Antimicrobials

Antimicrobials 1. Cell wall & membrane active an antibiotics tibiotics (β (β-lactams, -lactams, vancomyc vancomycin, in, daptomyc daptomycin) in) 2. Inh Inhibitors ibitors of bacteria bacteriall protein synthesis 3. Antimyc Antimycobacterial obacterial 4. Other an antibacterials tibacterials 5. Antifunga Antifungals ls 6. Antivira Antivirals: ls: HIV 7. Antivira Antivirals: ls: Hepatitis 8. Antivira Antivirals: ls: others 1.1 – “Prince “Princess ss Ellen’s New H Hope”: ope”: Penici Penicillins llins • β-lactam antibiotics all contain a 4 membered β-lactam ring (ringed planet). Include penicillins, cephalosporins, carbapenems, and all share similar MOAs & pharmacologic properties. • Bacterial peptidoglycan cell wall is synthesized by repeating D-alanyl-D-alanine oligopeptides (coccoid Death Star with D-ALA scaffolding). Penicillin binding proteins (PBPs) remove the terminal alanine in the process of forming crosslinks between peptides (Planetary Building Project workers). β-lactams inhibit this transpeptidation reaction by covalently binding PBPs, preventing bacterial cell wall synthesis. Effective in actively growing cells. • Bactericidal. • Work particularly well against G+ cell wall (e.g. staph & strep) (purple coccoid spaceships behind Death Star) • Penicillin (Princess Ellen holding purple pencil, fighting off the agalactiae empire.) o Penicillin V is the oral, acid stable form (V-ship in front of acid yellow nebula). Indicated in minor infections. Poor bioavailability, narrow spectrum, 4 qid dosing ▪ Oral form is acid. ▪ First line for streptococcal pharyngitis (red throat) and other infections caused by Group A strep ▪ Both V and G can treat post-strep rheumatic fever (Heart shaped planet Sydenham is very inflamed) o Penicillin G is the IV form (ivy rope distracting Princess Ellen). Benzathine salts of Penicillin G may be given via IM injection ▪ Left sided endocarditis caused by S. bovis, S. viridans (green emperor with miter hat) ▪ Group B strep infection for neonates of infected mothers; given intrapartum for group B strep prophylaxis for fetus (GBS galactic baby) ▪ Actinomyces israelii (Israeli flags on hyphae-like transport vehicles) ▪ C. perfringens (transport driver with road rash) ▪ Pasteurella multocida. Dog bites oft treated with β-lactams, as well as more broad-spectrum antibiotics like ampicillin, piperacillin (space dog) ▪ Single dose of benzathine treats primary, secondary, & early latent syphilis (running soldier with characteristic red boots & gloves on palms & soles) ▪ N. meningitidis, if isolate is penicillin sensitive (soldier wearing red mohawk helmet – recurrent symbol for meningitis; Gred, with diplococci-like booster packs) o Most common mechanism of resistance is production of β-lactamases, often expressed by plasmid genes (Ray gun has a plasmid-like ring around it). May also have PBP or porin mutations. o Generally well tolerated. Adverse reactions: ▪ Type 1 hypersensitivity (IgE mediated) (Rebel ship shooting what look like IgE missiles) • Up to 10% of people claim hypersensitivity, but 90% of those are skin test negative • 10% of those with a true hypersensitivity have cross reactivity with cephalosporins. More likely to cause a reaction if patient has had ⊕ skin test reaction and had definite IgE mediated reaction. ▪ Drug induced autoimmune hemolytic anemia. Will have ⊕ direct coombs test (IgG missiles attacking RBC shaped asteroids) ▪ Interstitial nephritis d/t mononuclear cells entering interstitium of the kidney. Blue cells on histology (kidney shaped nebula with blue stars) 1.2 – “The Staphy Staphylococci lococci Strike Back”: Nafc Nafcillin, illin, oxac oxacillin, illin, dicloxa dicloxacillin cillin • Nafcillin, oxacillin, & dicloxacillin are narrow-spectrum β-lactams of the penicillin class (β lactam planet). Indicated to treat methicillin-sensitive staphylococcus. • MOA: Bind PBPs and halt peptidoglycan synthesis. • Extended activity against β-lactamase-producing bacteria, as bulky R-groups prevent β-lactamase binding (bulked up rebel fighters are protected from plasmid-ring β-lactamase guns) • Narrow spectrum against staph (purple coccoid space station). Drug of choice for methicillin sensitive, penicillin resistant staph (even though methicillin isn’t used clinically anymore). Nafcillin & oxacillin for staph (pencil-shaped staff; ox horns) • Indications: o Mild to moderate localized staphylococcal infections when given orally. Given empirically for skin & soft tissue infections, e.g. folliculitis, abscesses (Red ox hump). o Given IV for systemic staph infection, e.g. staph endocarditis (tricuspid pyramids) & osteomyelitis (fish skeletons) • MRSA (merciless pharaoh): produces PBPs with low affinity for binding β-lactam drugs. This renders β-lactams ineffective (altered wall builders who continue wall synthesis with protective gear, despite rebel missiles) 1.3 – “Amped up at the Cantina”: Exten Extended ded spectru spectrum m pe penicillins nicillins (A (Ampicillin, mpicillin, amoxic amoxicillin, illin, piperacillin, ticarcillin) & β-lactamase inhibitors (clavulanate, ta tazobactam, zobactam, sulbactam) • β-lactam antibiotics contain a 4-membered β-lactam ring (ringed planet). Bacterial peptidoglycan cell wall is synthesized by repeating D-alanyl-D-alanine oligopeptides (coccoid Death Star with D-ALA scaffolding). PBPs remove terminal alanine in the process of forming crosslinks between peptides. β-lactams inhibit this transpeptidation reaction by covalently binding PBPs, preventing bacterial cell wall synthesis. Effective in actively growing cells. • Aminopenicillins: o Bactericidal. o Broad spectrum (prism with rainbow). Maintain penicillin spectrum plus expanded activity against GI & genitourinary Grods, e.g. E. coli. Not first line for the latter. o Amoxicillin (ammo box) ▪ β-lactamase sensitive (β-lactamase bouncer) ▪ Similar spectrum to ampicillin but has better bioavailability (Hans Cillin not wearing mask) ▪ Oral administration (Hans Cillin popping pills) ▪ Major indications: • HEENT infections (alien encapsulated by mask), including pharyngitis (red scarf around neck), otitis