Monday Sweatman Flashcards
1
Q
What are the most likely causative bugs in immunocompetent soft tissue infections? Complicated infections?
A
- Immunocompetent: S. aureus, Strep pyogenes, or other beta-hemolytic strep
- Complicated infections, e.g., w/burns, diabetes, infected pressure ulcers, or trauma/sx wound infections -> more commonly polymicrobial, and often include anaerones and G- bacilli like E. coli and Pseudomonas
- NOTE: GAS, S. aureus, Clostridium spp (w/or w/o other anaerobes) can cause fulminant soft tissue infections and necrosis, esp in pts w/diabetes
2
Q
What are the possible txs for uncomplicated, non-MRSA infections?
A
- Usually susceptible to beta-lactamase-resistant penicillins (Dicloxacillin, Nafcillin, Oxacillin) or 1st-gen cephalosporins (Cefazolin)
- If beta-lactam allergy, Clinda, a ribosomal INH, and Vanc, a cell wall INH
- Oral drug tx most convenient, and pt doesn’t necessarily require hospitalization
3
Q
Beta-lactam side chains and cross-reactivity
A
- Some pt exhibit IgE-mediated allergy to penicillins: urticaria, angioedema, bronchospasm, anaphylaxis
- POSSIBLE cross-reactivity w/1st, 2nd-gen Cephs
1. Related to similarities in molecular structure of R1 SIDE CHAINS, rather than beta-lactam - VERY LOW risk in pt w/PMH of less severe rxn to Penicillin, when using 1st, 2nd-gen Ceph w/dissimilar side chain, or any 3rd, 4th-gen Ceph
- Hypersensitivity still an issue w/all beta-lactam ABs
4
Q
What are the resistance mechs for the beta-lactams, Vanc, and Clinda?
A
- BETA-LACTAMS: orgs that lack cell wall, acquisition of resistance plasmid (beta-lactamase activity, reduced permeability, efflux pump, altered PBPs)
- LINCOSAMIDES (Clinda): ribosomal target (50s) mut or methylation, drug efflux or inactivation
- VANCOMYCIN: most G- bac intrinsically resistant bieng impermeable, expression of D-alanyl-D-lactate variation
5
Q
What are the common toxicities of Dicloxacillin? Admin? Elim?
A
- TOXICITY: hypersensitivity, GI pain, diarrhea, nausea, rarely interstitial nephritis
- ELIM: renal; no adjustment in RF
- ADMIN: oral
6
Q
Which 3 penicillins do not require dose adjustment in renal failure?
A
- Nafcillin
- Oxacillin
- Dicloxacillin (renal elim, but no dose adjustment necessary in RF)
- These rely on biliary elim, so renal dysfunction is not an issue
7
Q
Do Clinda and Vanc require dose adjustment in renal failure?
A
- Clinda: NO
- IV Vanc: YES -> eliminated unchanged (no metab)
8
Q
What are the common toxicities of Cephalexin? Admin? Elim?
A
- TOXICITY: hypersensitivity (don’t use if pt allergic to Ampicillin), diarrhea, rarely SJS
- ELIM: renal, adjust in RF
- ADMIN: oral
- 1st-gen Cephalosporin
9
Q
What are the common toxicities of Cefazolin? Admin? Elim?
A
- TOXICITY: hypersensitivity, pruritis, diarrhea, eosinophilia, rarely SJS
- ELIM: renal, adjust in RF
- ADMIN: IV, IM
- 1st-gen Cephalosporin
10
Q
What are the common toxicities of Nafcillin? Admin? Elim?
A
- TOXICITY: hypersensitivity, neutropenia, rarely interstitial nephritis, possible hypokalemia, INC ALT/AST
- ELIM: primarily hepatic; dose adjust in hepatic + renal dysfunction
- ADMIN: IV
11
Q
What are the common toxicities of Oxacillin? Admin? Elim?
A
- TOXICITY: hypersensitivity, diarrhea, nausea, fever, rash, rarely interstitial nephritis
- ELIM: hepatic; NO dose adjust in RF
- ADMIN: oral
12
Q
What are the common toxicities of Clindamycin? Admin? Elim?
