Pogue: Antimicrobials IIb Flashcards Preview

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31

Macrolide-Lincosamide-Streptogramin (MLS) resistance seen in what?

S.aureus can posses:

Can lead to:

How do you detect presence of erm gene?

Macrolide-Lincosamide-Streptogramin (MLS) Resistance in S.aureus:

S.aureus can posses an erm gene that can encode resistance to all 3 classes (all bind 50S subunit)

Can lead to inducible clindamycin resistance when isolate says “erythromycin resistant and clindamycin susceptible”

Can use a special D test to detect presence of the erm gene

32

Sulfonamides:

MOA
What does PABA do?
Bacteriostatic or Bactericidal?
Most commonly used agent:

MOA: structural analog of PABA, which blocks the production of dihydrofolic acid

Folic acid --> DHF --> THF --> Thymidines, purines

Bacteriostatic

Most commonly used agent: sulfamethoxazole (combined with trimethoprin= BACTRIM)

Bactrim (TMP/SMX): together, the two become bactericidal (synergy)

33

What is Trimethoprin?

Inhibitor of dihydrofolic acid reductase (next step in the production of purines and DNA); also bacteriostatic

34

Spectrum of Activity (TMP/SMX):

G+
Anaerobic
Miscellaneous:

Gram (+): staphylococcus (including MRSA), some streptococcus (notably lacks group B strep), no enterococcus

Anaerobic: minimal

Miscellaneous:
o Listeria and Nocardia
o DOC for Stenotrophomonas maltophilia

35

What is the DOC for Stenotrophomonas maltophilia?

TMP/SMX

36

Spectrum of Activity (TMP/SMX):

G-
Pseudomonas

Gram (-):

Enteric Gram negatives (variable; Klebsiella, Proteus, E.coli)

SPICE organisms (limited clinical use for these)

No pseudomonas coverage

37

Clinical Applications (TMP/SMX):

Outpatient UTIs: most commonly used agent for these

Skin infections when MRSA is a concern: but remember, no coverage of group B strep

DOC for many nasty infections:
o PCP (pneumocystis) pneumonia
o Stenotrophomonas maltophilia
o Nocardia

Treatment of multi-drug resistant Gram-negatives: role still debated

38

What is the most commonly used agent for outpatient UTIs?

TMP/SMX

39

What is the DOC of Nocardia and PCP Pneumonia?

TMP/SMX

40

TMP/SMX
Side Effects:

Hypersensitivity Reactions: most common agents that cause these (~3% of patients)
- Simple rash --> Severe skin reactions (SJS/TEN)

High concentrations can crystallize in the urine (Rare)

TMP SEs:
o Bone marrow suppression: anemia, leucopenia, and granulocytopenia
o Hyperkalemia

41

TMP/SMX
DDIs:

Increased INR (How thin blood is) when given with warfarin: INR is the measurement that indicates if warfarin is at therapeutic levels or not

42

NITROIMIDAZOLES:

MOA

Pharmacokinetics:

Agents:

MOA: not clearly defined; interaction with DNA that causes a loss of the helical structure and strand breaking, leading to cell death

Pharmacokinetics:
- ~100% bioavailability
- Minimal renal elimination

Agents:
- Metronidazole
- Tinidazole

43

Spectrum of Activity (Metronidazole):

ANAEROBES ONLY: better for lower GI anaerobes vs. mouth anaerobes (opposite of clindamycin)
o DOC for C.difficile**
- Some parasitic activity: T.vaginalis

44

What is the DOC of C.difficile?

Metronidazole - Mild
Vanco - Severe

45

Clinical Applications (Metronidazole):

Side Effects:

Drug Interactions:

Clinical Applications (Metronidazole):
- Anaerobic coverage for nosocomial patients
- DOC for C.diff
- T.vaginalis

Side Effects:
- N/V
- Metallic taste
- Disulfuram reaction with ethanol
- Peripheral neuropathies (rare)

Drug Interactions:
- Increased INR when given with warfarin

46

Drugs with anaerobic coverage (8)

Metronidazole
Penicillin
B-lactam/B-lactamase inhibitors
–Piperacillin/tazobactam, ampicillin/sulbactam
Clindamycin
Cephamycins
Carbapenems
Moxifloxacin
Tetracyclines (some)

47

RIFAMPIN

MOA:

