R-lactam Antibiotics Contain

• 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) • 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) • 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) • 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) • 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 • 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 • 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) • 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). • 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