining brown, muddy water, for muddy brown casts) ▪ May see ↑Crt & serum aminoglycoside levels. monitor drug concentration (peaks and troughs of mountainous terrain in the back) o Myasthenia gravis is absolute contraindication (rock that looks like an electrical outlet) o Deafness in neonate, so contraindicated in pregnancy (tarantula & pregnant woman) • RIPE therapy for tuberculosis (ripe tubers) given in 2 phase treatment: 4 drugs for 2 months, followed by 2 drugs usually for 4 months ($4 for 2, now $2 for 4), usually INH & rifampin. • Hepatotoxicity associated with all RIPE drugs. • Rifampin (the rifle sharpshooter) o Activity against mycobacteria & certain G- bugs. o Potent CYP450 inducer = “revs it up” (extremely active carriage) o MOA: binds bacterial DNA-dependent RNApol (shot RNA track switch, switching train from double stranded DNA track to single stranded RNA track) ▪ Resistance develops by mutations in RNA polymerase. Develop rapidly with isolated rifampin therapy. o Prophylactic monotherapy for close contacts for N. meningitidis, H. influenzae (carriage driver in close contact with rifleman; N.M. and logo on train for N. meningitidis; H. influenzae biplane) o Adverse effects ▪ Hepatitis is uncommon, but more common in patients with predisposing factors (including coadministration of other RIPE drugs & other hepatotoxic agents) (cow with liver spots) ▪ Orange-red discoloration of body fluids (literally everything – vomit, bile, urine, snot, CSF) (orange fluid spewing from carriage). Benign. • Isoniazid (isolated ranger): o most agents used alone will lead to rapid evolution of resistance. Not so INH. Sued in isolation for latent TB infections, preventing reactivation (ranger protecting sleeping - i.e. latent – cowboy next to cacti lacking upper lobe lesions – i.e. not reactivation TB). o Inhibits synthesis of mycolic acids, disrupting bacterial cell wall (fuchsia mycolic acid cacti beyond wall, ponchoed bandit being shot off wall) o Delivered as a prodrug activated by mycobacterial KatG catalase-peroxidase (bobcat with G-shaped tail is activating ranger). Resistance to INH develops by downregulating KatG (second bandit shooting bobcat). o Adverse effects sin ▪ Injury to nerves & hepatocytes ▪ Dose related peripheral neuropathy, ataxia, paresthesias (socking and glove). ▪ Metabolized by liver N-acetyltransferase. Slow acetylators have increased risk of adverse effects, higher drug serum concentrations, and increased half-life – increases risk for neuropathy (slow acetyl gunslinger). Caused by a pyridoxine (B6) deficiency d/t INH encouraged excretion. • Can prevent by coadministration of B6 (dice in ungloved hand) ▪ Acute OD can cause CNS toxicity including seizures (action lines on falling bandit) ▪ Hepatotoxicity (cow with liver spots): hepatocytes dysfunction so common will see asymptomatic ↑LFTs in many patients (LFT flag). However, serious hepatotoxicity can be fatal if not ceased. ▪ Drug-induced lupus (lone wolf for lone ranger) ▪ MUD PILES – can cause anion-gap metabolic acidosis (mud pile) ▪ Inhibits CYP450 (broken chrome bumper on inhibited carriage; INH inhibits) • Pyrazinamide (Pyromaniac) o Used only for TB o Nicotinamide analogue. May be bacteriostatic or bactericidal, depending on the concentration and susceptibility of the organism, although exact mechanism is unknown. It is active in vitro at an acidic pH of 5.6 or less, similar to that found in early, active tubercular inflammatory lesions o Adverse effects ▪ Hyperuricemia & needle-shaped uric acid crystal formation → gout (knitting needles). Not sufficient to discontinue therapy. ▪ Hepatotoxic, up to liver necrosis(cow with liver spots) • ethambutol (Ethel the horse whisperer) o Inhibits arabinosyl transferase → carbohydrate polymerization at cell wall (Ethel inhibiting an Arabian that is knocking over polymerized fencing) o Bacteriostatic (slowing horse, not killing him) o Adverse effects ▪ Optic neuritis – red green colorblind, loss of visual acuity (horse blinders) ▪ Hepatotoxic (cow with liver spots) • In the US, many mycobacterial infections seen are atypical, i.e. non-tuberculous. As with tb, resistance is a problem so typically use multidrug rx. • M. avium complex causes disseminated disease in AIDS, especially when CD4 < 50 (immunosuppressed cane; red AIDS ribbon; speed limit 50). Made of M. avium & M. intracellular (bird in a cage for bird – avium – and intracellular inside macrophages). Much less susceptible to standard RIPE therapy. o Tx: macrolide + ethambutol (crows + Sheriff Ethel). Azithromycin & clarithromycin both treat MAC & are the drugs of choice for prophylaxis with ↓↓immunity (crow sitting on speed limit sign) o Rifabutin may be used if a 3rd agent recommended (Arizona Buttes). Related to rifampin (rifle). Less potent CYP450 activator than rifampin (slowing down horse). Rifabutin recommended in HIV+ patients, d/t less activation of CYP450, i.e. less interference with ART. • M. leprae (leaping armadillo) o Armadillo is an animal reservoir in the US o Tx ▪ Dapsone (deputy zone) • Agranulocytosis (multi-lobed hourglass) • Hemolytic anemia in G6PD deficiency (G6PD watermelon, with bite marks & seeds – like Heinz bodies) ▪ Clofazimine (gun cleaning cloth) • Treat for lepromatous leprosy (lion face mask for leonine faces) ▪ Rifampin (rifle) • Treatment in combination with other drug for treatment of atypical mycobacteria. • Sulfonamides are anti-folate drugs. Mammals don’t synthesize folate, deriving it from dietary sources. However, many bacteria synthesize folate from Para-aminobenzoic acid (PABA) (Panda papa, with purine cookies), making them susceptible to disruption of the process. PABA converted to dihydrofolic acid by dihydropteroate synthase → THF (bamboo with 2 & 4 leaves – folate found in leafy greens – on 1st & 2nd steps). Inhibition of folate → inhibition of DNA synthesis • Trimethoprim/sulfamethoxazole (creepy twins) o SMX is a PABA analog that blocks dihydropteroate synthase (dihydropteroate affected by sulfa egg dropping cookies) ▪ Adverse effects (note that many are common to all sulfa drugs, not just SMX) (adverse effects on sidewalk) • 2nd most common allergy after β-lactams. Include fever, rash, urticaria (kid in devil costume doing an itchy jig) • Anemias may develop in allergy o Hemolytic anemia in G6PD deficiency (watermelon w bite cell) • Stevens-Johnson syndrome – rare, but has been seen (red mask sloughing off) o Technically, is a tengu mask and should remind us of toxic epidermal necrolysis (TEN) • Type IV RTA (mad scientist with 4 tubes of acid) o →↑K (shape) • Interstitial nephritis with monocytic infiltrate (little blue candies in kidney shaped bag) • Photosensitivity (snapping photos) • Kernicterus in neonate when used in last month of pregnancy. Displace bili bound to serum albumin →↑ free unconjugated bili (kernicteric candy corn baby brother) • Displaces other drugs from albumin e.g. warfarin (photos displaced from album) o Warfarin → ↑ anticoagulation leading to bleeding (bloody mother) • Inhibit CYP450 metabolism (sulfa egg vandalism) o TMP (TP): blocks DHFR (2 leaves ducking = reductase) ▪ Adverse effects: • Folate inhibition → DNA inhibition. Can cause pancytopenia a/o megaloblastic anemia (empty pan, firework blasts) • Teratogenic in 1st trimester d/t neural tube defects (spider décor) o Bacteriostatic individually, bactericidal in combination. o Often first line Tx for G- bugs for GI & urinary tract bacteria (red costume and porta-potty). Also G+ (purple fence) ▪ UTI (porta-potty with TP & eggs) ▪ Treats acute prostatitis in men (kid shoving eggs down man’s pants) ▪ MRSA (pharaoh with “No Mercy” graffiti) – but not first line ▪ Drug of choice for Nocardia (card dealing partly acid-fast cowboy painting nocardia) ▪ PJP (old ping pong man in PJs with immunocompromised cane). Used for both treatment and