Major Concepts of Antimicrobials

1. Major Concepts of Antimicrobials

2. Special Concepts r/t Anitmicrobials • Selective toxicity • Ability to target without harming host • Susceptibility • Prophylaxis • Neutropenia, Surgery, Endocarditis • Combination Therapy • Misuse – non-specific fevers, viruses

3. Resistance Fig 82-1

4. Aminoglycosides: Bactericidal Inhibitors of Protein Synthesis Chapter 86

5. Aminoglycosides: Background • Resistance is beginning to limit use • Gentamicin – cheaper but commonly used • 20 diff aminoglycoside-inactivating enzymes (like the beta-lactamases for PCN) • Reserve amikacin (in this class this is big gun, save it) • Bactericidal • concentration dependent (the more you get, the more it kills) • Post-antibiotic effect – several hours (it sticks around a lot longer than some other drugs) • NOT effective against anaerobes

6. Gentamicin (Garamycin) (Prototype) • MOA / Use: narrow spectrum for gram- bacilli – esp. pseud. aerugenosa, E. coli, Klebs., Serratia • ADME: • Poor CSF • Not absorbed orally (so?) (typically IV) • Toxicity w/ wound irrigation • Needs Peak and Trough • Binds tightly to renal tissue • Excretion primarily renal • Dosage varies widely (0.5 mg/kg to 25 mg/kg)

7. Adverse Effects • Ototoxic (if it stays above the baseline for therapeutic levels too long… want the level to drop low enough so the body can wash it out) • r/t excess trough levels – sensory hairs • HA (headache), N, vertigo then high-pitched tinnitis (Action?) If you noticed tinnitus, first action would be to stop the dose and call the dr! • Nephrotoxic • Total cumulative dose • ATN (acute tubular necrosis, tube in the nephron gets necrotic and leads to renal failure.(proteinuria (protein in the blood), casts (slough big particles), BUN (Blood Urea Nitrogen), Creatinine • Elderly and young and sick • Neuromuscular blockade • Hypersensitivity & blood dyscrasias (rare)

8. DD • PCNs, Cephs, Vanco used in combo • PCNs inactivate – schedule issue? • Ethacrynic Acid – will potentiate (increase) ototoxicity • Other nephrotoxics • Skeletal Muscle relaxants (r/t the neuromuscular blockade which makes them weak)

9. Aminoglycosides: Special Concerns • Neomycin most nephrotoxic (Not ever IM or IV, might see it preoperativly to sterilize the gut) Will also see it topically. • Scheduling once daily – Safer? (yes, lets trough get low to wash out of tissue) • Post-antibiotic effect • Washout – esp. in vestibule and kidneys • Typically only measure trough – up to 1hr prior to next dose – level should be ?

10. Antifungal Agents Chapter 91

11. Antifungal Agents Systemic mycotic infections • Opportunistic (r/t infections that set up house in debilitated pts): candidiasis, aspergillosis, cryptococcosis, mucormycosis • Nonopportunistic (ones you get because you were exposed to it): sporotrichosis, blastomycosis, histoplasmosis, coccidioidomycosis Superficial mycotic infections • Candidiasis • Dermatophytes

12. Antifungal Agents Systemic mycotic (fungal) infections • Opportunistic – host is sick, debilitated, immunocompromised pt • candidiasis, aspergillosis, cryptococcosis, • Non-opportunistic • blastomycosis, histoplasmosis, coccidioidomycosis Superficial mycotic infections • Candidiasis • Dermatophytes (little bugs with sharp teeth on that commercial…)

13. Antifungals: Major Classes • Polyenes • Azoles • Pyrimidine analogs • Echinocandins

14. Amphotericin B [Fungizone] MOA / TE • Broad spectrum antifungal agent binds to ergosterol component of fungal cell wall and increases permeability. Fungocidal. DOC for most progressive, potentially fatal systemic mycoses (you use this one when the bug is going to kill the person…) ADME • Highly toxic (sterols) (in the bug it breaks down ergosterol in the cell wall, you have sterols in you, hence, it breaks down the bugs sterols and can break down your sterols) • Poor GI absorption - SLOW IV USE ONLY • Poor CSF

