Bacteriostatic Agents

• erythromycin, clindamycin, tetracyclin, sulfonamides, chloramphenicol, linezolid
• primarily inhibit bacteria
• killing of organism is dependent upon host defense mechanism
• diasadvantages - in inadequate host defenses, any partially inhibited organisms may survive, replicate and produce recurrent disease when antibiotic is discontinued

Bactericidal Agents

• penicillins, cephalosporins, aminoglycosides, vancomycin, daptomycin, carbapenem, aztroconam, fluoroquinolones, metroniadazole
• depend less upon host factor
• preferable if pt is compromised - neuropenic, immunosuppressed
• preferable if the host defense mech do not operate well, eg - bacterial endocarditis, bacterial meningitis

Penicillin Mechanism of Action

• inhibits cell wall synthesis by covalently binding to active PBPs
• interferes w/ transpeptidation reaction of bacterial cell wall synthesis (stops cross-linking) - halts peptidoglycan synthesis
• autolysins and disruption of cell wall morphogenesis are invovled in the process of death
• penetration and diffusion is wide spread - especially across inflamed membranes (meninges, peritoneum)
• acid stability w/ phenoxymethyl penicillin and amoxicillin

Penicillinase-Resistant Penicillins

• parenteral - methicillin, naficillin, and oxacillin
• oral - claxacillin and dicloxacillin
• developed in repsonse to the rapid development of s aureus resistance to the natural penicillins
• addition of the side chain to penicillin protects the B-lactam ring from hydrolysis by penicillinases produced by staphylococcus species
• staphylococcus becomes methicillin resistant by altered PBPs (freq 50%) - MRSA

Aminopenicillins

• ampicillin, amoxicillin, bacampicillin
• greater activity against enterococcus and listeria than the natural penicillins
• added side chain does not inhibit hydrolysis by staph penicillinases or gram-neg B lactamases
• enhanced activity includes - H influenza, ecoli, proteus mirabilis, salmonella and shigella
• adverse effects - allergy, ampicillin specific rash, pseudomembranous colitis 
• carboxypenicillin (carbenicillin & ticarcillin) - same spectrum as ampicillin but also enterobacter, morganella and indole-positive proteus
• ureidopenicillins (azlocillin, mezlocillin, piperacillin) - gram neg in this class includes that of carboxypenicllins, but also klebsiella, serratia, enterobacter, enterococcus, and improved anaerobic activity

Cephalosporin Overview

• gram positive and gram negative spectrum
• binds to PBPs and rend them inactive (interferes w/ synthesis of peptidoglycan comp of cell wall
• most excreted by kidneys so dose adjustments in renal failrue
• hepatobiliary elimination - cefriaxone, cefoperazone, cefotaxime (partial, significant)
• adv rxs - nephrotoxic (rare, nephritis), diarrhea (nonspecific in hepatobiliary excreted drugs, C. Dif in all drugs), disulfiram-like rx (blocks acetaldehyde dhase, assoc w/ MTT), hypoprothrobinemia (in MTT group of vitk dep carboxylase)
• moxalactam reversibly suppresses ADP-induced platelet aggregation
• Hypersens rx most common adv effect - immediate IgE anaphylaxis/utricaria rare; maculopapular rash after several days most common

First Generation Cephalosporins

• active vs gram positive cocci except enterococci and MRS-
• active vs most ecoli, proteus mirabilis, klebsiella spp
• little to no activity vs anaerobes
• cefazolin use - perioperative prophylaxis for joint prosthesis; parenteral therapy for simple skin and soft tissue infections
• Cefadroxil use - oral therapy for skin infections, UTI, etc

Second Generation Cephalosporins

• less gram positive activity than first generation
• more activity vs ecoli, klebsiella sp, proteus sp (indole-negative)
• some w/ activity vs H influenza - cefamandole, cefuroxime, cefonicid
• some (cephamycins) w activity vs bacteroides fragilis - cefoxitin, cefotetan, cefmetazole
• uses - abdominal and pelvie surgery antibiotic prophylaxis
• treatment of mild intra-abdominal infections (cholecystitis)

Third Generation Cephalosporins

• relatively poor gram-positive activity - exception ceftriaxone and cefotaxime v streptococcus pneumonia
• excellent activity vs anaerobic gram neg bacilli including h influenza
• variable activity vs anaerobes including bacteroides fragilis
• some activity vs pseudomonas aer - ceftazidime
• ceftriaxone and cefotaxime - bacterial meningitis
• ceftriaxone and cefotaxime - community acquired pneumonia protocol
• ceftazidime - tx of pseudomonas and other gram neg infections (all types)

Fourth Generation Cephalosporins

• cefepime
• reduced affinity for calss-1 beta lactamases
• sig gram pos and gram neg activity incuding vs pseudomonas a.
• sig anaerobic activity
• effectiveness vs multi-resistant gram-neg bacilli
• not active against MRSA
• ceftobiprole (not in US) - effective against MRSA

Fifth Generation Cephalosporins

• ceftaroline
• binds to penicillin binding protein (PBP) 2a - MRSA specific PBP that has low affinity for most other beta lactam antibacterials
• high bidning affinity for PBP2a correlates well w. its low MIC for MRSA
• does not treat ESBL-producing gram neg bacilli
• spectrum does not extend to non-fermentative gram-neg bacilli - does NOT extend to psuedomonas

Amoxicillin - Clavulanic Acid

• well absorbed from GI tract - exctreted by kidneys
• penetrates tissues and extravasc fluids well (peritoneum,pleura, bone, bile, synovial fluid)
• antimicrobial activity - s aureus, h influenza, m caterrhalis, n gonorrhoeae, e coli, klebsiella, bacteroides, certain enterobacteriaceae, pausteurella
• no activity against pseudomonas, serratia, enterobacter, citrobacter, MRSA, penicllin resistant s pneumoniae
• uses - upper and lower resp tract infections bronchitis, UTIs, intra-abd and plevic infections, skin/soft tissue infections (animal/human bites)

Ticarcillin- Clavulanic Acid

• barely used due to piperacillin-tazobactam
• active against B lactamase producing gram neg rods and anaerobes
• active against most strains of pseudomonas, serratia, acinetobacter
• not active against MRSA or enterococcus
• clinical uses - nosocomail infections (polymicrobial), neutropenic fevers, complicated intra-abdominal infections (appendicitis/cholecystis), pelvic infections

Ampicillin - sulbactam

• serum half-life of 1 hour
• IV/intramuscular adm
• coverage is ismilar to augmentin (amoxicillin-clavulanic acid)
• spectrum - skin and soft tissue infections - diabetic foot infections, complicated wound, animal and human bites
• spectrum - intra abdominal, pelvic and lower resp tract infections
• limited activity against nosocomial pathogens
• still active against some extended spectrum B lactamase (ESBL) producing and other multidrug resistant gram neg rods (ecoli, klebsiella)
• activity against MDR acinetobator is due to sulbactam

Piperacillin-tazobactam

• active agaisnt - s aureus, strep, enterococcus, most anaerobes, aerobic gram neg (including pseudomonas), fastidious gram neg bacteria
• clinical utility - nosocomial infections (polymicrobial), neutropenic fevers (in conjunction w/ aminoglycosides) (vs ampicillin), complicated intra-abdominal infections, pelvic infections
• not active against MRSA and resistant strep
• less active against gram neg bacteria that have altered cell wall permeability to piperacillin

Monobactams

• aztreonam
• synthetic B lactam compound w/ an attached sulfonic acid group
• binds to PBPs; limited toxicity profile
• highly active against aerobic gram neg bacilli (including pseudomonas)
• excreted by kidneys
• not activity agaisnt - gram pos bacteria, anaerobics, enterococcus
• no synergistic activity w/ other B lactam agents
• use - complicated UTIs, nosocomial gram neg pneumonia/sepsis, neturopenic fevers (w/ aminoglycoside) (usually penicllin allergy pt), gram neg CNS infection

Carbapenems

• broadest activity of B lactam - Imipenem, meropenem, doripenem, ertapenem
• MOA - in periplasmic space bind to PBPs and inh peptidoglycan syn; can bidn multiple tpes of PBPs which allow better activity
• I, M, and D hit most gram neg, ESBLs, including pseudomonas; E does not kill PsA nor acinetobacter
• kills anaerobes close to 100%
• gram pos - I. good vs MSSA, sensitive enterococcus faecalis
• Resistance - B-lactamases, efflux pumps, mutations of porins or PBPs (KPC type of carbapenemase)
• Adv rx - seizures are the biggest fear, especially if not dosed for Renal failure

