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
What are the common toxicities of Trimethoprim/Sulfamethoxazole (Bactrim)? Admin? Elim?
- 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
What are the common toxicities of Minocycline/Doxycycline? Admin? Elim?
- 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
What are the common toxicities of Clindamycin? Admin? Elim?
- TOXICITY: rash, diarrhea, GI pain, N/V, jaundice, **rarely C-difficile infection**, SJS
- ELIM: hepatic; NO adjust in RF/LF
- ADMIN: IV/IM
28
What are the common toxicities of Linezolid? Admin? Elim?
- 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
Which CA-MRSA ABs are teratogenic?
- Bactrim
- Tetracyclines
30
How can Linezolid cause optic neuropathy?
- 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
Serotonin syndrome
- 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
How should pts with serious MRSA be treated?
- 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
How should complicated polymicrobial infections be treated?
- 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
Ceftaroline fosamil
- 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
MOA, admin, and resistance of Daptomycin?
- 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
MOA and admin of Piperacillin/Tazobactam?
- IV
- Beta-lactam + inhibitor: cell wall synthesis INH
- _Tazobactam_: inhibits beta-lactamase activity, sustaining active drug levels
37
MOA and admin of Imipenem/Cilastatin, Meropenem?
- 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
Elim and common toxicities of Daptomycin? Monitoring?
- 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
Elim and common toxicities of Piperacillin/Tazobactam? Monitoring?
- 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
Elim and common toxicities of the Carbapenems? Monitoring?
- 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
What is the tx for the two types of leprosy?
- _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
Dapsone metabolism
- 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
Dapsone mechanism(s)
- 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
How do Sulfamethoxazole and Trimethoprim inhibit folate synthesis?
- _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
Dapsone (Sulfone) Syndrome
- 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
What are the clinical utilities of Dapsone?
- _Labeled_: acne vulgaris, dermatitis herpetiformis, leprosy (Henson's disease)
- _Off-label, recommended_: granuloma annulare, ITP, malaria prophylaxis, pneumocystis pneumo
47
Rifampin
- 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
Why is Rifampin activity variable?
- 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
Rifampin AEs
- 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
Clofazimine
- 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
What routine monitoring is required for patients being treated for leprosy (table)?
- Basically, CBC and LFTs + screening for renal/hepatic disease and G6PD before starting tx
52
What 3 drugs are used in leprosy tx when Clofazamine is contraindicated?
- Drug resistance remains rare; no need for baseline resistance testing
53
What types of adverse rxns are possible with leprosy tx? How are they treated?
- _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
Thalidomide
- 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
What are the clinical uses for the antivirals (table)?
- Famciclovir is metabolized to active product, Penciclovir
- Valacyclovir and Valganciclovir are pro-drugs for acyclovir and ganciclovir