media, sinusitis (alien with drippy antennae), tonsillitis. d/t S. pneumoniae, Moraxella, H. influenzae (Hib biplane). • Lower respiratory infections, including PNA, d/t β-lactamase-negative Streptococcus spp. (α- and β-hemolytic strains only), S. pneumoniae, Staphylococcus spp., or H. influenzae. (Alien lungs) • Skin infections d/t β-lactamase-negative Streptococcus spp. (α- and β-hemolytic strains only), Staphylococcus spp., or E. coli. • H. pylori triple therapy, combined with clarithromycin and PPI (helicobacter helicopter) • Lyme disease in early stage or young children (Target: Robin of Ixodes – borrelia burgdorferi transmitted by Ixodes tick) o Ampicillin (cantina band has an amp) ▪ β-lactamase sensitive (β-lactamase bouncer) ▪ Similar spectrum to amoxicillin with decreased bioavailability (mask wearing band member). Resistance to isolated ampicillin use is common (band member kicking amp off stage) ▪ Indications: • Oral administration o Mild GI infections with sensitive strains (colonic stills behind bar) o Mild GU infections with sensitive strains o respiratory tract infections d/t non-penicillinase-producing H. influenzae and staphylococci, and streptococci, including S. pneumoniae. o Prophylaxis for encapsulated bacteria in asplenic patients (patron with spleen-shaped hole in shirt KO’d maskwearing patron) o Prophylaxis before dental procedures in patients at high risk for endocarditis (bar-fighter’s teeth flying) • IV administration for systemic infections (Ivy around lead guitar) o Susceptible G+ sepsis. o Endocarditis susceptible G+ organisms o Severe GI infections with susceptible organisms (colonic stills behind bar) o Bacterial meningitis d/t E. coli, group B streptococci, L. monocytogenes, and other G- bacteria (Neisseria meningitidis) (meningitis helmet). Consider Listeria with very old & very young patients who may need additional treatment o Anaerobic infections, including aspiration PNA (gas mask) o Enterococcus, although resistance is common (diplococcus drums). o UTIs d/t E. coli and P. mirabilis. • β-lactamase inhibitors: Clavulanate, sulbactam, & tazobactam (clarinet & back-to-back tambourines) o Prevent drug cleavage by β-lactamase (distracting β bouncer). Often combined with β-lactams to extend activity of penicillins o Amoxicillin/clavulanate (Augmentin®) o Ampicillin/sulbactam (Unasyn®) or tazobactam • Adverse effects o Skin rashes when prescribed in cases of acute viral illness, e.g. EBV (red lights around Epstein’s Bar) o Stevens-Johnson syndrome (red tengu mask sloughing off) o Augmentin one of the most common causes worldwide of drug induced liver injury • Piperacillin & ticarcillin (pipers with tiger stripes) o Paired with tazobactam & clavulanate, respectively. o Broad spectrum coverage includes anaerobic infections (gas masks) o Active against pseudomonas! Important to consider in hospital acquired infections (Mona Lisa) 1..4 nggee of of tth C Cep orrriiin 1. 4 – ““R R Rev Reeev the hhee Cep Ceeepphh”””:: Cep oosssp poori nnss vveeng eph phhaaalllo • Cephalosporins (cephalopods). • β-lactam antibiotics contain a 4-membered β-lactam ring (ringed planet). Bacterial peptidoglycan cell wall is synthesized by repeating D-alanyl-D-alanine oligopeptides (coccoid Death Star with D-ALA scaffolding). PBPs remove terminal alanine in the process of forming crosslinks between peptides. β-lactams inhibit this transpeptidation reaction by covalently (irreversibly) binding PBPs, preventing bacterial cell wall synthesis. Effective in actively growing cells. • There are 5 generations of cephalosporins (5 cephalopod generals). Most activity against G+ bacteria in early generations, with increasing G- activity in progressive generations (4th generation and on are broad-spectrum). • β-lactamases ineffective (β-lactamase guns are deflected from headquarters). However, resistance can evolve, e.g. by altering PBPs. This can be counteracted with carbapenems • Adverse effects o Shared with other β-lactams. May also see cross-reactivity with penicillins. o Type 1 hypersensitivity (IgE mediated) o Drug induced autoimmune hemolytic anemia. Will have ⊕ direct coombs test o Cephalosporins are notorious for disrupting GI bacteria and causing downstream vitamin K disruption & coagulopathies (all antibiotics can do this) o Interstitial nephritis d/t mononuclear cells entering interstitium of the kidney. Blue cells on histology • 1st generation includes cephalexin (first general Lex with flexed arm) & cefazolin (wearing a fez) o Mostly G+ activity (coccoid purple station models). Some G- activity. E. coli, Klebsiella, proteus spp. are often sensitive (PEK bacteria) o Indications: ▪ Often effective in G- UTI proteus, E. coli, Klebsiella (PEcK on red bladder cup) ▪ Oral used for staph & strep, including • Cellulitis (patches on shirt) • Strep throat (2nd line) (red scarf) ▪ Cefazolin penetrates most tissue well. Used for surgical prophylaxis. (Tool rack behind general) • 2nd generation includes cefuroxime (2nd general is furious), cefotetan (drinking tea), cefoxitin o Same spectrum of activity as 1st gen + additional G- bugs (purple coccoid & red bacilli models). Not often used as first line agents. ▪ HENS (H. influenzae, Enterobacter aerogenes, Neisseria spp., & Serratia) (HENS PEcK bacteria - red hens on teapot) o Oral administration o Indications ▪ Sinusitis ▪ Otitis ▪ Lower respiratory infections, including against S. pneumoniae, Klebsiella, Moraxella, H. influenzae. ▪ Mixed anaerobic infections (peritonitis, diverticulitis) but not first line • 3rd generation, including ceftriaxone (3 axes), cefotaxime, ceftazidime (General Taz) o Extended G- coverage. No MRSA coverage. Good penetration of tissue. Ceftriaxone, cefotaxime penetrate BBB. Used to treat a wide variety of resistant infection o Indications: ▪ Meningitis (1st line for empiric treatment). Cross BBB & have activity against N. meningitidis, H. influenzae, S. pneumoniae, and a few other G- enteric bacteria (red mohawk; H. influenzae biplane). • Vancomycin is often added for resistant S. pneumoniae. • Ampicillin may be added for younger & older pts for better coverage. ▪ PNA (community & hospital acquired) (lung shaped rust marks) • Especially with ventilator acquired PNA, must consider pseudomonas (Mona Lisa – ceftazidime covers pseudomonas). ▪ Endocarditis including S. viridans & HECKS bacteria (miter-hatted emperor figurine) ▪ Activity against G- GI bugs, e.g. salmonella, shigella (colonic armor). Useful in hospital acquired infections ▪ 1st line treatment of gonorrhea: single dose of IM ceftriaxone (drippy chandelier) ▪ Lyme disease, especially with neuro involvement or arthritis (Robin of Ixodes poster) • 4th generation includes cefepime (4th General Prime) o Broad spectrum (prism). A big gun for serious systemic infections from MDR organisms, including Pseudomonas. Highly active against G- & G+. No MRSA coverage o Crosses BBB; can treat meningitis (headdress) • 5th generation includes ceftaroline fosamil (General Tara) o Broad spectrum (prism) including MRSA coverage (No Mercy, pharaoh figurine) 1..5 Th caarrb 1. 5 – “T hhee coov vveeerrraaag ggee iiss sst str ttrro ng w wiiittth h tth hhiiiss oon nneee”””:: moon nno oob bbaaaccctttaaam m mss & car ppee nneeem m mss roon rbbaaap • Monobactams & carbapenems (car repair) • β-lactams (ringed planet). Bacterial peptidoglycan cell wall is synthesized by repeating D-alanyl-D-alanine oligopeptides (coccoid Death Star with D-ALA scaffolding). PBPs remove terminal alanine in the process of forming crosslinks between peptides. βlactams inhibit this transpeptidation reaction by covalently binding PBPs, preventing bacterial cell wall synthesis. Effective in actively growing cells. • Monobactams include aztreonam (one-eyed repair android AZ 3M) o Spectrum covers aerobic G- rods similar to 3rd gen cephalosporins. Has no activity against G+ or anaerobes (bellows blowing on red rod-shaped robot). Active against effective against Pseudomonas (android with the enigmatic smile). o Helpful with h/o penicillin anaphylaxis as there is no monobactam immunologic cross-reactivity (purple pencil stabbing infected robot) o Resistant to most β-lactamases (junkyard bot scaring off person with β-lactamase ring-shaped gun) o Penetrates CNS o Indications: ▪ PNA (lung shaped rust spots on android) ▪ Meningitis (red mohawk helmet) ▪ sepsis (red-colored android body) • Carbapenems include imipenem (Amy’s repair; Amy repairing car), ertapenem, meropenem, doripenem o Broad spectrum (prism hood ornament). Good activity against G+, G- rods including pseudomonas, anaerobes (android with the enigmatic smile standing between both sides; gas mask) o Imipenem (Amy) inactivated by dehydropeptidases in renal tubules. Co-administered with cilastatin to inhibit (pouring Cilastatin oil into car) o Indications. Penetrate tissue well and cross the BBB. (“When others fail, we get the job done.”) ▪ Intraabdominal infections ▪ Anaerobic PNA (Amy wearing gas mask) ▪ Systemic infections with G- bugs (red theme) ▪ Treatment of choice for infection with extended spectrum β-lactamases (ineffective rainbow β guard) o Side effects especially with imipenem ▪ Skin rash (rusty robot on ground) ▪ GI effects including diarrhea & abdominal pain (robot sitting in mud puddle) ▪ Lowers seizure threshold, especially in patients with renal dysfunction (seizing android) 1..6 S A S 1. 6 – ““M M MR R RS SA… SA A… wh hhy y ddiiid d iitt hhaaav ve to bbee M MR R RSA RS SA A???”””:: Va Van nncc oom m my yyccciiin n …w A • Glycopeptide antibiotic active only against G+ bacteria (staph, strep, enterococcus) (purple coccoid temples). Directly inhibits cell-wall synthesis by binding to D-ala-D-ala oligopeptides (temple wall hieroglyphs), sidestepping MRSA (and other bacterial) mutations to PBPs (mind altered Anubis minion). Resistant to β-lactamases (guard wearing ring-shaped jewelry trying to shoot down professor and missing) • Indications: o Administered IV (ivy rope). o Widely distributed in body including CSF, making it effective for meningitis (meningitis mohawk). Often combined with 3rd gen cephalosporin to treat meningitis. o One of the big guns for distributed infection with MRSA (no mercy pharaoh statue) o Effective against penicillin resistant S. pneumoniae (PRSP). o MRSA osteomyelitis d/t penetration of bone (fish bones) o Effective against most staph, including S. epidermidis which forms biofilms, especially on valves and lines (plumber under van). o Addition of vancomycin or other MRSA protection a good idea in empiric treatment of hospital-acquired infections (nurse with lung stains on uniform) o First line for empiric treatment of endocarditis (heart shaped headpiece of staph staff). o Poorly absorbed in GI tract, making it effective in C. difficile treatment (Mayan temple with chocolate-colored fountains) • Vancomycin-resistant enterococcus (VRE) are a growing concern d/t altered peptidoglycan structure. Terminal D-alanine is replaced with D-lactate (temple of doom constructed of D-lac blocks, with explorer’s adventure blocked by a block). May also see resistance impaired influx or increased efflux. • 90% excreted by glomerular filtration. Plasma monitoring is necessary especially if co-administered with other nephrotoxic agents or in patients with renal disease • Adverse effects o Red Man syndrome d/t direct activation of histamine release from mast cells (giant red statue). Treat with antihistamines or prolonged infusion. o Thrombophlebitis at injection site (veiny legs) o Ototoxicity & nephrotoxicity rare in isolation. More likely if administered in conjunction with other agents with these toxicities (red statue with cracked ears & cracked kidneys). o DRESS syndrome = “drug reaction with eosinophilia & systemic symptoms”. Presents with fever, generalized lymphadenopathy (Gal in spotted dress with eosinophil slingshot) 1..7 “Let L my goo”””:: D 1. 