Vancomycin

• bactericidal - inh of bactrial cell wall syn by binding to the D-A-D-A terminus of peptidoglycan inh incorporation of murein monomers - cell lysis
• bactericidal for gram pos, kills staph only if activity dividing
• synergistic w/ gentamicin and streptomycin agaisnt enterococcus faecali not resistant to aminoglycosides
• rate of killing depends on time of concentration of drgu exceeding the organisms Min inh concentration (MIC) (area under the time conc curve best predictor)
• use - bacteremia and endocarditis w/ s aurues, Vanco sensitive enterococcus (VSE), C dif diarrhea unresponsive to metronidazole
• adv rxs- Red-man syndrome, leukopenia, eosinophilia, ototoxicity, nephrotoxicity (esp in combo w/ aminoglycosides)

Daptomycin

• cyclic lipopeptide - bactericidal
• Ca dependent depolarization of cell membrane - lipophillic tail inserts into membrane forming an eflux channel
• poor penetration into lung, infected bone and CSF
• pharm - conc-dependent; prolonged post-antibiotic effect, inactived by alveolar surfactants
• use - serious infection w/ MSSA, MRSA, VRE, bacteremia and endocarditis unresponsive to vancomycin
• co-adm of statins may inc CPK and myopathy
• adv rx - constipation, nausea, inc CPK, myopathy, rhabdomyolysis, eosinophlic pneumonia and chronic pneumonitis

Fosfomycin

• inh of bacerial cell wall syn - in cytoplasmic enzyme enolpyruvae transferase and blocks addition of phosphoenolpyruvate to DUP=N-acetylglucosamine (1st step in formation of cell wall)
• active against both gram pos and neg bugs
• in vitro synergism w/ B lactam, aminoglycosides, or fluoroquinolones
• excreted by kidneys, urinary conc exceeding MICs for most urinary tract pathogens
• resistance fast; unsuitable for sustained therapy
• not recommended for children and >75yrs
• use - uncomplicated lower UTI in women; safe for use in pregnancy
• antacids (Ca carbonate) and food dec absorption

Fosfomycin Mechanism of Resistance

• inadequate transport of drug into the cell due to mutaitons that inactivate glycerophosphate transporter
• Tree resistance enzymes (FosA, FosB, FosX) funciton by neucleophillic attack on carbon 1 of fosfomycin, which opens the epoxide ring and renders it ineffective
• FosA and FosX enzymes are produced by gram negative bacteria
• FosB is produced by gram positive bacteria

Bacitracin

• cyclic peptide - inh of cell wall formaiton - interfres w/ dephosphorylation in cycling of the lipid carrier that transfers peptidoglycan subunits to the growin cell wall
• active against gram-positive; topical use results in local antibacterial w/o systemic toxicity
• not absorbed in GI tract; 10-40% of IM dose excreted via gomerular filtration
• only used topically; seen in ointment w/ polymyxin or neomycin for mixed bacterial flora)
• neuromuscular blockade may be enhanced w IM bacitracin (non-depolarizing muscle relaxants)
• adv rx - nephrotoxicity w/ IM use (proteinuria, oliguria, azotemia)

Polymyxins

• polymyxin B and polymyxin E (Colistin) - cyclic peptide w/ a long hydrophobic tail
• disruption of bacterial cell membrane - binding of LPS in the outer membrane of gram neg bacteria; also inactivation of endotoxin
• hydrophobic tail cause membrane damage as cationic detergents
• bactericidal for gram neg bacilli resistant to all other antimicrobials
• inc permeability of cell wall to other antibiotics and that of bacterial membranes to release toxins (shiga toxin from ecoli)
• intrathecal for meningits by resistant A. baumanni
• non-depolarizing muscle relaxant effects may be inc w/ systemic use
• adv reactions- nephrotoxicity and neurotoxicity (paresthesia, dizziness, vertigo, ataxia, blurred vision, slurred speech)

Streptococcal Pharyngitis

• sx - severe sore throat, fever, headache, abdominal pain; never hoarseness and never cough
• group A, rarely groups C and G
• diagnosis made by culture and confirmed by serology
• 10 days of penicllin to prevent Rheumatic fevere
• complications of streptococcal pharyngitis - scarlet fever, Rheumatic fever, acute glomerulonephritis (coca cola colored urine)

Scarlet Fever

• streptococci harbor a bacteriophage that codes for an erythrogenic toxin: SPE A and SPE C
• typically after pharyngitiss: rash, circumoral pallor, strawberry tongue
• severe cases - strep infection producing SPE A or SPE B leads to shock, renal impairment and death

Rheumatic Fever

• predisposed persons make antibody to streptococcal M protein that cross reactions w/ cardiac and articular antigens
• jones criteria - Major - carditis, arthritis, chorea, erythema marginatum, subcutaneous nodules
• Jones criteria - Minor - fever, arthralgia,  acute phase reactants, prolonged PR interval, evidence of preceding strep infection
• occurs 3 weeks after pharyngitis
• mngmt - penicillin to eradicate infeciton, aspirin for arthritis and prednisone for carditis
• prevention - daily penicllin prophylaxis until 20s or longer

Respiratory Syncytial Virus

• causes bronchiolitis in infants
• can be fatal in premature infants as well as in infants w/ cardiac or pulmonary problems
• passive prophylaxis w/ monoclonal Ab - synagis
• ribavirin used for t of severe cases

Pneumonia

• infection of the lower resp tract parenchyma
• 70% of CAP and 90% of nosocomial caused by S pneumonia, H influenza, s aureus, gram neg bacilli, legionella
• lobar - infiltrate w/ alveoli; bronchopneumoniae - patchy, disal bronchiole; interstitial - inflam of intersittium
• pathophys - aspiration of oropharyngeal contents - most common cause; "subclinical"
• recurrent pneumonia, condier defect of immune system (IgG def, HIV)
• Sx - cough, fever, chills, dyspnea, chest pain, sputum, rohonci (consolidation)
• CXR - NEW infiltrate (vs bronchitis where no new infiltrate)
• biomarkers(procalcitonin) - secreted in livr in response to bacterial cytokines
• CAP Tx - beta lactam; macrolides, fluoroquinolones, doxycycling

MRSA Pyoderma Treatment

• community assoc - oral trimethoprim/sulfamethoxazole; doxycycline; clindamycin
• Hospital acquired - vancomycin, linezolid, daptomycin, telavancin

Cellulitis 

• invovles deeper layers - subcutaneous tissue, dermis, epidermis
• borders blend w/ surrounding skin
• may spread rapidly; fever often present
• erythema, induration, heat, tenderness
• etiology - beta hemolytic strep most common
• consider s aureus if severe, prior staph infection, penetration woud, purulence present
• Tx - antimicrobial agents

Necrotizing Skin Infections

• Type 1 - polymicrobial (aerobic/anaerobic) - diabetic foot infection, decubitus infection, bite wounds
• Type 2 - s pyogenes (strep toxic shock syndrome) - group A strep necrotizing fasciitis - flesh eating bacteria
• erythema and swelling; bullae, gangrene
• type 1 may have a foul odor (mixed infection)
• initially severe pain
• pain more severe than expected (followed by anesthesia)
• necrosis, toxic shock syndrome and elevated CPK level can also be clues

Fluoroquinolones

• ciprolfoxacin, levofloxacin, moxifloxacin, gemifloxicin
• blocks DNA syn by inh bacterial topo II(gyrase) and IV - both enzymes essential for cell growth
• most aerobic gram negs and pseudomonas (cipro and levo)
• New FQ (levo and moxi) good for gram pos s pneumo
• no longer recommended for gonococci - inc resistance
• high bioavail; concentration dependent killing; tissue and intracellular levels exceed serum levels
• excretion: renal - nor, cipro, levo; biliary - moxi; both gemifloxacin
• use - UTI (including prostatitis), respiratory infections (CAP and Nosocomial), bacterial diarrhea, chlamydia, osteomyelitis, skin (esp gram neg) and intra-abd (moxi)
• CI - pregnancy/pediatrics

Drug Effects of Quinolones

• drug interactions - xanthines (caffeine/theophylline) - some FQs cause dec metabolism of xanthine resulting in higher levels
• antacids/iron/zinc - divalent cations (Ca, Mg, Fe) sig dec absorption of FQ (chelates them)
• adv effects - nausea/vomiting, diarrhea, headache, cartilage toxicity (interfere w/ formaiton) so CI in pregnancy, tendonitis (rupture) when also taking steroids or organ transplant
• Structural side effect relationship in FQ - CNS toxicity through GABA binding, phtotoxicity and genetic toxicity, arrhythmia (prolongation of QTc interval)
• gemifloxacin can cause non-allergic, mild rash 