A
- TOXICITY: rash, diarrhea, GI pain, N/V, jaundice, rarely C-difficile infection, SJS
- ELIM: hepatic; NO adjust in LF or RF
- ADMIN: oral
13
Q
What are the common toxicities of Vancomycin? Admin? Elim?
A
- TOXICITY: Red Man and hypotension (rapid IV), fever, nausea, rash, tinnitus, INC BUN/Cr
- ELIM: hepatic/renal; dose adjust in RF
- ADMIN: IV; used oral to tx enterocolitis
- Think NEPHROTOXICITY, OTOTOXICITY, THROMBOPHLEBITIS
1. Hypotension: histamine-related thrombophlebitis
14
Q
Why is Vanc administered IV for systemic infection? What is the exception?
A
- Poor bioavailability
- Remember: oral dosing is sometimes used for enterocolitis, where retention of drug in the GI tract is a therapeutic advantage and has little discernible systemic toxicity
15
Q
Which ABs have risk of hypersensitivity?
A
- Beta-lactams
- Dicloxacillin
- Cephalexin (don’t use if pt allergic to Ampicillin)
- Cefazolin
- Nafcillin
- Oxacillin
16
Q
Which ABs have potential for interstitial nephritis?
A
- Penicillinase-resistant penicillins
- Dicloxacillin
- Nafcillin
- Oxacillin
17
Q
How can Vanc affect the ear?
A
- IV admin may cause damage to auditory branch of 8th cranial nerve
- Permanent hearing loss has been reported
18
Q
How can Vanc affect the kidney?
A
- Vanc-induced NEPHROTOXICITY usually shows transient INC in BUN or serum creatinine, and presence of hyaline and granular casts and albumin in the urine
- Generally reversible after discontinuation of the drug, but deaths have occurred
19
Q
What is CA-MRSA? What does it cause? How should it be treated?
A
- Community-acquired MRSA: predominant cause of suppurative skin infections in many parts of US
- Usually causes furunculosis (painful, pus-filled bump under the skin caused by infected, inflamed hair follicles), cellulitis, and abscesses, but necrotizing fasciitis and sepsis can occur
- For simple abscesses and o/less serious CA-MRSA skin and soft tissue infections, I & D alone may be effective
- If not, CA-MRSA strains are usually susceptible to oral: Trimethoprim-Sulfamethoxazole (BACTRIM), Minocycline, Doxycycline, Clinda, Linezolid
-
Fluoroquinolones should NOT be used empirically to treat MRSA infections bc RESISTANCE is common and INC in both community and nosocomial settings
1. Floxacins
20
Q
What is the MOA of Bactrim?
A
- PO/IV
- Folic acid antagonists: sequential antagonists of folate synthesis
21
Q
What is the MOA of Minocycline and Doxycycline?
A
- PO/IV tetracyclines
- Bind 30s ribosomal subunit, INH binding of aminoacyl-tRNA molecules
22
Q
What is the MOA of Clinda?
A
- IV/IM
- Lincosamide: 50s ribosomal INH of translocation
23
Q
What is the MOA of Linezolid?
A
- PO/IV
- Oxazolidinone: binds 23s ribosomal RNA of 50s subunit, preventing initiation complex formation with 70s ribosomal subunit
24
Q
What are the resistance mechs to the folic acid antagonists, tetracyclines, and oxalidinones?
A
- FOLIC ACID ANTAGONISTS: permeability barrier and/or efflux pumps, natural target insensitivity, change in target enzyme expression or mutational, recombinational changes, and acquired resistance by drug-resistant target enzymes
1. May be different mechs for e/component - TETRACYCLINES: drug efflux or metabolism, ribosome protection
- OXALIDINONES: mutation (plasmid carried Cfr rRNA methyltransferase) of 23s rRNA and ribosomal proteins L3 and L4, drug efflux, biofilm formation and DEC cell wall penetration
25
Q
What are the common toxicities of Trimethoprim/Sulfamethoxazole (Bactrim)? Admin? Elim?