7 – “Le Leett m y chhiiiccck kkeeen nnss go Daaap pptt oom m my yyccciiin n • Daptomycin (police department) • Similar spectrum to vancomycin (police van), covering G+ bugs by preventing formation of cell walls (protesters in purple outfits forming a wall). The drug is a cyclic lipopeptide that inserts into lipid cell-membrane, causing depolarization of the cell & cell death (depolarization – taser → protester going down) • Activity against vancomycin resistant strains (tazering the protestor resisting getting into the vanco van), especially enterococcus, which is a G+ diplococcus (drummer). • Activity against staph, even vancomycin resistant strains (MRSA pharaoh X-ed out). Staph aureus (2 golden staphs supporting roof). o Bacteremia (“It’s in our blood”) o Tricuspid endocarditis (roof) o Skin & soft tissue infections o Should NOT be used in PNA because is antagonized by surfactant • Adverse effects o Myopathy. Rare rhabdomyolysis (bite out of chicken leg). Monitor CPK (Crispy chicken) on long-term treatment 2..1 ur ddee Cyc C yycccllliiin 2. 1 – ““L L Lee Tour Cy nnee ss”””:: Te Tetttrrraaacccy yycccllliiin nneeess • Tetracyclines (cycles) inhibit bacterial protein synthesis by binding to and inhibiting ribosomal transcription; bacteriostatic (ribosome paper jammed typewriter). Includes doxycycline, demeclocycline & minocycline. Enter microbes and concentrate inside. Bind 30S rRNA subunit, blocking translation (30 second timer in secretary’s hand). • Broad spectrum (prism medals), with activity against G+ & G- including MRSA (no mercy pharaoh in 1st place), although not first line for MRSA. Also treats rickettsia & atypical infections (often first line). • Administered orally. Absorbed primarily in proximal small intestine. Chelate metals, so concomitant administration of administration of multivalent cations causes decreased absorption (Ca, Fe, Mg medals). Eliminated fecally, so can be used safely in renal failure patients (colon pipeline). • Indications: o Tetracyclines, doxycycline especially, are effective against tick-borne illnesses including Rickettsia, Ehrlichia, Francisella, Borrelia (early stages or disseminated) (deer with ticks). o Doxycycline for many other zoonoses ▪ Brucellosis (cow in background) ▪ Q-fever (Coxiella) (sheep with Q horns) ▪ Plague (Yersinia) (squirrels) o Doxycycline for one week first line in chlamydial cervicitis, urethritis. Also used in PID, endometritis; in this case, consider doxy + cephalosporin (female biker with uterine handlebars) o Oral doxycycline is a treatment mainstay for atypical community acquired PNA including mycoplasma, chlamydia (snowshoer, clam bra) o Used in moderate to severe acne with anaerobic bacteria (mountains) • Resistance can develop either by efflux pumps (efflux pump) or ribosomal mutations. • Adverse effects o Teratogenic (pregnant woman & tarantula). Causes enamel dysplasia d/t deposition in calcium tissue (baby eating calcium medal) o Nausea, vomiting, diarrhea (mud puddle) o Photosensitivity with systemic administration (paparazzi taking photos) o Fanconi syndrome (Type 2 proximal renal tubule acidosis) has been associated with use of expired tetracyclines o Demeclocycline impairs the action of antidiuretic hormone (ADH) at its receptor, causing nephrogenic diabetes insipidus, which manifests as urinary frequency and polydipsia. A water deprivation test would reveal inappropriately dilute urine in the context of decreased water intake as a result of nonfunctional ADH 2..2 C 2. 2 – ““T “Th T Th The he Cr Cro r oow w w”””:: M Maaacccrrro oollliiddee antti tib iibbbiioot oti ttiiicccss • Reversibly binds the 50S subunit of the bacterial ribosome, inhibiting translocation. Bacteriostatic (crow jamming ribosomal typewriter). • Macrolides active against gram-positive aerobes and gram-negative anaerobes, making it an excellent choice for managing dental infections, particularly in patients with a penicillin allergy (amoxicillin is usually the first-line treatment). • Azithromycin, clarithromycin, erythromycin, clindamycin o Bordetella pertussis (boarded soldier) & prophylaxis for close contacts (family photo) o S. pneumoniae, H. influenzae, Moraxella community acquired PNA (rusty armor chest plate). Can be used in pts with h/o penicillin allergy (pencil stabbing armor). o Azithromycin for atypical PNA (Mycoplasma, legionella, chlamydia) (snowshoer, legion of ships, clam lady for each infection). o Azithromycin for chlamydia urethritis & cervicitis (Venus painting) o Oral erythromycin for neonatal chlamydial & gonorrheal conjunctivitis (red crow, dripping uterine chandelier) o Clindamycin + atovaquone treats babesiosis (vampire babe) o Erythromycin for diphtheria (minotaur) o Azithromycin for cat scratch fever (Bart the leopard) o A & C have activity against mycobacteria avium (caged mockingbird) o Azithromycin prophylaxis with CD4 < 50 (birds A-Z & chart with title “50”) o Clarithromycin + amoxicillin + PPI for H. pylori (“Keep Clear” sign, helicopter) • Adverse effects o Diarrhea (muddy floor) o Acute cholestatic hepatitis → jaundice (jaundiced Poe) o Prolonged QT (torsades ribbons) o CYP450 inhibition, except for azithromycin (broken chrome bumper on buggy) 2..3 C roob C 2. 3 – ““K K Keeeeeep p iin nng g iitt Cle Cllleeeaaan n aatt tth hhee Annaaaee ro biicc G Gy yym m m””: Cli Cllliiin nnd ddaaam m my yyccciiin nn!! • Clindamycin (“Keep it Clean” sign) • Acts on 50S ribosomal subunit inhibiting translocation & protein synthesis. Bacteriostatic. (jammed ribosomal typewriter) • Indications o Has activity against G+ (staph & strep) (Coccoid dumbbells) ▪ Penetrates well into tissues, including skin & soft tissues. First line for group A strep (pie & cellulitis red puffy gloves) ▪ Community acquired MRSA (“No mercy” pharaoh tattoo). On the exam (less so in clinic) linezolid, daptomycin, & are vancomycin first line for MRSA. o Has activity against anaerobic bacteria, including Clostridium & Bacteroides (gasmask) ▪ Actively transported into macrophages so has excellent abscess penetration (e.g. lung abscess) (lung stains with holes in the shirt) ▪ Aspiration PNA (think oral strep spp. & oral anaerobes including Bacteroides fragilis) (lung stains on shirt; bacteria water bottle in background) • With ↓mental status in an elderly person, think aspiration PNA. ▪ Topical clindamycin treats moderate to severe inflammatory acne (mountains) ▪ Endometritis if polymicrobial with anaerobes, which will often Gentamycin + clindamycin (sai for aminoglycoside gentamycin) ▪ Bacterial vaginosis caused by Gardnerella vaginalis (Venus fly traps) ▪ Active for C. diff (exploding toilet) • On exam: Clindamycin above the diaphragm, metronidazole below. Important exceptions in clinical practice: o Clindamycin for C. difficile (exploding toilet) o Clindamycin for Clostridium perfringens (road rash from a stationary bicycle) • Adverse effects o Diarrhea, usually mild & self-limited (mud puddle) o Associated with C-diff pseudomembranous colitis. May occur several weeks after cessation of antibiotic therapy (exploding toilet). 