Metronidazole

• nitroimidazole
• taken up by bacterial DNA forming unstable molecules - this occurs only when metronidazole is partially reduced which only occurs in anaerobic cells
• thus litle effect on human cells or aerobic bacterial
• spectrum - anarobic bacteria and some protozoa (giardia, amoeba, trichomonas); H pylori
• hepatic clearance
• uses - anarobic infections - c diff, vaginitis, h pylori
• drug interactions - alcohol-disulfiram effect; potentiate coumarin
• adv effects - nausea, abnormal taste, neuropathy, seizures

Rifampin

• rifamycin; rifabutin and rifapentine
• inh RNA syn  binds to subunit of bacterial DNA dependent RNA polymerase
• spectrum - mycobacterium, staph, strep (including pneumo), listeria, some gram negs (N meningitis, H influenza)
• hepatic clearance; high intracellular penetration; wide distribution into body tissue and fluids
• combo for TB and staph; monotherapy for  meningitides meningitis prophylaxis
• effects metabolism of any other drug metabolized by CYPs
• adv - nausea, hepatitis, red-orange discoloration of body fluids
• since rate of resistance is high, rifampin is not used as monotherapy unless prophylaxis

Tetracycline

• bacteriostatic; enter thru porins and inh protein syn at the 30S ribosome subunit
• broad spectrum - aerobes and anaerobes; no activity against pseudomonas
• Tigecycline has broadest coverage (3rd gen); hihger affinity to ribosome and less sens to resistance from efflux or ribosomal protection proteins (RPPs)
• food inh absorption of tetracyclines
• 1st gen 60-80% bioavail; 2nd 90-100%; 3rd poor
• toxicity- hypersens and photosens, discoloration of teeth (CI in <8yr), GI (food alleviates but dec bioavail), neurotoxicity (headache, dizziness, pseudotumor cerebri)
• Clinical indication for almost anything except pseudomonas

Macrolides

• erythromycin, clarithormycin, azithromycin
• large ring, 14 member lactone, oral, IV, ointments
• inh protein syn by binding to 23s rRNA of 50s ribosomal subunit; inh translocation of tRNA and interferes w/ formaiton of 50s Subunit
• erythro s aureus, strep, mco, bordetella, chlamydia, legioneela, campylobacter, clostridium
• chlarithro 2-4x more active against MSSA, strep; also H influ, m avium, moraxella
• azithro less active against s aureus and strepto than erythro  but more active against H influ, moraxella
• MLS_Bresistance phenotype - macrolide, lincosamide, streptograminB - erm gene A-C
• Erytho - interfere w/ hepatic CYP3A subclass; drug persists in tissue longer than serum; concentrate in neutrophils and macrophages
• clarithro-excreted by bile and urine; adjust for renal failure; levels in tissue and concentrates in neutrophils more than erythro
• azithro- higher tissue penetration(10-100x); conentrates in phagocytes; no adjustment for renal/hepatic failure
• adv - GI, cholestatic hepatitis (estolate), ototoxicity, QT prolongation (IV ery), pyloric stenosis (ery)

Ketolide

• new class w/i macrolide family - telithromycin
• subs of 14 ring w/ ketone group
• enhanced binding at 23s rRNA site - 2 domains of 23s rRNA (II, V)
• low induced of MLS_Bresistance
• improved activity for most gram pos; including M (eflux) and inducible MLS_Bstrains of strep
• not active against constitutive MLS_B resistance
• considerations - elevation of liver enzymes, exacerbation of myasthenia gravis, interferes w/ CYPs (similar to erythro and clarithro)

Aminoglycosides

• streptomycin, amikacin, tobramycin, gentamicin, neomycin, paromycin, spectinomycin
• conc-dep killing, synergistic w/ beta lactams; post antibiotic effect
• bactericidal by irreversibly inh protein syn - oxygen dependent diffusion thru porins and bind to 30S ribosomal subunit; block initiation ocmplex and translocation
• uses - severe infection (facultative/aerobic gram neg bacilli); emperic therapy for sepsis (combo), esp immunocomp, neutropenic, psudomonas; synergism
• inc risk of nephrotoxicity when combo w/ vancomycin; use of furosemide inc risk of neprho and ototioxicity, manitol inc risk of ototoxicity
• adv- nephrotoxicty (lower risk w/ once daily dosing), ototoxicity (early high freq loss; cumulative) - neomycin>gent>tobra>ami>netil; rash, drug fever
• unusal to have  both nephro and ototoxicity concurrently
• neuromuscular blockade - rare, rapid rise of drug serum conc; pos assoc w/ myasthenia gravis, low Mg or Ca, Ca channel blockers; reversible w/ calcium gluconate or neostigmine

Oxazolidones

• linezolid and tedizolid
• syn antibiotics w/ broad gram pos activity
• bacteriostatic against most gram positive organisms but bactericidal against strep
• MOA - inh protein syn by preventing formaiton of ribosomal complex; binds to 23s ribosomal RNA of the 50S subunit
• metabolized by oxidative metabolism; CYP neutral
• uses - skin and soft tissue infection, CAP and nosocomial pneumonia, and VRE
• drug interactions - weak inh of MAO - can precipitate serotonin sickness in non-sel MAO, SSRIs, SNRIs
• major toxicity is hematologic -thrombocytopenia; anemia and neutropenia
• optic neuritis, peripheral neuropathy and lactic acidosis occur w/ prolonged use from inh of mitochondrial protein syn

Clindamycin

• lincosamide - binds to bacterial 50S subunit (same site as macrolides); disrupts protein syn by blocking translocation
• staph, viridans strep, s pyogenes, s pneumo, potent anaerobic acitivity, toxo, actinomyces, p falciparum, p vivax
• D test to check for inducible resistance - positive test indicates resistant present
• use - anaerobic broncho-pulm infections, use in combo w/ other agents, serious soft tissue group A strep (PCN allergies), combo w/ primaquine for jiroveci and w/ pyrimethamine for CNS toxo, endocaridits prophylaxis (if PCN allergic)
• Adv - rash, C dif infection, 

Streptogramins

• quinupristin-dalfopristin
• MOA - share same ribosomal binding site as macrolides and clindamycin, inh protien syn; rapidly bactericidal except against enterococcus faecium, which is killed slowly
• no dose adjustment for renal failure; dose reduction needed w/ hepatic insuffiency
• clinical use - staph and vancomycin resistant starins of E. faecium but no E faecalis
• drug - inh CYP3A4
• adv - infusion related events

Infective Endocarditis

• virulence factors - extracellular dextran mediates adherence to platelet-fibrin thormbus (s mutans, s bovis, s sanguis), FimA surface adhesion expressed by viridans streptococci, important colonization factor, TFA induction by s aureus from intact endothelial cells
• subacute IE - fever, often remitting, nonspecific malaise, weight loss, fatigue, chills and night sweats common
• Microvasc phenomena can lead to persistant fever
• most common complication is new regurgitant murmurs, and CHF sx
• major criteria - blood culture positive for IE or anti phase 1 IgG Ab titer 1:8000, and evidence of endocardial involvement (echo positive - TEE or TTE)
• emergency surgery indicaiton - acute AR w/ early closure of mitral valve, rupture of sinus valsalva aneurysm into R heart chamber, rupture into pericardium
• Urgent (w/i 1-2) - valvular obstruction; unstable prosthesis; septal perforation, acute aortic regurge or MR w/ heart failure, major embolism w/ mobile vegetation
• neurologic complications develop in up to 40% of all pts w/ IE (embolic phenomenon)
• renal complications in up to 50% w/ staph IE

Coagulase-negative Staphylococcus

• most common cause of early Prosthetic Valve Endocarditis
• native valve CoNS IE assoc w/ outcomes of heart failure and mortality almost as bad as SA
• staph lugdunensis - usually community acquired  - weakly coagulase positive, usually oxacillin-susceptible; destructive disease often needs surgical therapy; mortality up to 50%

Streptococcal Endocarditis 

• most commonly strep sanguis, strep bovis, strep mutans and sstrep mitis
• strep bovis assoc w/ GI malignancy or mucosal lesions - recommended colonoscopy
• Nutritionally-deficient streptococcus (requires pyridoxal containing culture media) - abiotrophia and granulicatella - may be more resistant
• group C and grp G streptococcus - uncommon, also look for mucosal lesions
• strep pneumonia, need MICS - uncommonly encountered - relatively resistant MICs can be treated w/ high dose PCN or ceftriaxone; if high grade resistance consider vancomycin and rifampin

Rubeola

• measles virus
• high contagious via resp droplets
• cough, coryza, conjunctivitis, koplick spots (found in mouth)
• measles rash - initially discrete reddish lesions that blanch; quickly merge and become brownish
• spreads cephalocaudally (head down)
• dx - clinical, virus isolation, detection of IgM Ab, detection of 4fold rise in IgG Ab
• complications - otitis media, encephalitis, altered measles
• pneumonia - due to virus (giant cell pneumonia) or bacterial superinfection
• prevention immune serum globulin, live attenuated virus vaccine