15. Amphotericin B (cont’d) Adverse effects – almost 100% - varying • Phlebitis (slow IV helps prevent this) • Fever, chills, nausea (common) – pre-treat w/ benadryl / acetaminophen so they don’t suffer so much • Nephrotoxicity – residual if 4 g/day, 1 L NS (keep them hydrated with saline), Monitor urine q 3-4 days (looking from protein, cast, and serum Creatinine) • Hypokalemia (lowered potassium) • Bone marrow suppression (will lower reds, whites, and browns (platelets)) DD: nephrotoxics - flucytosine

16. Itraconazole (Sporanox) MOA / TE • Azole group of antifungal agents that inhibits sythesis of ergosterol – fungistatic to treat histoplamosis, meningitis of cryptococcus neoformans & disseminated candidiasis ADME • PO or IV • Food  abs. capsules,  abs. of suspension • Metabolized in liver • 40% excreted unchanged in urine

17. Itraconazole (Sporanox) cont’d Adverse effects • Common – N, V, and D, rash, HA, edema • Rare - Hepatic necrosis, transient cardiosuppression DD • Inhibits cytochrome P450 isozymes (if system is impaired, your drug levels are going to rise, will also raise other drug levels) • Increases levels of warfarin, digoxin, sulfonylureas (antidiabetic drug-watch blood sugar), cyclosporine, quinidine and many other drugs • Acid reduces decrease drug levels • Pepsid, prilosec, etc. will impair absorption of Itraconazole

18. Azoles: Special Considerations • Fluconazole [Diflucan] • Lower toxicity level • Can be taken orally • SJS syndrome (Steven’s johnson Syndrome is a side effect of this medication. Looks like a chemical burn) • Ketoconazole [Nizoral] • Effect on sex hormones – inhibits production (will impair fertility)

19. Drugs for Superficial Mycoses • Dermatophytic infections (e.g., ringworm) • Tinea pedis, tinea corporis, t. cruris, & t. capitis • Drugs • Clotrimazole (Gyne-Lotrimin) – DOC for topical dermatophytic and candida infections of skin, mouth, vagina • Vulvovaginal candidiasis • Griseofulvin (Grifulvin) - oral • Onychomycosis (fungal infection of the toes (toenails)

20. Griseofulvin (Grifulvin V) MOA / TE • Superficial mycoses only – inhibits fungal mitosis – incorporates into keratin (that’s how is suppresses the bugs) Adverse effects • Transient headache, rash, GI upset • Contraindicated in hepatocellular disease (this is liver intensive medication, like most of the antifungals) DD • Decreases warfarin

21. Antiviral Agents I: Drugs for Non-HIV Viral Infections Chapter 92 They mutate readily, they live in your cells (so they’re hard to get to). They are harder to treat b/c they are harder to target...

22. Viral Infections • Dilemma (see previous slide) • Types • HSV (Herpes-simplex) More sensitive to antivirals • Genitalia, mouth, face (HSV-2) • VZV (Varicella Zoster) Moderately sensitive to antivirals. Relative to HSV • Chicken pox – Shingles • CMV (Cytomegalovirus) Less sensitive to antivirals = more resistant

23. Herpes • Look in book for some box on herpes. There is no cure for viral infections like Herpes. All we can do is treat them an live around them… • Just get that the same antivirals are used over and over again…

24. Drugs for Non-HIV Viral Infections Prototype: Acyclovir [Zovirax] • MOA / TE: Suppress synthesis of viral DNA and is useful in treating HSV1,2 & VZV – no cure • Adverse Effects • Intravenous: reversible nephrotoxicity, phlebitis • Infuse slowly – hydration (trying to protect the kidneys) – during & 2 hr after • Oral: GI, vertigo • Topical: stinging