2..4 Spplllaa sh sh ooff G Ch llo 2. 4 – ““A A Sp Grrraayy”””:: Ch oorrraaam m mp pph hheeen nniiiccco ooll • Rarely used in the US d/t growing resistance and more effective alternate therapies with fewer adverse effects. • Inhibitor of microbial protein synthesis. Reversibly binds 50S bacterial ribosome subunit, inhibiting peptide bond formation (jammed typewriter) • Two main uses: o Meningitis – often cheapest treatment available outside of the US (globe beach ball). Active against N. meningitidis, H. influenzae, S. pneumoniae (space helmet swim cap). empiric treatment often involves 1 – 2 IM injections of Chloramphenicol. o Rocky mountain spotted fever: alternative in serious rickettsia infections (spotted hand and foot on climber). Especially important in pregnancy when doxycycline is contraindicated • Adverse effects o Dose related reversible reducing in RBC production (deflated red innertubes) o Rare but potentially fatal aplastic anemia d/t bone marrow suppression (plastic bone float) o Gray Baby Syndrome ▪ neonates lack glucuronic acid conjugation system needed for chloramphenicol breakdown (liver shaped floaty) ▪ Accumulation → flaccidity, grey color, hypothermia, shock (baby) ▪ Used with caution & in limited doses in babies 2..5 Noott C oossssss”””:: Lin L 2. 5 – ““D D Do o Not Crrro oss Liiinnnez neezo d zoollliiid • 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) 2..6 2. 6 – ““F F Feeeu uud daall assssaassssssiinnsss”””:: am miiin n oggl gly llyyyccco oosssiiid ddeeess • 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) 3..1 he M 3. 1 – “The Mag Maagn nntt F Fo oou uurrr”” gnniiifffiiiccceeen • 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) 3..2 Feew morre iffaaam mb olll,, cclllo 3. 2 – ““F “Fo F Fo yco cco ob re” ee”””:: Rif mppiiin nn,, riifffaaab bbu uutttiiin n, eettth hhaam mbu bbuuuttool, oofffaaazziim imi m miiin nnee oorr a Few w Myyc obbaaaccctttee riiaa mo • 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. 4..2 or Tr 4. 2 – “Tr Trriiiccck k or Treeeaaattt,, pyyrriim py m meeettth hhaa m miiin nnee//sssu uulllfffaaad ddiiiaaazziin nneee)) Smel meelllll m my y Dr D Dru rru ug uggsss””: Sullf lfa ffaa ddrrru uug gs ((TM TM MP/ P P///S SM MX X X,, • 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 4..2 orddiiicc Sp Sprriiin oqqu 4. 2 – ““A A Nor nng g””:: F Flllu uuo oorr oq uuiiin nno oolllo oon nneeess • 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. 4..3 rddeeerr on on thhee M Ex 4. 3 – ““M M Mu urd Meeetttrrro oE Exp xxp pr prreesssss”” • 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) 5..1 01 m 10 inn,, fllu ny 5. 1 – ““B B Bio Biiio o 101 meeeeettss M Mu uusssiiicc 1101 00111”””:: aam m mp pph hho oottteeerrriiiccin luc uuccy oosssiiin nneee,, nnys n cytto yysssttaatt iin • 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. 5..2 C nyym anntttiiifffu 5. 2 – ““We W n Cand Caanndi ddiid m mo oorrreee”””:: aazz oolllee an uun nng ggaa llss Wee’’’rrree noott iin iddaa Any • 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 5..3 hheerreee’’ s no no pplllaaacccee lliikkee C Grriisseeeo n, tteeerrbbiiin no nddiiin 5. 3 – ““T T Th her Caaan nnaaad ddaa ””:: Gr oofffu uulllv vvii n, nnaaffi fin iinnnee, eeccch hhiinnoc oocccaand nnss • 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. 6..1 Is ((aabba r, ddiiiaaad 6. 1 – ““L “Le L Le M Mo orrtttee d’’H ’HI H HIIIV V ””:: N NRT R TIs bac aacccaaav v ir, ddn nno oosssiiin nneee,, eem m mttriiccciitta tab aabbbiiin nneee,, llaaam m miiiv vvu uud ddiiin nneee,, RT sstttaaav nooffov ovviir, zziiid vvu uud ddiiin nneee,, teno ddo oov vvu uud ddiiin nneee)) • 6 classes of ARTs are combined depending on the characteristics of the patients, adverse effects, and bug profile. Usually 2 NRTIs + at least one other agent from a different class form the backbone of multidrug therapy. • Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTIs) (Knights of the Round Table). Act by competitive inhibition of HIV reverse transcriptase (reverse trasncriptum spell book has been stolen). Because NRTIs are nucleotides/sides, incorporate into DNA transcription but lack the 3’ hydroxyl, blocking 3’-5’ phosphodiester bond formation and causing premature chain termination (nucleoside mace with broken 3’ -OH group; page #s; broken helix bookmark) • “-dine” suffix attached to some of the NRTIS (meal) • Nucleosides must be phosphorylated & activated by cellular enzymes (activating Ⓟ scroll). • Shared adverse effects o All are associated with mitochondrial toxicity (table shape) o Lactic acidosis (sour milk) • Lamivudine (Sir Lancelot) o Used to treat Hep B (hippo, hippies, secret society banner). Especially helpful in HIV/Hep B coinfection. Note that in the latter case, discontinuation of the drug may lead to a hepatitis flair. o Adverse effects ▪ Peripheral neuropathy (Lancelot’s stockings and gloves) • Tenofovir (Sir Tristan) o Nucleotide not nucleoside (Tenofovir starts with a T) o As a nucleotide, does not need to be activated by cell enzymes (sailing on the tide while the others must wait inside, doesn’t need to wait for the Ⓟ signal) o Also has hep B activity • Zidovudine (Isolde with the dove crest) o Used during pregnancy and breastfeeding to reduce vertical transmission (pregnant woman) o Infants born to HIV+ mother usually receive several doses of zidovudine in the first weeks of life. o Adverse effects ▪ May cause myelosuppression (empty bone-shaped dish), causing anemia/neutropenia & agranulocytosis (white dress; sand timer) ▪ Lipodystrophy, with ↑central adiposity, ↓peripheral fat (silly looking horse) • Stavudine (Sir Steve) o Adverse effects ▪ Peripheral neuropathy (Lancelot’s stockings and gloves) ▪ Lipodystrophy • Didanosine (Sir Dan) o Major toxicity: dose dependent pancreatitis (pancreas shaped sponge) o ↑risk of peripheral neuropathy when coadministered with stavudine (Lancelot’s stockings and gloves) • Abacavir (abracadabra; merlin) o Hypersensitivity strongly associated with HLA-B 57:01 allele (Spell name). Presentation of cell peptides to immune system → delayed Type 4 HS reaction (he’s distracted and has a delayed reaction to spotted rash) • Emtricitabine (Excalibur) o Hyperpigmentation of palms and soles (badass gloves) 6..2 he Cou ouun of Elf E raaapppiiin avviirre 6. 