German Measles

• rebulla virus
• spreads via respiratory droplets
• mild symptoms - lymphadenopathy and polyarthralgia
• rash is milder in appearance and more rapid in progression - three day measles
• Dx - virus isolation, detection of IgM Ab, detectio of fourfold rise in IgG Ab
• complications - congenital rubella (ophthalmologic, cardiac, auditory, neurologic), encephalitis, thrombocytopenia
• prevention - live attenuated virus vaccine, immune serum globulin

Roseola

• exanthema subitum - Human Herpesvirus 6 and 7
• spread via close contact
• Sx - high fever in young infant followed by erythematous maculopapular rash
• occasionally adenopathy, GI or resp symptoms and red TM;s
• Dx - clinical, IgM or 4fold IgG ab rise, rius isolation, HHV-7 serology may be hard to find
• complications - febrile seizures
• immunocompromised pt- fever, hepatitis, bone marrow suppression, pneumonia, encephalitis

Fifth Disease

• Parvovirus B19; also known as erythema infectiosum
• spread via resp secretions
• flu like illness followed by 7-10 days later by facial rash (slapped cheek); symmetric maculopapular, lace like rash
• spreads from extremties to trunk
• dx - clinical, IgM Ab or 4fold rise in IgG Ab
• in utero infection - fetal hydrops and death
• In adults - arthirtis
• in chronic hemolytic anemia (sickle cell) - aplastic crisis
• in immunodef - chronic anemia

Chickenpox

• varicella-zoster virus (VZV) spread via direct contact or resp droplets
• generalized pruritic, vesicular rash - progress cephalocaudally; papules, vesicles and crusted lesions all present at the same time
• Dx - clinical, Tzanck smear and IF staining, detection of IgM Ab and 4fold rise in IgG Ab
• Pathology - EC, NK, MN found on histo
• Tx - acyclovir (oral/IV)
• prevention - live attenuated virus vaccine, VZIG (no longer available)
• complicaitons - bacterial cellulitis, thrombocytopenia, arhtritis, encephalitits or meningitis, hepaittis, glomerulonephritis, pneumona, fetal infection
• risk of disseminated dz and mortality inc if steroids given during incubation period

Smallpox

• variola virus - spread via resp droplets - clothing and bed linens can spread infection
• incubation period is 12-14 days
• afer 1 to 2 days fo fever and myalgia rash appears - goes papules to vesicles  to pustules to scabs - all the same lesions at the same time; after deep pitted scars remain
• mouth -> face -> arms -> trunk -> legs
• mortality rate is 30%
• Tx - vaccine w/i 4 days of exposure - lessens or prevents weakness; cidofovir active in vitro

Molluscum Contagiosum

• unclassified poxvirus - spread by direct contact
• discrete, papular, waxy skin lesions w/ central umbilication
• dx - clinical and identification of intracytoplasmic inclusions
• tx - mechanical removal, cryogenically, silver nitrate
• complications - recurrent or disseminated lesions in AIDs

Streptococcus pneumonia

Pediatric Vaccine

• polysaccharide capsule - most important virulence factor (protects against phagocytosis by granulocytes and macrophages)
• elicits a T cell indepenent (not boostable) immune response
• approx 90 serotypes identified based on its antigenic composition
• incidence of invasive pneumococcal disease in children highest at 6-17 months of age

Poliomyelitis Vaccine

OPV vs eLPV

• OPV - preents paralysis; givens humoral immunity and intestinal immunity; duration of immunity is long, can cause contact immunization and virus excretion; paralysis sequalae rare
• eIPV - prevents paralysis and gives humoral immunity but only minimal intestinal immunity; long duration of action; no contact immunizaiton, virus excetion or paralysis sequelae

Sulfonamides

• sulfamethoxazole (often combo w/ trimethoprim), sulfisoxazole, sufladiazine, sulfadoxine, suflasalazine
• selectively inh blocks dihyroopteroate synthase which converts pteridine and PABA to dihydrofolic acid
• a PABA anologue that competitively inh incorporation of PABA
• SMX acetylated in liver, active drug and metabolite excreted in kidney by glomerular filtration
• resistance mech - mutations resulting in overproduction of PABA, low affinit of dihydropteroate syn enzyme for sulfonamide, impaired permeability - also efflux mech

Folate Reductase Inhibitors

(pyrimidines)

• trimethoprim - selectively blcoks folate reduction in some bacteria
• pyrimehtamine - inh folate reduction in some protozoa (toxo and malaria)
• mech of resistance - reduced cell permeability ot drug, overproduciton of dihydrofolate reductase target enzyme, production of altered dihydrofolate reductase w/ dec affinity for drug
• avoid in pts w/ folate deficiency or G6PD deficiency
• dont take two together (ex methotrexate and trimethoprim)
• co-adm of folinic acid can prevent/reduce antifolate activity in humans w/o affecting antimicrobial activity

TMP-SMX

(trimethoprim-sulfamethoxazole)

• broad spec - aerobic gram neg (not psuedo), jiroveci, some aerobic gram pos, some protozoa
• bactericidal - max synergistic inh in susceptible when peak serum conc for TMP:SMX of 1:20
• CSF penetration good (30-40%) and excreted in urine (about 50% in first 24 hrs)
• uses - acute uncomplicated cystits/UTI, prostatitis (penetrates welli into prostate), travelers diarrhea and shigellosis, nocardiosis, listeria monocytogenes (if PCN allergy), pneumocystis jiroveci pneumonia (DOC - primary Tx and prophylaxis)
• adv reaction rate higher in HIV infected pts
• most common adv - GI (nausea, vomiting, diarrhea, hepatotoxic), and skin and mucosal surfaces (rash, erythema ultiform, SIS, TEN)
• less comon adv - hematologic (all the penias), and renal (inc Cr, crysalluria, acute interstitial nephritis, hyperklameia (TMP induced, collecting tubule)
• avoid TMP in 1st trimester and SMX close to delivery (kernicterus); avoid if breastfeeding

Dapsone/Sulfones

• diaminodiphenylsulfone (dapsone) most widely used
• closely related to sulfonamides - also act by inh folate synthesis
• used for tx of leprosy (m leprae) in combo w/ other drugs; also can be used for prophylaxis and Tx of pneumocystits pneumonia
• absorbed in GI tract and excreted into bile and reabsorbed in the intestine; urinary excretion is variable
• adv effects - hemolysis if G6PD deficiency (pre screen), methemoglobinemia, GI upset, fever, rash/itching

Nitrofurantoin

• antibiotic used for UTI - cystitis in particular (not indicated for pyelonephritis
• MOA- reduced form is highly reactive and damages DNA
• excelent activity to ecoli and s saprophyticus
• concentrates well in urine; in renal impairment, conc in urine may be subtherapeutic
• no activity against proteus, pseudomonas, providential, acinetobacter, m organella serratia
• adv effects - anorexia, nausea, vomiting, hypersens pneumonitis and pulmonary fibrosis
• neuropathy and hemolytic anemia in G6PD deficiency
• must be taken w/ food

Fosfomycin

• MOA - analog of PEP, blocking enoyl-pyruvate synthetase; and peptidoglycan synthetase
• requires glycerophosphate transporter for entry into cells (target for resistance)
• used in Tx of uncomplicated UTIs w/ ecoli and enterococcus faecalis
• excreted unchanged in urine; excellent tissue penetration

Methenamine

• urinary antiseptic, works by releasing formaldehyde at pH <5.5; may be given w/ acidifying agents
• nonspecific antibacterial properties
• proteus, which alkalizes urine is resistance 
• limited use because of side effects
• adv effects - headache, dizziness, GI upset, distinct redidsh urine which is harmless
• avoid in G6PD def because of hemolytic anemia
• pgiment change in skin or eyes w/ renal impairment

Fidaxomicin

• nonsystemic, narrow spectrum abctericidal macrolcyclic compound
• indicated for Clostridium Dificile
• acts locally in the GI tract; mainly excreted in feces
• MOA - inh bacterial RNA polymerase, preventing RNA syn
• in vitro synergistic effects w/ rifampin/refaximin against C dif noted
• adv effects - nausea/vomitting, abdominal distension, tenderness, dspepsis, flatulence, interstinal obstruction, drug eruptions, pruritis, rash
• inc alkaline phosphate, inc hepatic enzymes, dec platelet count

Polymyxins

• clistimethate sodium (colistin), polymixin E produced by bacillus polymyxa
• bactericidal; resistance is rare
• excellent gram neg activity; now used for MDROs - pseudomonas, acinetobacter, naumannii, even NDM-1 enterobacteriaceae
• MOA - polycationic and lipophilic, detergent action on the bacterial outer membrane; snergy w/ rifampin
• adv effects - nephrotoxicity and neurotoxicity