PJP prophylaxis with CD4 < 200 (old man; mailbox no.) ▪ Toxoplasmosis prophylaxis with CD4 < 100 (crazy toxo cat lady with Gandhi gat for toxoplasma gondii; mailbox no.) . • Pyrimethamine/sulfadiazine (pyramid witch hat, dyed super eggs) o Similar MOA to TMP-SMX o Treat ▪ Toxoplasmosis • Fluoroquinolones (Tiptoeing through the flowers). Mainly indicated in G- infections (red flowers). • Include ciprofloxacin, levofloxacin, moxifloxacin, delafloxacin. • Inhibit DNA topoisomerases, including DNA gyrase (unwinding braid). Inhibit normal transcription & replication, are therefore bactericidal. • Generally well absorbed when taken orally. Decreased by divalent & trivalent cations (trivalent medals). Should be administered a few hours before or after milk, antacids, and supplements. • Resistance can develop with mutations to the DNA gyrase, impaired influx, or increased efflux. • UTI & GI bug coverage o E.g. E. coli, proteus (red bladder cup) ▪ Uncomplicated UTIs usually treated with Bactrim or urinary agent like Fosfomycin or nitrofurantoin (in their own classes). o Fluoroquinolones are usually saved for complicated UTIs, e.g. h/o diabetes or urinary tract obstruction ▪ Levofloxacin & ciprofloxacin treat pseudomonas (e.g. nosocomial UTIs) (elevating and sipping from the glass) ▪ Levofloxacin & ciprofloxacin empiric treatment for pyelonephritis (polyurea) (milky kidney shaped flask) ▪ Treat acute prostatitis, and have good tissue permeation (kid pushing egg down man’s kilt) o Effective in treatment of G- gastroenteritis, including shigella, salmonella, E. coli, campylobacter (intestines on table with red flowers surrounding; salmon for salmonella; fish bone for G- osteomyelitis) ▪ Sickle cell patients specifically are high risk for osteomyelitis, especially from salmonella (Viking with a sickle) • G+ bugs o Bacillus anthracis → hemorrhagic & necrotizing PNA (bloody anthrax axe) o Levofloxacin & moxifloxacin are respiratory quinolones. Have improved activity against G+ particularly S. pneumoniae (rusty lung plate), H. influenzae. Used in treatment of both typical & atypical community acquired PNA (walking PNA) (snow-shoer), Legionella (legion of ships) • Adverse effects o Risk of prolonged QT interval (streamers) o N/V, diarrhea (guy looking nauseated at table) o Risk of tendon and cartilage damage, including tendon rupture in the elderly (old king gnawing on bones) & those on steroids (moon face). ▪ Damage to growing cartilage → arthropathy in fetal development and children under 10 yo (pregnant woman with tarantula sigil; kid gnawing on bones) ▪ Famous for Achilles tendonitis especially o Ciprofloxacin specifically can cause interstitial nephritis. o Fluoroquinolones have varying binding affinity for the CYP450 enzyme, with inhibitory effects. The order from most P450inhibitory to least, is enoxacin > ciprofloxacin > norfloxacin > ofloxacin, levofloxacin, trovafloxacin, gatifloxacin, moxifloxacin. • Metronidazole (metro) • Bacteroides fragilis. Coverage of polymicrobial anaerobic infection, as e.g. in intraabdominal infection (man stabbed in stomach). Also has activity against some protozoa. • MOA: Forms toxic free-radical metabolites that disrupt bacterial DNA; bactericidal (oxidized DNA-shaped rails) • Clinical indications (clindamycin above the diaphragm, metronidazole below) o Activity against Entamoeba histolytica. Intestinal protozoa → dysentery, liver abscess (Do not enter sign from entamoeba sketch). o Giardia (protozoan shield) o Trichomonas: treats vaginitis & cervicitis with strawberry cervix (magician with hat & strawberry) ▪ STD. Given to both patient and partner (couple in the back) ▪ Wet mount test to inspect for trichomonas (“does the alibi hold water?”) o Gardnerella caused vaginosis (Ms. Gardner with Venus fly trap) o Substitute for amoxicillin for H. pylori treatment in penicillin allergy (helicopter outside) o Activity against anaerobic bacteria including (gas masks) ▪ Bacteroides, Prevotella, Fusobacterium, Clostridium ▪ C-diff pseudomembranous colitis (chocolate fountain) • Concurrent ingestion of alcohol during metronidazole treatment (oral or vaginal administration) causes a disulfiram-like reaction, with flushing, tachycardia, palpitations, N/V (hip flask with XXX) • CYP450 inhibitor (cars yield to trains) • Amphotericin (amphibians with fungi) o Ergosterol found in fungal cell membranes (compared to human & bacterial cholesterol) (“non-sterol” sign). Amphotericin forms pores in ergosterol cell wall allowing leakage of cell electrolytes & macromolecules and eventual cell death (frog aquarium has holes and amphibians are escaping). o Resistance evolves when structure of ergosterol involves changing molecular components of membrane (e.g. ↓ergosterol) o Amphotericin B has the broadest spectrum of action of the antifungals. Used for severe systemic or life-threatening fungal infections (body model with exposed organs). o Generally administered IV (ivy in terrarium). Given as a liposome, because of the high toxicity of the drug (liposome shaped frog). o For CNS infections, administered intrathecally (frog tongue looks like intrathecal line). Used to treat cryptococcal meningitis, often in conjugation with flucytosine (Anthony & Cleopatra, Act V: The Crypt). o Toxicities ▪ All result from amphotericin binding to mammalian cholesterol instead of ergosterol (frog binding to cholesterol themed necktie) ▪ Infusion related immediate reactions • Nearly universal • Fever, chills (“shake & bake”), spasms, vomiting, headache, hypotension, fainting (baking frog; fainting from frog on tie) • Thrombophlebitis at injection site (blue veiny frogs) ▪ Slow cumulative toxicities • Renal damage is most significant. Occurs in nearly all patients. (chemist) o Reversible prerenal azotemia o Irreversible tubular injury (Type 1 RTA) (graduated cylinder shaped like 1 filled with acid). Associated with hypokalemia (banana peel) o Renal magnesium wasting (falling magnets) o Usually have volume expansion with IV normal saline prior to amphotericin administration to help prevent renal damage (emergency saline wash). o Anemia d/t ↓EPO production (drained kidney scaring off white frog; broken tubules) ▪ Intrathecal administration • Seizures and major neuro damage (seizure lines) • Flucytosine o Flucytosine starts as a fluorinated cysteine. Converted by cytosine deaminase into 5-FU (Music C knocked over to U). o Halts fungal DNA & RNA synthesis (DNA and RNA like music on chalkboard being smeared by frog). • Nystatin o Forms pores in ergosterol cell wall allowing leakage of cell electrolytes & macromolecules and eventual cell death (frog aquarium has holes and amphibians are escaping; “Be Nyce” sign) o Active against most candida spp. (Canada flag with snow) o Topical Treats mucocutaneous candidiasis, including vaginal (snowball to the crotch) o Nystatin rinse for oropharyngeal candidiasis (drinking fountain). Esophageal candidiasis treated by systemics. • Azoles include the imidazoles: ketoconazole, miconazole, clotrimazole; & triazoles: itraconazole, fluconazole, and voriconazole. Spectrum of actions broad. • MOA: ergosterol forms fungal membrane (emerald ergosterol blocks; postmodern fungus). Synthesized from lanosterol (munchkin builders inhibited by crushing house; “Lane Closed”). Azoles halt fungal CYP450 that synthesizes ergosterol (crushed car) o All are prone to drug interactions d/t effects on mammalian CYP450. • Voriconazole (car crushing vortex) o Preferred for invasive aspergillosis (aspirating scarecrow with lung hyphae) o Excellent treatment for candida, including candida esophagitis (Canadian flag). o Adverse effects ▪ Blurry vision or flashes of light, changes to color vision, usually transient (blurry flashes of light in tornado; sepia tones) ▪ Particularly potent inhibitor of mammalian CYP450. Dose reduction of many CYP450 substrates (including cyclosporine, tacrolimus, statins) required on initiation of therapy • Fluconazole (flying monkeys) o Used to treat mucocutaneous candida (yeasty snow). Given in a 1-time dose to treat vaginal candidiasis (crotch monkey). o Systemic fluconazole treats candida stomatitis & esophagitis in which case it’s given IV (esophagus like gutter snow) o Treats cryptococcal meningitis for lifelong maintenance (crypt with permanent monkey statues) o High levels of CNS penetration (meningitis mohawk helmets). Works some against dimorphic fungi but not drug of choice, but mainly against monomorphic. • Itraconazole (good witch) o Systemic infections with dimorphic fungi (e.g. histoplasmosis, blastomycosis, coccidioidomycosis, Sporothrix) (dimorphic butterflies) – “itraconazole for fungi with two iterations” o Used for onychomycosis & dermatophytosis (ruby slippers with tarnished toes) • Topicals, often miconazole or clotrimazole (“My cone” & close trim) o Tinea (tin man with ring-like rust rash) o Vaginal candidiasis (snowball to the crotch) • Ketoconazole (tin man’s key) o Cream form to treat cutaneous dermatophytosis o Other agents have a much better safety profile when administered systemically, as ketoconazole has a greater affinity for the mammalian CYP450. o Inhibits overproduction of cortisol in Cushing’s syndrome (moon face). May be used o Adverse effects ▪ Inhibition of cholesterol hormones (adrenal & sex hormones) by inhibiting 12,20-desmolase & 17-α-hydroxylase (first step of steroid synthesis from cholesterol) (key “locking” the adrenal gland shaped lock; moon face, M & F symbols. Witch synthesizing) ▪ Antiandrogenic Adverse effects, including gynecomastia, d/t inhibition of 17,20-lyase involved in synthesis of androgens • Dermatophyte infections include tinea corporis, tinea pedis, & tinea cruris (rust spots on the tin man) • Griseofulvin (grease can) o Fungistatic. Binds fungal cell microtubules, halting mitosis in M-phase (vines binding tin man look like M-phase) o Administered orally to treat dermatophytosis (grease in mouth). Has been largely replaced by newer agents. o Accumulates in keratin containing tissues. Most effective in treating scalp & skin. Can be used for onychomycosis, although recurrence is common (farmhand has some gnarly nails). o First line therapy for tinea capitis in children, along with terbinafine (kid in tin-funnel hat standing between the tin man and the pigpen). o Adverse effects ▪ GI distress ▪ Headache ▪ Rash ▪ Hepatotoxicity ▪ Granulocytopenia ▪ Activation of CYP450 (chrome bumper & CYP450 license plate on a functioning car; thumbs up for upregulation) • Terbinafine (turban) o Fungicidal. Interferes with ergosterol synthesis by inhibiting squalene epoxidase → accumulation of squalene (squealing pigs) o Dermatophytosis (little tin man in crystal ball) o First line therapy for tinea capitis in children, along with griseofulvin (kid in tin-funnel hat standing between the tin man and the pigpen). o Administered orally for onychomycosis (wiz is biting his nails) o Adverse effects ▪ GI upset (mud in pigpen) ▪ Hepatotoxicity. Rare, but calls for monitoring (liver shaped mud spots) • Echinocandins (Echino-Canadians fur cap) o Caspofungin, micafungin, anidulafungin o Inhibit synthesis of β-1,3-glucan, a major polysaccharide component of fungal cell wall (note the cell wall, not the cell membrane which is composed of ergosterol) (walled hay truck) o Excellent activity against candida (Canada flag and yeasty snow). Given IV for systemic candida infections (ivy on flagpole) ▪ Also given for mucocutaneous candidiasis, candidemia, and prophylaxis of candidiasis in transplant patients. ▪ Candida esophagitis (exhaust pipes on truck) o Invasive aspergillosis, particularly with poor response to amphotericin (scarecrow with straw coming out of his lower lung fields) o Adverse effects: extremely well tolerated, with GI & flushing reported rarely.