2 – ““T T Th he nnccciiill of Elllffaav avi vviiirrr”””:: N NN N NR RTIs (N Neeev vviirrap nneee,, efav ren eennnzz, ddeeellaav avi v iirrddi din iinnneee)) • Non-nucleoside RT inhibitors. Do not need intracellular phosphorylated for activation. (Outside Camelot, so not knights of the round table; Ⓟ knight riding away toward Camelot) Bind directly to HIV RT resulting in allosteric inhibition, preventing viral synthesis of DNA polymerase activity (spell book blocked directly by arrow cleaving DNA bookmark) • Adverse effects o May have Life threatening hepatic failure within 6 weeks of starting therapy. Abrupt onset flu-like symptoms, abdominal pain, jaundice, fever (stag with yellow glow and liver shaped spot) o Teratogens (massive spider & pregnant lady) o Numerous drug-drug interactions d/t induction of CYP450 system (functional buggy with CYP450 plates). Both efavirenz & delavirdine activate & inhibit system, as well as broken down by it; nevirapine less activating. o Skin rash; Stevens-Johnson syndrome-TEN (orc with tengu mask) • Efavirenz (Elf Queen) o Principle adverse effects unique to efavirenz are all CNS. Include dizziness, drowsiness, headache, psychosis, insomnia, nightmares (queen clutching head; gazing at trippy antlers; dark night). • Delavirdine (Princess Delavir) o Not an NRTI despite the suffix! 6..3 annd thhee S 6. 3 – ““L L Lad Laady nneeev vveeerrree an d tth hhee S Sw w wo oorrrd d iin n th Sttto o nneee””: P Prrro oottteeeaaasssee iin nnh hhiiib bbiiittto oorrrss dy Guuiiin • Protease inhibitors often end in -navir suffix (Guinevere) including ritonavir, atazanavir, indinavir. Do not need Ⓟ by intracellular enzymes (knight running away with Ⓟ scroll). • HIV proteases serve to cleave the single long poly-protein product of the HIV gene products, which must be cleaved into proteins needed to construct virion particles (sword to cleave things). With proteases inactivated, the virion remains immature (immature page boy). • HIV pol gene encodes enzymes including RTs & proteases (Paul the blacksmith crafting protease blades). o Pol gene mutations → resistance. Never used as monotherapy, as may rapidly develop resistance to the entire class. • Adverse effects – many are metabolic o Hyperglycemia d/t insulin resistance, which may lead to diabetes eventually (elevated candy) o Dyslipidemias, with ↑TG & LDL (elevated butter) o Lipodystrophy (silly steed) o Inhibition of CYP450 (chrome bumper on inoperable wagon) causing numerous drug-drug interactions. Ritonavir especially (Right on! High fives) ▪ Can be used to advantage by boosting levels of other protease inhibitors ▪ Rifampin contraindicated when taking protease inhibitors d/t CYP450 activation → ↓protease inhibitor levels (rifampin crossbow utilized by wizardly henchman). May use rifabutin. • Indinavir (indigo princess) o May cause nephrolithiasis d/t urinary crystallization (stones in kidney fountain). May occur within days of beginning therapy. Adequate hydration is critical (drinking kid) 6..4 HIIV C 6. 4 – ““H H Ho oow w HI V was tth hw waaarrrttteeed d aatt tth the hhee G Gaaattteeess ooff Cam Caaam meeelllo oottt”””:: Enntttrrry y iin nnh hhiiib bbiiittto oorrrsss,, ffu ussi sio iio on m on iin orrrsss,, iin grraaasssee iin nnh hhiiib bbiiittoors nntttee gra nhhi hib iibbbiiittto oorrrss • HIV infects macrophage, dendritic cells, & CD4 T-cells (crusader cross on neighboring castle). Once incorporated into host DNA, commandeers host machinery to transcribe viral genes. Gag, pol, env code for polyprotein precursors that produce viral virions, which will then bud off and invade next cells o gag structural gene encodes for virion core proteins, including p7 & p24 (sundial, gagged prisoners guarded 24/7) o env structural gene encodes envelope proteins including gp41 & gp120 needed for infiltrating membrane of host cells (envoy boat). Proteins are initially sent to the host cell ER for processing (reef around env boat) o pol gene encodes for proteases, reverse transcriptase, and integrase (Paul the blacksmith) • HIV invasion 1) For HIV to infect a cell, HIV surface glycoprotein gp120 must bind host cell CD4 molecule + a chemokine R (CCR5 or CXCR4) (envoy gaining entry with 120 battering ram; helper squire and CCR5 banners). 2) Fusion. Gp41 facilitates HIV fusion (envoy throwing 41 grappling hooks over castle walls). 3) Once inside the cell, RT transcribes viral RNA into dsDNA (reverso transcriptum spell book) 4) Integrase allows viral DNA to integrate into host cell DNA (keys to unlock nucleus of castle with double helix stairs) • Entry inhibitors o Maraviroc (rearing mare) binds CCR5 receptor, blocking HIV binding and consequent invasion. Before beginning therapy, should determine if HIV strain invades via CCR5. • Fusion inhibitors o Enfuvirtide binds gp41 surface protein, preventing fusion (knight on wall deflecting grappling hook; enfuvirtide for fusion) • NRTIs & NNRTIs act against RT (King Arthur & Queen Elfavir defending the castle) o Mutations to pol gene confer resistance to these classes as well as protease inhibitors & integrase inhibitors (Paul the blacksmith making swords, spell books, and keys for proteases, RT, & integrases respectively). • Integrase inhibitors o Raltegravir disrupts ability of HIV DNA to integrate into host chromosomes; may also be considered to prevent transcription of viral mRNA (knight deflecting key) o Mutations to pol gene confer resistance (mutated key not deflected by slacking knight) o May rarely cause rhabdomyolysis (bite out of chicken leg) 7..1 “Innssseeerrrtt Cyyt to Co C Intte α, IIF 7. 