Enterohemorrhagic E. coli

(EHEC)

• typically bloody diarrhea w/ little fever - mediated by shiga toxin and usually serotype 0157H7
• incubation period about 3-4 days - initially non-bloody diarrhe w/ abdominal pain; vomiting (50%) and bloody diarrhea in 30-65%
• usually resolves in 4-10 days
• Dx - clinical suspicion or stool culture (special)
• Hemolytic Uremic Syndrome (5-10% of child pts, esp <5) - fever, leukocytosis, acute renal failure, thormbocytopenia nad microangiopathic hemolytic anemia; begins at same time diarrhea resolves

Shiga Toxin

• virtually identical to toxin produced by shigella dysenteriae
• encoded by bacteriophage (stx gene)
• toxin produciton may be enhanced by exposure to antibiotic; it is disseminated form the GI tract thru out the blood stream
• endothelial cell intoxicaiton may lead to microvasc thrombosis
• kidneys most vulnerable organ; brain, eyes, colon may also be affected (thrombotic thrombocytopenic purpura)

Enterotoxigenic E. coli

(ETEC)

• a major cause of travelers diarrhea - secretory watery diarrhea
• Heat labile enterotoxin - closely related to cholera toxin - activates adenylyl cyclase (cAMP) and then CF transmembrane conductance regulator w/ subsequent active secretion of chloride into the small bowel lumen causing copious fluid secretion 
• Heat stable enterotoxin - binds to guanylin receptor of small bowel enterocytes which stimulates production of cGMP and then activation of CF transmembrane conductace regulator and chloride secretion

Bacterial Secretion Systems

• Type I - toxin secreted directly into extracellular space
• Type II - toxin synthesized as a precursor protein and subsequently cleaved
• Type III - a complex system in which exotoxin is injected directly into host cell cytoplasm (shigella, salmonella, campylobacter) - evolved from flagella apparatus, encoded by blocks of genes termed pathogenicity islands, molecular structure that spans the bacterial cell wall and resembles a syringe)

Rotavirus

• noneveloped RNA virus - peak incidence in winter
• most important cause of severe, dehydrating gastroenteritis in children <5 in all social groups in all regions of the world
• virtually all infants infected by 3yrs, severe gastroenteritis occurs btw age 6mo and 2 yrs
• dairrhea lasts 1 to 4 days w/ anorexia, crampy abdominal pain and low grade fever
• typically begins w/ vomiting and fever lasting 2-3 days followed by profuse watery diarrhea
• stool negative for blood, pus and peripheral WBC is typically normal
• Dx by positive stoola ntigen assay (from onset of sx up to 4 to 10 days)
• Tx- rehydration and supportive care
• vaccine -1st one withdrawn (caused intussusception); rotaTeq and Rotarix are live attenuated vaccines

Noroviruses

• small, non-enveloped RNA virus
• transmitted by fecal contamination of food & water
• causes epidemic watery diarrhea w/ nausea and vomiting; accounts for about 50% of all gastroenteritis
• usually self-limiting (1-3days), but can be debilitating and fatal in immunocompromised
• immunocompetent hosts often shed virus for 20 to 40 days beyond resolution of sx (reinfections are possible)
• characterized by pronounced eema of the small bowel
• stools are never bloody; fever in up to 30%
• Dx - RT-PCR highly sens and specific
• Tx - hydration and supportive care

Mycobacterium Tuberculosis

• small rod-shaped bacterium; obligate aerobe; acid fast; facultative intracellular parasite
• 2nd most common infectious cause of death in world
• pathogenesis - acquired by inhalation of droplet - phagocytized by macrophages in alveolus - proliferates intracellularly and spreads systemically - attracts dendritic cells and T cells as effector cells - Ag specific T cells release cytokines to attract and activate more macrophages
• latent phase follows primary infection where viable organisms slowly replicate - can get reactivation
• delayed type hypersensitivity results in positive tuberculin skin test rx by 4-6 weeks
• pulmonary parenchymal dz (85%) and extrapulmonary (15%) or both - chornic cough, hemoptysis, pleuritic chest pain, rhales, consolidation, abnormal chest film in pulmonary
• Interferon Gamma Release Assays (IGRA) are gold standard test - blood (lymphocytes) from sensitized pt will release IFN gamma - measured by ELISA - no cross reacivity w/ BCG vaccine but does not distinguish btw latent or active dz
• culture also gold standard but may take 8 weeks
• CXR can show cavitary infiltrate, mass lesion, diffuse interstitial infiltrate, and miliary pattern 

Tuberculous Meningitis

• reactivation of latent foci in CNS - variable clinical course, progression
• fever, headache, vomiting, confusion, meningismus
• basilar meningeal exudate, cranial nerve involvement, vascular thrombosis, strokes, hydrocephalus
• Dx requires spinal tap - lymphocytic pelocytosis, low CSF glucose, elevated CSF protien, cultures usually negative
• prognosis related to age, duration, severity of Sx
• TX - INH and PZA (good CSF levels), rifampin, and ethambutol for 1 yr
• corticosteroids if altered mental status or focal neurologic sign

Leprosy Hansen's Disease 

• M. leprae cannot be cultured in vitro - obligate intracellular
• infection involves skin and peripheral nerves - nerve may be damaged by direct invasion of schwann cell or by immune response to infectino
• infection manifested by skin lesions and loss of cutaneous sensation +/- motor function
• 205 new cases - contact w/ armadillos, lepromatous state, genetics, age
• tuberculoid form - abundant lymphocytes and well formed granulomas; few microorganisms in lesion and is asymp and well demarcated
• Lepromatous form - few lymphocytes, few or absent granulomas, large number of bacteria
• invade schwann cells, cause demyelination of peripheral nerves; immune response may also damage nerve
• reversal reaction refers to a systemic inflammation reaction - worsening of nerve damage when treated

Isoniazid (INH)

• penetrates into macrophages - active against extracellular and intracellular organisms
• bacericidal against active growing MTB; bacteriostatic against slowly dividing MTB
• MOA - inh syn of mycolic acid ocmponent of mycobacterial cell wall
• metabolized by liver enzyme N-acetyltransferase; slow acetylators have higer serum levels
• adv - hepatic toxicity, agranulocytosis and aplastic anemia, peripheral neuropathy (esp in slow acetylators), memory loss, seizures, pschosis, optic atrophy, anemia
• promotes excretion of vitB6 - concomitant use VB6 is recommended
• drug interactions - primarily due to inh of CP - phenytoin toxicity is potentiated 
• INH hepatoxicity most often develops in first 3 mo; must dif from asymptomatic minor elevations in transaminases (up to 3x normal) which are common

Rifampin

• active against gram pos and gram neg cocci, chlamydia, enteric bacteria and mycobacteria
• MOA - binds to bacterial RNA polymerase, inh proteinse synthesis
• well absorbed orally - excreted in bile and undergoes enterohepatic circulation
• resistance arises from mutations in rpoB gene, reducing binding to polymerase
• uses - combo w/ other TB drugs; alternative to INH in latent TB infection; HiB prophylaxis
• adv - orange discoloration of body fluids, rash, throbocytopenia, nephritis, cholestatic jaundice, hepaittis, proteinuria, tubular necrosis
• Strong induced of CYPs

Pyrazinamide (PZA)

Ethambutol

• bacteriostatic, usually well tolerated
• MOA - inh mycobacterial arabinosyl transferases; inh cell wall syn
• partially metabolized and mostly excreted in urine
• adv - optic neurtiis (impaired red-green, usually slowly reversible), peripheral neuropathy, GI upset, hyperuricemia, hypersens (rash, arthralgia, fever)
• commonly included as fourth drug along w/ INH, rifampin, and PZA in pts w/ active MTB at risk for drug resistance
• can be part of 2 drug reginmen in combo w. INH or rifampin for active MTB but must be extended for 18months
• safe during pregnancy; available orally

US Influenza Vaccine

• prepared from embryonatd chicken eggs inoculated w/ specific strains of virus
• TIV - killed, injectable - all comers 6 mo and older
• TIV Intradermal - approv for 18-64yr 
• LAIV - live attenuated, cold adapted nasal (cannot replicate at body temp) - nasal spray: very minimal viral shedding; indicated for healthy ppl 2-50yrs
• High dose TIV for 65+ population - same production process as TIV; higher Ag dose - higher efficacy by 24% for A, B strains