A
- TOXICITY: N/V, rash, photosensitivity, dizziness, dyspepsia, human fetal risk
- ELIM: renal; dose adjust in RF
- ADMIN: PO/IV
- Maintain hydration -> a sulfamethoxazole metabolite has limited aqueous solubility
26
Q
What are the common toxicities of Minocycline/Doxycycline? Admin? Elim?
A
- TOXICITY: N/V, rash, photosensitivity, hepatotoxicity (most evident in pre-existing dysfunc and with pregnancy), tinnitus, vertigo, ataxia, discolored teeth (dysplasia, discoloration of teeth enamel), human fetal risk
- ELIM: hepatic/renal; dose adjust in RF
- ADMIN: PO/IV
27
Q
What are the common toxicities of Clindamycin? Admin? Elim?
A
- TOXICITY: rash, diarrhea, GI pain, N/V, jaundice, rarely C-difficile infection, SJS
- ELIM: hepatic; NO adjust in RF/LF
- ADMIN: IV/IM
28
Q
What are the common toxicities of Linezolid? Admin? Elim?
A
- TOXICITY: diarrhea, N/V, headache, anemia, thrombocytopenia, myelosuppression, rash, HTN, rarely SJS, optic and peripheral neuropathy, vision loss, serotonin syndrome, seizures, lactic acidosis
1. Usually well-tolerated, w/few described AEs
2. Serious AEs in bold require withdrawal of the drug - ELIM: hepatic/renal; caution in RF
- ADMIN: IV/PO
29
Q
Which CA-MRSA ABs are teratogenic?
A
- Bactrim
- Tetracyclines
30
Q
How can Linezolid cause optic neuropathy?
A
- Damage is thought to be caused by mitochondrial dysfunction in the optic N bc mammalian mito DNA uses ribosomes that more closely approximate that of bacteria and are therefore susceptible to drug INH
- Mito DNA dysfunction a common mechanism to several classes of drugs possessing specific organ toxicity
31
Q
Serotonin syndrome
A
- Caused by excessive levels of circulating serotonin in CNS/periphery
- Mental status changes, autonomic hyperactivity, and neuromuscular abnormalities ranging from imperceptible to almost lethal -> MOST cases appear w/in 6 hours
- Lg # of diverse drugs assoc w/SS: SSRIs, TCAs, MAOIs, some opiate analgesics, Isoniazid, amphetamines, Procarbazine, St. John’s Wart, Ginseng (herbals)
- Overall low incidence of SS when Linezolid and SSRIs simulataneously administered -> paucity of prospective data
- Effective treatments for SS
32
Q
How should pts with serious MRSA be treated?
A
- Pts w/complicated MRSA skin, soft tissue infections should be hx and tx w/IV Vanc (even if SUSPECTED, should be treated empirically)
- While not bactericidal against staph, Linezolid appears to be as effective as Vanc for serious MRSA infection -> advantage (over Vanc) of INH bacterial toxin production (protein synthesis inhibition)
-
Daptomycin bactericidal for MRSA in vitro and appears to be as effective as Vanc for tx of MRSA skin and soft tissue infection
1. Inactivated by surfactant
33
Q
How should complicated polymicrobial infections be treated?
A
- Add an MRSA drug to broad spectrum parenteral AB
- Piperacillin/Tazobactam or Imipenem-cilstatin, Meropenem
- Ceftaroline fosamil is a new (5th-gen) IV Cephalosporin with activity against MRSA that may be effective as monotherapy if infection w/P. aeruginosa and anaerobic bacteria is unlikely
34
Q
Ceftaroline fosamil
A
- IV Cephalosporin binding to PBPs
- Bactericidal against S. aureus, Strep pneumo, Strep agalactiae (GBS), E. coli, Kleb pneumo, Kleb oxytoca
1. Noninferior to Vanc + Aztreonam - Mainly renal elim; dose adjust in RF
- Common AEs: diarrhea, nausea, rash, constipation, hypokalemia, phlebitis
1. C. difficile, ALT/AST elevation, and hemolytic anemia are rare but reported in post-marketing studies
2. MONITOR pts for devo of ANEMIA (CBC)
35
Q
MOA, admin, and resistance of Daptomycin?