1 – “I yto tto n to Con o nntttiiin nnu uueee”””:: In ter eerrffe fer eerron α, F FN N N--β β,, IIF F FN N N-- γ ooccooiiin • Interferons are host cytokines than produce antiviral, immunomodulating, & antiproliferative effects. Released by infected cells → intracellular signals activating immune response (virus infected manager is spreading cyto-coins). Upregulation of INF synthesis in infected cells accomplished by interleukins (Luke enabling activating kiddos). • Clinical uses of IFN-α (pachyderm man) o Interferon α treats hep B & C infections (hippo). Given as injections. Pegylated INF allows longer half-life and steadier concentrations, requiring less frequent dosing. o Approved for treatment of many neoplasms ▪ Hairy cell leukemia (hairy creatures) ▪ Malignant melanoma (melatonin ghost) ▪ Kaposi’s sarcoma by HHV-8 (Kate’s posies on cabinet and in maze) ▪ Renal cell carcinoma (crab in kidney shaped claw machine) o Condyloma acuminatum caused by HPV (pill bug jar) o Has many adverse effects (why we want new Hep C treatments!) ▪ Flu like syndrome with headaches, fevers, malaise, myalgias within 6h after dosing (fevered kid). In as much as 30% of patients after initiating therapy. Generally resolves. ▪ Neuropsychiatric complications with chronic treatment, including tinnitus, retinopathy, confusion, psych disturbances, profound fatigue (sick kid) • Depression resulting from INFα treatment can be profound and may include suicidal ideation. Contraindicated in severely depressed or suicidal patients. ▪ Pneumonitis, interstitial fibrosis ▪ Myelosuppression (maze is bone-shaped and red cell dots are being eaten). Important to consider when giving other myelosuppressive agents. ▪ Metabolic complications, including thyroid dysfunction, low-grade fever ▪ Dermatologic complications, e.g. alopecia ▪ Rarely, drug induced lupus (plush wolf in claw machine) • Interferon β (β Invaders) o Approved for use in relapsing type MS (“Combat lesions though Time & Space”) • Interferon γ (Gammaga game) o Treats CGD. May activate macrophage otherwise unable to form oxygen species needed for oxidative burst (bursting asteroids) 7..2 L stto enntt ((Ri R viiirrriin, n, so soffos fo 7. 2 – ““D “Dr D Drr Liv Liiiv on uum m meee???”””:: H Heeep p --C C ttrreeaaatttm men Rib Riibbbaavvir oossb uvi vviiir, rr, vveeerr-sto onneee,, I pprrreeesssu sbuuv ssiiim m meeep prreeev vviiirrr)) • Hep C can cause acute and chronic hepatitis. Acute infection is often self-limited and commonly causes chronic infection. Decision of treatment regimen, dosing, and duration of therapy depends on stage & state of infection as well as infecting genotype (sketch of yellow hippo with genotype? highlighted). Fibrosis stage usually assessed as well, usually by history and exam; biopsy is not necessarily standard of care (stony “fibrosed” liver under microscope). • Treatment causes ↓M&M and improved quality of life in all patients with virologic evidence of chronic HCV infection (photographic evidence on board). Standard of care is to treat all HCV⊕ patients except those with limited life expectancy. Goal of treatment is the eradication of viral RNA which is predicted by a sustained virologic response (i.e. HCV RNA not detected by PCR for 6 months after stopping treatment) (6 mos. sustained search for Sea Hippo). Achieving SVR means 99% change of sustained seronegativity on long term follow-up. • Treatment: Once weekly pegylated-IFN-α (α-antenna) + daily oral ribavirin (ribs) is traditional therapy. Several newer therapies with fewer adverse effects are available. • Ribavirin o Given oral daily as part of combination therapy along with pegylated-IFN-α o Guanosine nucleoside analog (purine shaped stakes). Needs Ⓟ by intracellular enzymes into active nucleotide form (3 pepper shakers) o Inhibits RNA production (RNA ropes) o Also used in RSV (though has largely been replaced with palivizumab) (RSV tombstone) o Adverse effects ▪ Dose dependent hemolytic anemia (tomatoes) ▪ Teratogenic – category X (enormous tarantula). Not to be used in M or F of childbearing age not on birth control. • Polymerase inhibitors: sofosbuvir (sofa with nucleoside pattern) o Nucleoside analog that inhibits the NS5B RNA-dependent RNApol inpatients infected by genotypes 1,2,3,4 (nucleotide pattern on sofa). o Direct polymerase inhibitor that disrupts RNA production (disrupted ssRNA rope) o May be part of a regimen with ribavirin, IFN-α, or the newer ones that are all oral; latter regimens highly effective & welltolerated, without interferon toxicities. o Adverse effects (tired Dr Livingstone) ▪ Fatigue ▪ Nausea • Protease inhibitors (NS3/4A inhibitors) (machete) o Simeprevir (and other protease inhibitors) work with HCV genotype 1 (simmering food over the fire). o Cleave HCV-encoded polyproteins o Adverse effects ▪ Photosensitivity & rash (flashing camera) ▪ Substrate & inhibitor of CYP450 system (broken down truck in the background) • New investigational drugs (North Sea investigative map) o 2nd gen NS3/NS4A protease inhibitors o NS5A inhibitors o None require ribavirin & INF administration 8..1 arree Noow Freeee tto mo abbo Gaan 8. 