New Influenza Vaccines

• QIV - Quadrivalent inacive QIV - killed, injectable, all comers 6mo or older; 2 A strains and 2 B strains
• Quadrivalent LAIV - live attenuated, cold adapted nasal
• Flucelvax - in place of chikcen eggs, use animal cellsl aprov for > 18yr
• Flublok - recombinant vaccine (RIV) - egg free hemagglutinin influenza vaccine produced by recombinant DNA; proudces virus like particles, hemaglutinin; ages 18-49; only 16wk shelf life
• flublok vaccine of choice for true egg allergy

Meningococcal Vaccine

• inactive vaccine
• polysacharide quadrivalent - serogroups A, C, , W-135
• Quadrivalent conjugate vaccine - same serogroups; approv for ages 2-54 - better longevity and immunity
• indications - college freshmen (CDC not yet saying this)
• NOW recomended by CDC w/ booster dose of tetravalent meningococcal vaccine should be routinely adm to adolescents 5 years after first dose is given at ages 11 through 13 yrs
• travelers at high risk areas also indicated

Classic Fever of Unknown Origin

(FUO)

• Criteria: fever > 38.3C on several occasions noted over more than 3 wks duration; fever unexplained despite approp investigatino after 3 clinic visits or 3 days in hospital
• most are bactial infections; most common problems w/ unusal presentation
• younger person w/ FUO think infection; older consider malignancy (esp pre-leukemia phase)
• non-infectious inflam dz causion FUO - adult stills dz, rheumatic fever, seronegative RA in elderly, periarteritis nodosa
• granulomatous dz causing FUO - giant cell arteritis, polymyalgia rheumatic, IBD, sarcoid
• suspect GCA in elderly w/ fever and headaches (>50)

Other Types of Fever of Unknown Origin

• Nosocomial Fever-often postop or ICU related - uncertain after 3 days despite appropriate investigations, including at least 2 days of incubation of microbiologic microbiologic cultures
• Neutropenic or Immune-deficient fevers - neutrophil count <500 in peripheral or expected to fall below that # in 1-2 days; ucnertain after 3 days despite appropriate investigations, including at least 2 days of incubation of microbiologic cultures
• HIV related fevers - fever on several occasions of more than 3 wks duration as an outpatient or more than 3 days duration in hospital; uncertain after 3 days despitie appropriate investigation, including 2 days of incubation of microbiologic cultures

Surviving Sepsis Campaign Bundles

• to be completed w/i 3 hours - measure serum lactate and obtain blood cultures prior to antibiotics (draw 2 cultures from 2 different sites); adm broad spectrum antibiotics; adm crystalloid for hypotension or a serum lactate 4 or greater
• To be completed w/i 6 hours - apply vasopressors if hypotension does not repsond to fluids to maintain MAP >65mmHg; if persistent hypotension measure CVP and Central Venous oxygen saturation; remeasure serum lactate if initial value elevated

Parameters to follow in Sepsis Tx

• bloood pressure - systolic >90 mmHg
• Mean arterial blood Pressure - target 65mmHg or higher
• CVP - normal 8-12 mmHg; if on ventilator 12-15 mmHg
• serum lactate - target <4
• SvO2 - venous oxygen saturation - nl 60-80%

Hepatitis A

• accounts for 20-40% of viral hepatitis in the US
• picronaviridae; spread by fecal-oral route
• prodrome phase 1-14 days - then abrupt onset of anorexia, malaise, nausea, vomiting, fever, HA, abdominal pain
• jaundice 70%; icterus phase preceded by dark urine
• hepatosplenomegaly; cervical lymphadenopathy
• Complications - cholesatis, arthritis, myocarditis, optic neuritis, TTP/aplastic anemia.red cell aplasia, IgA GN
• Dx - HAV igM (positive for about 3-6 months); AST/ALT (8x), bilirubin (5-15x), AP minimally elevated
• prevention is key - vaccination (active vs passive) - routine vaccination for all children age 12-23 and adults

Hepatitis C

• cirrhosis/HCC - #1 reason for liver transplant in US
• RNA virus from family falvivirdae; replication in cytoplasm; does not integrate into host genome
• exposure either leads to resolved (13%) or chronic infection (87%)
• HIV and alcohol help led from chronic infection to HCC
• Dx - serology HCV ab; HCV RNA (molecular test, viral load), genotype (affects tx, duration, response rate)
• Tx - (PEG-IFN), RBV, DAA - sofosbuvir, simeprevir, direct acting antivirals) 

UTI Pathogen Virulence Factors

• Ecoli serotypes (OKH) - inc adhernce to vaginal epithelium, resistance to bactericidal substances, K capsular antigen protects bacteria from phagocytosis
• Type 1 Fimbriae (pili) filamentous organelle; mannose-sens; chromosomal - type 1-> phagocytosis -> survive -> relapse; bind to tamm-horsfall protien, common in cystitis-causing strains
• P fimbriae - mannose resistant; bind to globoseries rec; induce infalmmatory response but neutrophils lack P fimbriae rec; assoc w/ pelonephritis and bacteremia
• Adhesins such as S, Dr fimbriae, others - aerobactin, siderophore

Prostatitis Therapy

• acute prostatits -> antibiotics for atleast 4 wks to prevent development of chronic infectious prostatitis
• chronic - very difficult to cure
• surgical managemnt such as partial transurethral partial prostatecotmy may help
• antibiotics of choice are TMP/SMX and fluorquinolones
• antibiotic treatment not recommended in type III prostatitis - chornic pelvic pain syndrome

Syphillis

• treponema pallidum - spirochete order
• visualized on darkfield microscopy - corkscrew
• primary syphilis - occurs 1-3 wks after initial exposure; painless lesion (chancre); resolves in 1-3wks
• secondary syphilis - 25% of untreated pts wks to months later - rash (palmar), fever, headache, myalgia, malaise, lymphadenopathy, anorexia)
• Tertiary syphilis - 30% of pts who have latent infection - neurosyhpilis, cardiovasc syphilis, gummatous syphilis
• sdetected by RPR and VDRL test - take 4-6 wks to become positive and are highly pos in secondary syphilis
• Tx - penicillin is DOC for almost all forms of syphilis; can also doxycycline or ceftriaxone
• penicillin is the only treatment option for pregnant pts (if allergic have to desensitize)

Gonorrhea

• n gonorrhoeae - gram neg diplococci
• attachment to the surface of columnar epithelial cells is via pili, filamentous outer membrane appendages
• Men Sx - dysuria followed by purulent copious urethral discharge; 4 days after infection
• Women Sx - vaginal discharge, dysuria, pain in anorectal area, endocervical infection (cervicitis -> PID)
• dx - culture on thayer-martin media gold standard
• gram stain shows neutrophils w/ intracellular gram negative diplococci
• complications - PID, fitz-hugh curtis syndrome (perihepatitis), gonococcal conjunctivitis, gonococcal arthritis

Chlamydia Trachomatis

• most common reported STD in US
• obligate intracellular bacteria; primarily infects columnar and transitional epithelial cells
• Dx - urehtral gram stain >5pmns per field, urinalysis in men, chlamydial endocervical infection can have >30WBC per field
• Complications - PID, acute epididymitis, reiter syndrome (seronegative), proctitis
• nonpregnant DOC -azithromycin or doxycycline
• pregnant DOC - azithromycin or amoxacillin

Peritonsillar Abscess

• quinsy
• Hx - fever,malaise, sore throat, dysphagia, trismus, ipsilateral ear pain
• febrile, drooling, muffled voice (aka hot potato voice), tender cervical adenopathy and torticolli, swelling of anterior tonsillar pillar and soft palate, uvular deviation
• micro - typically group A strep plus anaerobes
• Tx - drainage (can be needle or surgical-ENT consult); antibiotics (ampicillin/sulbactam or clindamycin

Parotitis

• ductal obstruction w/ secondary infection; can be related to sialothiasis
• presentation - firm, erythematous swelling of pre- and postauricular areas extending to mandile - High fever, chills, toxic appearance
• complications - massive swelling of neck (resp obstruction), septicemia, osteomyelitis of facial bones
• micro - strep plus anaerobes (bacteroides, peptostreptococcus), s aureus (worry about MRSA)
• tx - empirical vancomycin plus metronidazole or clindamycin

Diffuse Otitis Externa

(Swimmer's Ear)

• inflammation of all of the exernal canal
• pruritis and pain
• pseudomonas and pain
• pseudomonas and other gram negatives are typical
• management - remove debris; 50% Burrow's Solution can be used to reduce inflammation
• also 10 days of topical antibiotics which are anti-pseudomonas - fluoroquinolones; neomycin +/- polymyxin