Pharmacokinetics:

Spectrum of Activity:
G+:
G-:
Miscellaneous:

MOA: binds to b-subunit of DNA-dependent RNA polymerase, blocking RNA synthesis

Pharmacokinetics:
- ~100% bioavailability (IV dose=PO dose, but food may delay absorption)
- No renal dosing necessary

Spectrum of Activity:

Gram (+): S.aureus (including MRSA) and streptococcus; not used as monotherapy

Gram (-): used in combination with cell wall agent for synergy; minimal activity alone

Miscellaneous: standard therapy for mycobaterial infections

48

RIFAMPIN

Clinical Application:

Side Effects:

Clinical Application:
- Synergy:
o Severe staph infections
o Multi-drug resistant gram (-) bacilli
- Mycobacterial infections: part of standard TB regimen

Side Effects:
- Hepatotoxicty (HIGHLY)**
- Discolored fluids

49

RIFAMPIN

Drug Interactions:

STRONG inducer of multiple CYP450 isoenzymes**

Contraindicated with many HIV meds

Significant interactions with:
o Antifungals
o Anti-hypertensives
o Statins

50

What is part of the standard therapy for mycobaterial infections?

Rifampin

51

POLYMIXINS:

MOA:

Bacteriostatic or Bactericidal?

Why was use abandoned? What lead to re-emergence?

MOA: Cationic detergent that damages the cytoplasmic membrane, leading to leakage of intracellular substances and rapid cell death

Electrostatically interacts with the LPS outer membrane of G- organisms

Bactericidal

Originally utilized in the 1950s
Associated with high rates of nephrotoxicity and neurotoxicity, so use abandoned;
Multi-drug resistance Gram negatives in the 1990s lead to re-emergence

52

POLYMIXINS

Agents:

Pharmacokinetics:

Agents:
- Colistin (IV)
- Polymixin B (IV,PO,topical)

Pharmacokinetics:
- Poorly understood

53

POLYMIXINS

Spectrum of Activity:

G+
G-
Anaerobic

Gram (+): NONE

Gram (-):

Pseudomonas, A.baumannii, K.pneumoniae, E.coli;

No activity against serratia and proteus

Anaerobic: NONE

54

Clinical use

Adverse events

DDIs

Clinical Use:
- Mulit-drug resistant gram (-) organisms in the hospital: when there are no other options!
o Usually pseudomonas, A.baumannii, and K.pneumoniae (KPC- carbapenamase producing organism)

Adverse Events:
- Nephrotoxicity: up to 40% of patients; dose dependent and reversible
- Neurotoxicity: parasthesias

Drug Interactions:
- Additive toxicities

55

Antipseudomonal Agents (Full List)

Piperacillin, Piperacillin/Tazobactam
Cefepime, Ceftazadime
Meropenem, Imipenem, Doripenem
Aztreonam
Gentamicin, Tobramycin, Amikacin
Ciprofloxacin, Levofloxacin
Polymixins

56

CHLORAMPHENICOL:
MOA:

Clinical Use:

Side Effects:

MOA: ribosomal 50S inhibitor

Clinical Use: not clinically used any more due to toxicity

Side Effects:
- Bone Marrow Suppression: dose-dependent
- Aplastic Anemia: non-dose dependent
- Gray-Baby Syndrome

57

Gray-Baby Syndrome:

SE of Chloramphenicol

Lack of an enzyme in phase II metabolism of the drug; leads to accumulation of a toxic metabolite (causes graying of the skin and cyanosis, among other symptoms)

58

NITROFURANTOIN:

MOA:
Spectrum of Activity:
Clinical Use:
Side Effects:
Contraindications:

MOA: inhibition of a variety of bacterial enzyme systems interfering with metabolism

Spectrum of Activity: organisms causing UTIs

Clinical Use: only to treat lower UTIs (First line)

Side Effects: rare inflammatory lung process

Contraindications: cannot use if GFR <60mL/min (completely filtered by the kidney)

59

DAPSONE:

MOA:
Clinical Use:
Side Effects:

MOA: antagonist of PABA (similar to sulfa drugs)

Clinical Use: prevention/treatment of PCP pneumonia when TMP/SMX cannot be used (ie. allergy)

Side Effects: hemolysis; generally infrequent but more common in patients with G6P deficiency