1 – ““Yo Y ou u ar w Fr o m mov oovvvee ab oou ut tth hhee Gan ng lia iiaaa”””:: A Acccy yycc llo oov viir, rr, vvaaalllaaacccy yyccclllo oov vviir, Yo nglli ffaaam m mccciiiccclllo oov v ir, cciiid doofffo oov vviiir, rr, ffo oossscccaaarrrn nneeett • Oral purine nucleoside analogs used for HSV (Hermes for herpes) & VZV (Zeus) infections • Acyclovir, valacyclovir, famciclovir all treat HSV. Short course of 7-10 d Tx with primary oral, genital, HSV infection → ↓viral shedding, time for lesion healing, and ↓local pain. Does not affect recurrence rates. o Can offer in recurrence daily to take any of the medications daily. Valacyclovir preferred as it is dosed qid & has superior bioavailability (“valet parking for frequent flyers” & “Daily rate” signs; attendant popping pills over “↑available↑” sign) o Can also be used as HSV prophylaxis in immunocompromised patients (lady with cane) ▪ In pregnancy with active recurrent genital herpes, give suppressant acyclovir at 36w to reduce risk of C-section & active shedding (pregnant lady) ▪ Transplant patients (organs on ice) • Acyclovir (recycling bins) o G-purine nucleoside analog that gets Ⓟ via herpesvirus encoded thymidine kinas → acyclovir monophosphate; occurs selectively in virus-infected cells (guanosine nucleoside shaped Gucci luggage labeled with Ⓟ luggage tag by Hermes attendant). This is the rate-determining activation step (“Rate limit”) (also the point where bugs can develop resistance). Subsequent Ⓟ steps taken over by cellular kinases (blue-collar workers slapping on 2nd & 3rd). Triphosphate can compete with deoxy-guanosine triphosphate. When incorporated, halts viral DNA synthesis via DNA-dependent DNA polymerase (bags jamming DNA-shaped conveyor belt) o Absence of thymidine kinase confers resistance (absence of attendant at closed baggage check) o Effective against herpes zoster (shingles is reactivated VZV) o Only drug here that is available for IV use in US (ivy). ▪ Treatment of serious HSV & VZV infection, including HSV encephalitis (helmet wings), neonate HSV infection (baby). • Valacyclovir o Acyclovir prodrug with better oral bioavailability (oral eating; ↑available) o Effective against herpes zoster (Zeus sign). Superior activity and less frequent dosing. ▪ Hasten resolution of cutaneous lesions & acute neuritis. ▪ Unknown effect on post-herpetic neuralgia. ▪ Valacyclovir & famciclovir are most effective when administered within 3d of symptom onset (“Great Value: 3-Day family vacation”) • Famciclovir o Effective against herpes zoster (“3-Day family vacation”) • Cidofovir (Cid the security guard) o Does not require viral kinase Ⓟ so effective against acyclovir or ganciclovir resistant HSV, VZV, CMV (Cid the security officer has Ⓟ tags so can bypass the closed luggage counter). This is especially important in immunocompromised patients, as thymidine resistant strains of VZV are found almost exclusively in immunocompromised populations o Directly inhibits viral DNApol (security officer directly turning off conveyor belts). • Foscarnet (car with a net) o Does not require Ⓟ by viral kinase (cart bypassing closed checkpoint). Active against acyclovir or ganciclovir resistant HSV, VZV, CMV. o Directly inhibits viral DNApol; pyrophosphate analog that selectively inhibits the pyrophosphate binding site on viral DNApols (security officer directly turning off conveyor belts). • Adverse effects o IV acyclovir can cause interstitial nephritis or crystalline nephropathy (sharp crystalline objects causing tubular obstruction in kidney shaped can). Uncommon with slower infusion rate & sufficient hydration (tossing water bottles) o All can cause CNS effects (delirium confusion, vertigo, hallucinations). Especially with high dose a/o IV administration (shaky kid setting off alarm in detector) 8..2 an up up on Aiissslllee HH C M 8. 2 – ““C C Cle Cllleean HVHV V-55”””:: CMV CM MV tre rreeaatttm m meeen nt ((G G Gaannccciiiccllo oov vviir, vvaalggaaan ncci cic iiccclloov ovi vviiir, rr, V ttr cciiid rnneeettt,, pr prro ddo oofffo oov vviiir, rr, fosscccaarn oob bbeeen nneeeci ecciid dd)) • CMV infection (Mega-lo Market) occurs predominantly in immunocompromised, notably HIV (CD4 < 50) (“50 items or less” – should be “fewer”) & organ transplant (organ counter). Classically presents with CMV retinitis with retinal hemorrhages and infiltrates (pizza box). • Shared adverse effects o Associated with bone marrow suppression (bone marrow tray). Usually managed with hematopoietic growth factor s. Should be monitored for hematologic suppression. Effects may be additive with other myelosuppressive agents, especially with Zidovudine (pregnant princess eating bone marrow). • Ganciclovir (cans only recycle bins) o Guanosine analog, like acyclovir. Has to be tri-phosphorylated, before incorporating into viral DNA & jamming DNApol (jammed DNA conveyor belt). ▪ First Ⓟ step converts to ganciclovir monophosphate with a virus encoded kinase (UL97) which enables CMV-infected cell specificity (Market employee labeling Ⓟ for virus encoded . ▪ Following steps done by cellular kinases (kids going crazy with label guns) ▪ Protein kinase mutations can cause resistance o Incorporation stops DNA synthesis • Valganciclovir (great value samples) o Prodrug of ganciclovir with increased oral bioavailability (lady with open mouth) o As effective as IV ganciclovir for CMV retinitis o Used for prophylaxis in bone marrow & organ transplant (organs on ice) o Same MOA as ganciclovir • Foscarnet (fast car with a net) o Does not require Ⓟ by viral kinase. Active against acyclovir or ganciclovir resistant HSV, VZV, CMV. o Directly inhibits viral DNApol (kid crashing into register); pyrophosphate analog that directly selectively inhibits the pyrophosphate binding site on viral DNApols (bypassing phosphorylating CMV worker) o Available IV o Adverse effects ▪ May induce renal insufficiency. Appears to be directly toxic to renal tubular cells (spilled kidney beans) ▪ Hypocalcemia (broken milk bottles) ▪ Hypomagnesemia (falling magnets) ▪ Hypokalemia (banana peels) ▪ Seizures may result from electrolyte disturbances (shaky lines) • Cidofovir (Cid the security guard) o Does not require viral kinase Ⓟ so effective against acyclovir or ganciclovir resistant HSV, VZV, CMV (Cid the security officer has Ⓟ tags). This is especially important in immunocompromised patients, as thymidine resistant strains of VZV are found almost exclusively in immunocompromised populations o Directly inhibits viral DNApol (directly stopping DNA belt shut off switch) o Adverse effects ▪ Nephrotoxic, → proteinuria, azotemia, metabolic acidosis (broken kidney-shaped bottles) ▪ Must be coadministered with probenecid (probation officer Cid); blocks tubular secretion of cidofovir, limiting renal toxicity (probation offer protecting). Also blocks excretion and increases plasma concentration of many different drugs, including penicillins, MTX, & NSAIDS (druggie cashier not touching kidney bottles).