Malignant Otitis Externa

• extension of infection from epithelium to adjacent soft tissue, blood vessels and bone
• pseudomonas very common
• almost always some underlying immunodeficiency - diabetes, HIV, chemo
• presentation - severe, unremitting otalgia, sensation of fullness, otorrhea, conductive hearing loss, headache, temporomandibular joint pain and trismus
• swollen, tender external auditory canal, purulent otorrhea, granulation tissue or exposed bone
• dx - culture of tissue, imaging helpful (CT or MRI)
• Tx - surgical eval, 6-8wks therapy - antipseudomonal beta lactam, aminoglycosides, fluoroquinolones

Conjunctivitis

• infection of the mucus membrane covering the eye
• itching of the eye, lack of eye pain, lack of visual acuity change, conjunctival hyperemia, discharge, pre-auricular adenpathy
• Viral conjunctivitis - acute onset, typically bilateral, pre auricular adenopathy common, red eye; adenovirus or hepes virus (dendritic ulcer)
• Bacterial - more often unilateral, heavy purulent, matting of eye lides, more glassy, s aureus, H influenza, s pneumonia, tx - topical fluoroquinolone
• chlamydial - subacute onset of red eye w/ mucopurulent; concomitant GU dz may be present (more common in men) - tx tetracycline

Keratitis

• infection of cornea rather than overlying mucus membrane
• eye pain, conjunctival injection, photophobia, discharge usually absent, defect can usually be seen w/ fluorescein
• most common is herpetic - systemic antiviral - acyclovir
• if bacterial or fungal suspected, admit the patient - ceftazidime and aminoglycoside 

Histoplasmosis

• endemic areas - ohio and mississippi river valleys
• mold form w/ tuberculate macroconidia
• found in soil w/ bird and bat dropping - inhalation of microconidia (infectious form)
• most cases asmptomatic - phagocytized by macrophagesa nd convert to yeast form intracellularly
• causes acute pulmonary histo and acute life threatening pneumonia (immunocompromised)
• chronic pulmonary histo -apical cavities, mediastinal fibrosis; reactivation in older adults
• Tx - lipid formulation of amphotericin B, itraconazole

Blastomycosis

• location - mississippi river basin; decaying organic matter (inhalation of conidia)
• mold form - oval clonidia; yeast form - broad based budding and blastoconidia
• thick yeast cell wall=double contoured walls (more resistant to phagocytosis/killing); too large for ingestion by macrophages
• BAD-1 - adhesion and immune modulator
• pulmonary - asymptomatic; can cause acute pneumonia which can progress to ARDS or chronic pneumonia
• cutaneous - papular, pustular or ulcerative nodular; painless and localized to exposed areas
• Tx - mild itraconazole; life threatening - amphotericin

Aspergillosis

• classified as a mold, NOT a yeast
• conidia reach distal alveolar space and attach to damaged depithelium
• hyphae then spread through lung parenchyma and blood vessels causing hemorrhage and necrosis
• Allergic bronchopulmonary apsergillosis (ABPA) - asthma, pulmonary infiltrates, eosinophilia, elevated serum IgE, hypersensitivity reaction to Ags
• Aspergillomas (fungus balls)
• Chronic cavitary pulmonary aspergillosis (CCPA) - chronic low level invasion and fungus balls;
• Invasive sinopulmonary aspergillosis/disseminated aspergillosis - direct failure of immune system
• Tx - voriconazole or amphotericin B

Mucormycosis

• mold - Rhizopus (most common)
• angio-invasive -> tissue infarction and necrosis (hallmark); mortality rates 70-100%
• in soil and decaying vegetation - can be present in hospitals; usually very immunocompromised pts
• Rhizopus produces an enzyme ketone reductase, which alls growth in high glucose, acidic environments (diabetic ketoacidosis)
• Rhino-orbital-cerebral, pulmonary, cutaneous, GI, disseminated
• Dx - definitive dx of zygomycosis almost always require histopathologic evidence of fungal invasion of tissue; ribbon-like aseptate, nonpigmented broad hyphae w/ irregular branching in tissue
• amphotericin B, posaconazole

Coccidioidomycosis

• endemic - desert southwestern US/mexico
• mold form - alternating arthroconidia; yeast form - spherules w/ endospores
• found in soil; enhanced by rodent and bat droppings
• drought/wind favor aerosolization of arthroconidia (infectious form)
• arthroconidia become spherules in lung; spherules produce endospores by progressive cleavage
• primary coccidioidomycosis (60% asymp; flu like), secondary coccidioidomycosis (pulmonary noduels and cavities), primary dissemination and extrapulmonary
• Tx - fluconazole, itraconazole, ketoconazole, amphotericin B

Amphotericin B

• polyene macrolide
• binds to ergosterol in fungal cell membrane - alters permeability of cell by fomring pores; leakage of intracellular contents which leads to cell death
• poor CNS penetration
• liposomal formulation less toxic (binds to human membranes less)
• adv - infusion related eactions (fever, chills, etc), nephrotoxicity (renal tubular acidosis and sever K and Mg wasting), abnormal liver enzymes, seizures or chemical arachnoiditsi (intrathecal only)
• use initially to rapidly reduce fungal burden then switch to azole

Flucytosine 

• pyrimidine analog
• MOA - 5-FU - interferes w/ DNA syn and transcription in fungal
• use - commonly used in combo w/ amphotericin B in cryptococcal meningitis to improve CNS penetration
• resistance - altered metabolism; never use as monotherapy (fast resistance)
• penetrates well into all body fluids including CSF (synergistic w/ amphotericin B
• adv - bone marrow toxicity, transminitis, toxic enterocolitis, blood levels accumulate in renal failure

Azoles

• MOA - reduction in ergosterol syn by inh of fungal CYP enzymes
• ketoconazole - imidazole - rarely used do to less selective for fungal CYPs
• Fluconazole - renal excretion - crypto, some candida, coccidioides
• Itraconazole - absorption of capsule requires an acidic environment (take w/ coke) - histo, blasto, coccidioides, aspergillus
• Voriconazole - hepatic metabolism - inh CYP3A4 - adv rash, photosens dermatitis, abnormal liver enzymes, visual disturbance
• posaconazole - broadest spectrum of all azoles

Echinocandins

• newest class of antifungals - IV only - caspofungin, anidulafungin, micafungin
• MOA - inh syn of B(1-3) glucan in fungal cell membrane leading to disruption of fungal cell membrane and fungal cell death
• spectrum - candida, aspergillus
• does not cover cryptoi, muco, histo, blasto, coccidioides
• renal excretion
• adv - histamine mediated synd w/ rapid infusion (rash, utricaria, pruritis hypotension - primarily anidulafungin), and abnoraml liver enzyes

Griseofulvin

• MOA - unclear, can deposit in newly forming skin and bind to keratin - fungistatic
• only oral - abs improved w/ fatty food
• adv effects - allergic syndrome (serum sickness), hepatitis, drug interactions
• clinical uses - dermatophytosis (tinea capitis), largely replaced by itraconazole and terbinafine

Terbinafine

• synthetic
• MOA - interferes w/ ergosterol biosyn -> inh fungal enzyme squalene epoxidase - acum of squalene which is toxic for fungal cell
• Keratophlic, fungicidal, requires prolonged use of 12+ weeks for nails
• adv - GI upset, headache,
• use - dermatophytes and onychomycosis

Nystatin

• polyene macrolide
• activity - most candida, primarily for thrush, vaginal candidiasis and intertrigo
• pharm - very poorly absorbed and very little toxicity
• topical; too toxic in parenteral form

Acyclovir

• acts selectively on cells infected w/ herpes virus - treats active dz; does NOT eradicate latent infection
• MOA - acyclovir converted to acyclovir monophosphate by herpes virus specific thymidine kinase -> host kinase than converts to a triphosphate form which leads to incorporation into DNA and terminates syn
• MOA -  inh of herpes virus DNA polymerase
• renally excreted; requires dosage adjustment
• adv - minimal renal dysfunction from acyclovir crystals (minimized by >1hr infusion)
• resistance - mutation of thymidine kinase or DNA polymerae (HSV or VZV) - foscarnet usually effective
• indicaitons - genital HS, mucocutaneous;compromised, visceral HSV (encephalitis), neonatal HSV, varicella, zoster
• valacyclovir - no CI in HIV w/ usual dose, may cause thrombotic microangiopathy
• Famciclovir - intracellular conc higher than acyclovir

Foscarnet

• an inorganic pyrophosphate analog; does not have to be phosphorylated
• IV only
• active against herpes (I, II, varicella, CMV) - including those resistant to acyclovir and ganciclovir
• direct inh of DNA polymerase and RT
• adv effects - nephrotoxicity, electrolyte abnormalities, CNS toxicity
• Foscarnet should only be given during pregnancy when benefit outweighs risk