A
- ADMIN: IV
- MOA: lipopeptide -> binds to and depolarizes bacterial membrane, inhibiting DNA/RNA/protein synthesis
- RESISTANCE: changes in cell wall thickness, drug binding site mutations, biofilm production
36
Q
MOA and admin of Piperacillin/Tazobactam?
A
- IV
- Beta-lactam + inhibitor: cell wall synthesis INH
- Tazobactam: inhibits beta-lactamase activity, sustaining active drug levels
37
Q
MOA and admin of Imipenem/Cilastatin, Meropenem?
A
- ADMIN: IV
- MOA: carbapenem (beta-lactams) -> cell wall synthesis inhibitors
-
Cilastatin: inhibits renal dihydropeptidase I (brush border), preventing metabolism
1. Dihydropeptidase produces inactive, but renotoxic metabolite
38
Q
Elim and common toxicities of Daptomycin? Monitoring?
A
- ELIM: renal; dose adjust in RF
- TOXICITY: diarrhea, vomiting, throat pain, rarely myopathy, rhabdomyolysis, renal failure
1. MONITOR pt creatinine kinase levels
2. Remember that rhabdomyolysis is most commonly associated with antilipidemic statin drugs
39
Q
Elim and common toxicities of Piperacillin/Tazobactam? Monitoring?
A
- ELIM: renal; dose adjust in RF
- TOXICITY: GI distress, headache, rash, hypersensitivity rxns, rarely SJS, agranulocytosis, leukopenia, neutropenia, C. difficile
1. MONITOR for changes in BUN/serum Cr
40
Q
Elim and common toxicities of the Carbapenems? Monitoring?
A
- Imipenem/Cilastatin, Meropenem
- ELIM: renal; adjust dose in RF
- TOXICITY: GI distress, skin rash, seizures at high serum drug levels
1. MONITOR for changes in BUN/serum Cr - REMEMBER: Meropenem not susceptible to dihydropeptidase activity, and w/lower risk of seizures
41
Q
What is the tx for the two types of leprosy?
A
- Tuberculoid: Dapsone + Rifampicin daily -> 12 mos, then therapy discontinued
-
Lepromatous: Dapsone + Rifampicin + Clofazimine daily -> 24 mos, then therapy discontinued
1. Dead bacilli may remain in tissues for several years
2. Clofazimine is no longer widely available
42
Q
Dapsone metabolism
A
- Metabolized to a series of inactive, but potentially toxic products, esp. Hydroxylamine -> hemolysis + methemoglobinemia
1. Methemoglobinemia: iron in Hb oxidized, and less capable of carrying O2 -> O2 sats can fall, w/blue nail beds/lips, esp. in pts w/already compromised pulmonary reserve - CONTRAINDICATED in pts with G6PD deficiency
-
Drug interxns w: Rifampicin -> INC toxicity
1. Cimetidine/Omeprazole (for gastric hyperacidity) -> DEC toxicity
2. Trimethoprim -> INC serum level of both drugs - Renal func important; DEC clearance will lead to potential drug accumulation (i.e., w/Probenecid)
43
Q
Dapsone mechanism(s)
A
- Folate antagonist producing bacteriostatic effect
1. Distinct from actions of Sulfamethoxazole and Trimethoprim - INH of 2nd messenger pathways involved in poly chemotaxis (incompletely understood)
44
Q
How do Sulfamethoxazole and Trimethoprim inhibit folate synthesis?
A
- Sulfamethoxazole: structural analog of p-aminobenzoic acid (PABA) that competes with PABA for binding to bac dihydropteroate synthase
-
Trimethoprim: binds to and reversibly INH dihydrofolate reductase, preventing formation of tetrahydrofolic acid, the metabolically active form of folic acid
1. W/o THF, bacteria cannot synthesize thymidine, leading to interference with bacterial nucleic acid and protein formation - Synergistic combo against some bacteria
45
Q
Dapsone (Sulfone) Syndrome
A
- Long-term use of Dapsone is assoc w/a # of AEs (see attached table)
- In combo, called Dapsone (Sulfone) Syndrome
1. Sequence: dermatitis, LAD (esp. along posterior border of SCM mm), hepatitis - Liver enzyme abnormalities worsen over the period of the exposure, but are reversible once tx ends
1. Hemolysis also resolves, albeit over a longer time scale - Maculopapular rash (upper limbs + forehead, or disseminated)
1. SJS also reported
46
Q
What are the clinical utilities of Dapsone?