25. Acyclovir [Zovirax] • Nursing Implications • Resistance – type of clients (seen in just about everybody that is on the drug long term) • IV indicated for immunocompromised pt • STI control (just b/c your partner is on antivirals doesn’t mean that you won’t get it or that you’re safe) STI is new acronym for STD (Changed it to infection) • Treatment for VZV in elderly and children (w/i 24 hr)

26. Acyclovir [Zovirax] cont’d • Nursing Implications (con’td) • po (low availability), topically or IV • NO IV bolus (you can’t take a big piece of the drug and stick it in fast), NO IM, or NO SubQ injections • Valacyclovir [Valtrex] – prodrug that increases oral bioavailability (of acyclovir) by 55% • Without regard to meals

27. Ganciclovir [Cytovene, Vitrasert] • MOA / TE • Suppresses replication of viral DNA to treat CMV retinitis of immune compromised clients & prevent CMV in transplant patients • Adverse effects • Granulocytopenia (a piece of your wbc’s) & thrombocytopenia • Mutagenesis, carcinogenesis • Teratogenisis and infertility – (90d following cessation) • valganciclovir (Valcyte) – prodrug for oral use (of ganciclovir) • Take intact – with food

28. Hepatitis C (HCV) • Transmission—blood and semen • Typically asymptomatic • Leading cause for liver transplants • Among most common causes of liver cancer • Drugs • Pegylated interferon alfa combined with ribavirin (Used in combination to treat HepC)

29. Interferon alfa (Peg-Intron)immune modulatory, antineoplastic, antiviral • MOA / TE • Blocks entry of virus, synthesis of viral m-RNA and proteins, and viral assembly. Tx of chronic Hep B (first choice is to vaccinate) & C • ADME • Pegylated - longer acting • Only parenterally (subQ usually) • Adverse Effects • Flu-like (fever, myalgia, HA, fatigue) & depression (makes you feel real bad) • Long/High dose – thyroid dysfunction, heart damage, bone marrow suppression • Alopecia, GI, injection site pain, bruising

30. Ribavirin (Rebetol) • MOA unclear (Goes with Interferon) • Used with Interferon A - together are DOC for Hep C (HCV). • Therapy 24 to 48 weeks. Goal is SVR – sustained virologic response (loss of detectable viral RNA) • Adverse effects • Hemolytic anemia (anemia due to broken blood cells) • Teratogenic (Category X) – two forms of BC • Dosage based on weight

31. Hepatitis B - HBV • Transmission—blood and semen • Drugs • HBV vaccine • Interferon alfa-2b [PEG-Intron] • Lamivudine [Epivir-HBV] (high resistance) • Adefovir [Hepsera] • Duration of treatment and relapse • They really don’t know yet if it has to be lifelong… but probably.

32. Flu Vaccines • 3 strains – selected by CDC, FDA, & WHO • Inactivated • IM • Live attenuated – LAIV (Flumist) – 2003 • Intranasally • MUST BE FROZEN • Only ages 5-49 (r/t to ability to do something about immune response)

33. Flu Vaccine (cont) • Efficacy – Who should receive it? Most people… • 1-2 wks & lasts for 6 mo • Adverse effects • Fever, malaise, myalgia • Guillain-Barré syndrome – Swine flu vac. 1976 • LAIV (inhaled version) – runny nose, HA, cough – rare GBS, anaphylaxis • Precautions and contraindications • Acute febrile illness, hypersensitivity to eggs

34. Flu Vaccine (cont) • Who should NOT without MD approval? • Allergy to egg • Previous severe reaction • GBS • Moderate, severe illness w/ fever • Children under 6 months • LAIV not for: adults over 50, children under 5, preggers, children or adolescents on long-term ASA therapy, chronic heart, lung disease

35. Drugs for Influenza Prototype: oseltamivir (Tamiflu) • MOA / TE: inhibit viral replication of Inf A&B and is used to prevent and treat same – effective if implemented within 2 days of sxms • Adverse effects • N&V • Confusion, self injury • Expensive – must be started prior to 48 hr (must be given quickly or it’s ineffective...)