Amantadine and Rimantadine

• MOA - interferes w/ influenza A by blocking M2 protein; no activity against Type B (intrinsically resistant - H3N2)
• administer w/i 48 hours to reduce severity and shorten duration of illness
• amantadine for children and adults; rimantadine only adults
• safety - CNS reactions (assoc w/ high plasma lvls)
• adjust dosage for amantadine in modest renal dysfunction and rimantadine for severe liver Dz
• seasonal H1N1 influenza A susceptible but most A strains resistance
• resistance caused by point mutations in viral M2 protein gene

Selective Neuraminidase Inhibitors

• w/o neuraminidase, the hamagluglutinin of the virus binds to sialic acid, forming clumps and preventing virus release
• inh this enzyme in both Influenza A and B, effectively stoping viral replication
• selectivity denotes lack of activity against human neuroaminidase
• reduce length of illness if taken w/i 48hrs
• Oseltamivir - Tx in adults and children >1yr; prophylaxis in >13yr- seasonal H1N1 resistant - adv effects GI(10-15%)
• Zanamivir - tx in adults and children >7yr; seasonal H1N1 susceptible - inhaled 2 puffs - adv of bronchospasm (dont use in airway dz unless fast acting)
• can be used as chemoprophylaxis

Acute HIV Primary Infection

Diagnostic laboratory Testing 

• standard ELISA Ab first become positive 22-27 days after acute infection
• P-24 Antigen Test - licensed for early detection of HIV infection - sens 88%, and spec 100%
• Fourth generation ELISA - detects Abs AND/OR p24Ag
• cases of acute HIV infection has been acurately dx on basis of high plasma RNA levels

Trofile

• testing for HIV tropism - if the virus population uses CCR5 or CXCR4 as its chemokine co-rec to enter the CD4 cell
• may be dual/mixed population
• should be done before using a chemokine co-rec antagonist (maraviroc)
• newer test is very sensitive

Nucleoside Analogs 

(NRTIs)

• abacavir, didanosine, emtricitabine, lamivudine (3TC), stavudine, tenofovir, zidovudine (AZT, ZDV)
• zidovudine - anemia, headache, myopathy
• didanosine (ddl) - peripheral neuropathy, pancreatitis
• Zerit (d4T) - neuropathy, lactic acidosis, lipoatrophy
• Lamivudine (3TC, epivir) - very rarely liver toxicity
• Tenofovir - renal - dec in GFR, fanconi like syndorme
• Abacavir hypersensitivity - more common in whites and higher CD4s - rash, fever, fatal especially in rechallanged pts, assoc w/ HLA-B5701
• pts are tested for HLA-B5701 and if positive would not use abacavir 

Protease Inhibitors

• indinavir, nelfinavir, ritonavir, saquinavir, ataanavir, tipranavir
• PI boosting - ritonavir greatly inc levels of other PIs through CYP system, can give less amounts of PI
• neflinavir not affected by ritonivir boosting
• New booster - cobisistat (tybost) used w/ elvitegravir, atazanavir, darunavir
• inc use of PI causes drastic dec in HIV mortality
• metabolic SE - lipohypertrophy, hyperlipidemia, insulin resistance; buffalo hump
• kidney stones - indinavir or atazanavir
• hepatotoxicities, GI side effects, many drug interactions

Non-Nucleoside Reverse Transcriptase Inhibitors

(NNRTIs)

• nevirapine, efavirenz, rilpivirine, etravirine
• all can cause rash (15%)
• sustiva - CNS side effects and hyperlipidemia
• hepatotoxicity - esp viraune - inc risk if higher CD4 counts

Other HIV Antiretrovirals

• Integrase Inh -raltegravir, dolutegravir, elvitegravir
• prevent viral strand transfer to integrate viral DNA into host DNA; very potent, reduces viral load very quickly
• Viral Entry Inh (Fuzeon) - enfurvitide
• binds to gp41 subunit, preventing conformational change for fusion of viral/cellular membranes
• Chemokine Co-rec Antagonist - maraviroc
• blocks binding to CCR5 rec (must be CCR5-tropic)

HIV Treatment

Mitochondrial Dysfunction

• medicatinos, esp nukes cause inh of DNA polymerase gamma
• this depletes mitochondrial DNA
• major culprits are the "d" drugs, d4t(zerit), ddl(didanosine)
• thought to cause lipoatrophy, neuropathy, lactic acidosis, possibly pancreatitis

Antiretroviral 

Drug Interactions

• PPIs and H2 blockers
• Statins - safest if pravastatin 
• Seizure Meds - use keppra
• ED meds - must use less of a dose w/ PIs
• Some inhaled steroids, esp flonase, watch for cushings syndrome
• Local steroid injections, joint injections
• St johns wort, polyvalent cations, calcium channel blockers, anti-arrythmics, coumadin, methadone

Vaccines in HIV pts

• flu shot, pneumovax, prevnr, hepB, hepA, Tdap/Td
• HPV vaccine if age 9-26
• MMR if needed for school or job if CD4 >200
• meningococcal vaccine if indicated
• Varicella if indicated and CD4 >200
• Zoster is CI at this time

Pulmonary Inflitrates in 

Cellular immunodeficiency

• Diffuse Infiltrates - pneumocystitis jiroveci (PCP) - indolent progression SOB, weight loss and fevers w/ AIDS, but more rapid progression w/ immunosuppressive drugs; high LDH, severe hypoxia, absence of hilar adenopathy
• Focal or Patchy Infiltrates - TB - typically focal but can present w/ atypical pattern in T cell deficiency, night sweats, weight loss, blood, thick sputum
• Focal or Patchy Infiltrates - Fungal - hilar adenopathy, often nodular infiltrates; histo often disseminated dz and hepatosplenomegaly

Initial Immunodeficiency 

Screening Tests

• Antibody Mediated Immunity - quantitative Ig lvls, Ab response to vaccines, isohemagglutinin titers (IgM)
• Cell mediated Immunity - CBCB, total lymphocyte count, platelet count, CD markers, delayed hpersens skin tests
• Neutrophil function - CBC w/ differential (ANC), chemotaxis, oxidative burst (nitroblue tetrazolium test (NBT)
• Complement System - total hemolytic omplement (CH50) or quantitation of serum components (C2, C3, etc)

Travel Assoc Infections

Incubation Period

• short < 10 days - arboviral (dengue), enteric bacterial, hemorrhagic fevers, plague
• Medium - 10-21 days - malaria, typhoid, rickettsial, brucellosis, leptospirosis, african trypanosomiasis
• long >21 - malaria, viral hep, TB, acute HIV, amoebic liver abscess, katayama fever, filariasis

Malaria

• Falciparum - fever w/i 48-72 hrs; 90% fever w/i a month; blood smear - gametocytes - cylindrical looking
• P vivax - 50% sx w/i month; fever cyclical, splenomegaly, resistant to chemo prophylaxis; blood smear - enlarged infected red cell which bunch of black dots in it
• Dx - thick/thin smear at least twice (quantify buffy coat-acridine oragne); low platelets, high LDH, serology (para sigth), DNA fingerprint
• admit all non-immune patients

Dengue 

• flavivirus transmitted by aedes mosquitos; urban areas
• incubation period 4-7 days 
• fever, headache and myalgia (backache and joint pain) - break bone fever
• 50% also have adenopathy and skin rash
• Raised ALT, leucopenia and thrombocytopenia
• Dengue shock syndrome, dengue hemorrhagic syndrome (DSS/DHS) - 98% had dengue infection
• dx - 4fold inc in Ab titer acute vs convalescent titer cross reactivity w/ west nile virus

African Trypanosomiasis

• Sleeping sickness
• tsetse fly bites, headache, and chancre in sub saharan africa
• onset of Sx a few days to few weeks after infected bite
• stage 1 pt presents w/ fever and typical chancre
• Stage 2 patients may develop CNS involvement
• untreated dz leads to death in weeks/months
• little purple worm like things on blood smear
• chagas dz is south american trypanosomiasis - chronic form can affect heart, esophagus, colon and PNS

Equine Encephalitis

• togaviridae
• Eastern - freshwater swamps/east coast - mosquitos/birds - rapid onset of encephalitis - death in 1/3 of cases - young and old most affected
• Western - alphavirus - mosquito and vertebrate host (amplifying) - meningitis, encephalitis - extremes of age (1/3 < 1yr old), neurologic sequale high (esp in infants

West Nile Virus

• flavivirus - ssRNA
• mosquito vector and bird resorvoir
• incubation 3-14 days
• neuroinvasive WNV - west nile encephalitis and West nile poliomyelitis
• WNE - most severef orm of dz - fever, headache, alterations of consciousness (lethargy to coma), focal neuro deficits, including paralysis and cranial nerve palsies
• WNP - flaccid paralysis is less common - acute asym limb weakness or paralysis