A
- Labeled: acne vulgaris, dermatitis herpetiformis, leprosy (Henson’s disease)
- Off-label, recommended: granuloma annulare, ITP, malaria prophylaxis, pneumocystis pneumo
47
Q
Rifampin
A
- INH bacterial and mycobac RNA synthesis via beta-subunit of DNA-dependent RNA polymerase
1. Eukaryotic cells unaffected - Effective against rapidly growing + slowly dividing orgs -> no antiviral activity (shouldn’t be used)
- Widely distributed in body: crosses inflamed meninges, placenta; elim in BREAST MILK
- Hepatic metabolism and elim: enterohepatic recirc
- CYP inducer: 1A2, 2B6, 2C19, 2C9, 3A -> multiple drug-drug interaxns
48
Q
Why is Rifampin activity variable?
A
- Genotype (from pt to pt)
- Pts can express differences in CYP activity or polymorphisms in genomic targets (PXR, RXR) upon which inducers act
- Differences in P-gp activity and capacity
- Drug-drug interactions are possible, but NOT absolute
49
Q
Rifampin AEs
A
- Transient INC in hepatic enzymes and severe, sometimes fatal, liver toxicity
- Makes mgmt of diabetes more difficult
- Therapy interval -> not less than twice weekly
1. Hemolysis, hemoglobinuria, hematuria, renal insufficiency/failure
2. Flu-like syndrome of fever, chills, myalgias - Can discolor bodily fluids -> warn patient (urine, saliva, tears, sputum, contact lenses)
50
Q
Clofazimine
A
- Preferential binding (not intercalator) to mycobac guanine in DNA -> freq of mycobac guanine and cytosine >>>>> human DNA
- Progressive, dose-dependent anti-inflam and immunosuppressive effects -> can tx reversal rxns and erythema nodosum leprosum
- Highly lipophilic w/long (mos) persistence in fatty tissues and reticuloendothelial system
- Hepatic elim, unchanged -> hepatitis, jaundice reported
-
Staining of body, bodily fluids, suckling infant
1. Skin discoloration may trigger depression -> suicides reported - Feces may appear black or tarry (misinterpreted as GI hemorrhage)
51
Q
What routine monitoring is required for patients being treated for leprosy (table)?
A
- Basically, CBC and LFTs + screening for renal/hepatic disease and G6PD before starting tx
52
Q
What 3 drugs are used in leprosy tx when Clofazamine is contraindicated?
A
- Drug resistance remains rare; no need for baseline resistance testing
53
Q
What types of adverse rxns are possible with leprosy tx? How are they treated?
A
- Type 1 rxns: red patchy skin lesions, erythema, swollen hands and feet, joint pain -> GCS anti-inflam therapy
- Type 2 rxns (erythema nodosum leprosum): sudden eruption of numerous, painful, nodules and neuritis -> GCS, Clofazamine, Thalidomide
- Primarily tx w/GCS and NSAIDs; Clofazamine and Thalidomide also used for this purpose
54
Q
Thalidomide
A
- INH NFkB-mediated transcriptional upregulation and TNF-alpha production (among o/intermediates)
1. Blocks leukocyte migration: inflammation intimately involved in disease process
2. Also anti-angiogenic (used in tx of myeloma) - TERATOGEN
- INC in plasma HIV viral load (MONITOR)
- AEs: somnolence (sleepiness) > rash > headache
- Rarely peripheral neuropathy
55
Q
What are the clinical uses for the antivirals (table)?
A
- Famciclovir is metabolized to active product, Penciclovir
- Valacyclovir and Valganciclovir are pro-drugs for acyclovir and ganciclovir
