Module 5: Special Considerations

Type 1 Immune reaction

IgE (soluble antigen)

Type 1 Allergy

Immediate hypersensitivity (5 to 30 mins)

Effector mechanism of Type 1 allergies

mast cell activation

clinical manifestation of typle 1 allergies

allergic rhinitis

asthma

anaplylaxis

Type 2 immune reaction

IgG/IgM (associated antigen)

Type 2 allergy

antibody-mediated cytotoxic hypersensitivity (minutes to hours)

Effector mechanism of Type 2

complement mediated phagocytosis

clinical manifestation of type 2

-drug allergy

-graves disease

-anemia

type 3 immune reaction

IgG/IgM (soluble antigen)

Type 3 allergy

immune complex mediated hypersensitivity (3-8 hours)

Type 3 effector mechanism

tissue damage induced by immune complexes

clinical manifestation of type 3 allergies

-rheumatoid arthritis

-serum sickness

-SLE

Type 4 immune reaction

T cells (soluble or cell bound antigen)

Type 4 allergy

cell-mediated hypersensitivity (48-72 hours)

Type 4 effector mechanism

T cell medicated inflammation or cytotoxicity

Type 4 clinical manifestation

-contact dermatitis

-graft rejection

-chronic asthma

type 1 and 4

What are the most common types of allergies?

Type 1

What is the worst type of allergy?

10%

What % of patients report a penicillin allergy?

0.2-0.4%

What % of penicillin allergies are anaphylaxis?

0.7-1%

What % of penicillin allergies have hypersensitivity reactions?

0.004-0.04%

What % of allergies have anaphylactoid reactions?

10%

Cephalosporins have ____ cross reactivity with penicillin allergies.

1%

Carbapenems have a less than ___ cross reactivity with penicillin allergies.

3-8%

What % of the pop has sulfa allergies?

rash

What is the most common manifestation of Sulfa Allergies?

Type 1 Sulfa allergy

•anaphylactoid reaction: ONLY N1 substituent

-NO non-antibiotics with a S contain and N1 substituent

Type 2/3 sulf allergies

•antibody formation

-Antibodies do NOT cross-react to ANYTHING but sulfonamide antibiotics

Type 4 sulfa allergies

•at N4: nitroso metabolite

•Increased incidence of allergy with penicillin than non-antibiotic containing sulfonamides (multiple drug allergies)

Cephalexin

Which antimicrobial is MOST likely to cross-react with amoxicillin?

A.Cefepime

B.Ceftriaxone

C.Cephalexin

D. Sulfamethoxazole

Cefoxitin

What drug cross reacts with Penicillin?

Ampicillin and Cephalexin

What drugs cross reacts with Amoxicillin?

Amoxicillin and Cephalexin

What drugs cross react with Ampicillin?

Amoxicillin and Ampicillin

What drugs cross react with Cephalexin?

Cefoxitin, Ceftriaxone, Cefotaxime

What drugs cross react with Cefuroxime?

Penicillin and Cefuroxime

What drugs cross react with Cefoxitin?

Cefuroxime, Cefotaxime, Cefepime, Ceftazidime

What drugs cross react with Ceftriaxone?

Cefuroxime, Ceftriaxone, Ceftazidime

What drugs cross react with Cefotaxime?

Ceftriaxone

What drug cross reacts with Cefepime?

Ceftriaxone and Cefotaxime

What drug cross reacts with Ceftazidime?

-Optimal vs. permissible therapy

-ADEs

-Outcomes

Why should you clarify allergies?

•What allergies do you have? (all allergies should be noted)

•What happened when you took this/these medications?

•How did you take the medication? (note route)

•When did you have these reactions? (in your lifetime)

•When did you have the reaction, relative to the first dose?

•How many doses did you have before seeing the reaction?

•Were you taking any other medications at the same time?

•Were you exposed to other allergens at the same time?

•How did you manage the reaction? (self-care versus seek help)

•What happened when you stopped taking the medication?

•Have you taken that medication again since then? Did you tolerate it?

•Have you taken any similar medications since then? Did you tolerate it/them?

What questions should you ask when assessing an antimicrobial allergy?

Category A FDA Pregnancy Category

adequate and well controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters)

Category B FDA Pregnancy Category

Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well controlled studies in pregnant women

Category C FDA pregnancy category

Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well controlled studies in humans but potential benefits may warrant use of the drug in pregnant women despite potential risks

Category D FDA pregnancy category

there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks

category X FDA pregnancy category

studies in animals or humans have demonstrated fetal abnormalities and or there is pos evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits

provides information and data but not categories and is required for all new agents, new indications and new package inserts

includes:

pregnancy (labor and delivery)

lactation (nursing mothers)

females and males of reproductive potential

The classification system of pregnancy regulation updates:

-Penicillins

-Cephalosporins

-Carbapenems

-Vancomycin

-Clindamycin

-Daptomycin

-Fidaxomicin

-Metronidazole

What are the safe antimicrobials in pregnancy?

-Aminoglycosides

-Fluoroquinolones

-Tetracyclines

-Clarithromycin

-Lipoglycopeptides

What are the antimicrobials that we have concerns with use?

Aminoglycoside concerns with pregnancy

-Hearing loss, particularly in first trimester

-Particularly with streptomycin

-Others okay for short-term use

Fluoroquinolone concerns with pregnancy

-Animal studies: renal toxicity, cardiac defects, CNS toxicity, bone and cartilage damage

-Avoid use unless benefit outweighs risks

Macrolides: Clarithromycin concerns with pregnancies

-Cardiac abnormalities, particularly in first trimester

-Use clarithromycin/erythromycin with caution and only if benefit outweighs risks

-Azithromycin is generally safe

Tetracyclines concerns with pregnancy

-Congenital defects, discoloration of bones and teeth

-Avoid in pregnancy

Lipoglycopeptides concerns with pregnancy

-Limb and skeletal malformations and fetal weight loss

-Particularly with televancin

-Avoid unless benefit outweighs risks

Oxazolidinones concerns with pregnancy

-Decreased fetal body weight

-May use if benefit outweighs risks

Bactrim concerns with pregnancy

-1st trimester: Major congenital malformations

-After 32 weeks: kernicterus

-Avoid in first trimester and after 32 weeks gestation

-Acyclovir

-Valacyclovir

-Famciclovir

What are the antivirals that are generally safe in pregnancy?

-Cidofovir

-Ganciclovir

-Foscarnet

-Amantadine & Rimantadine

What drugs do we have concerns with use in pregnancy?

Cidofovir specific concerns with pregnancy

-Soft tissue and skeletal abnormalities

-Avoid unless benefits outweigh risks

Ganciclovir specific concerns with pregnancy

-Embryo death, growth retardation, cleft palate, aplastic organs, hydrocephaly

-Use with caution and only if benefits outweigh risks

Foscarnet specific concerns with pregnancy

-Skeletal abnormalities (bone and teeth growth)

-Use with caution

Amantadine and Rimantadine specific concerns with pregnancy

-Embryotoxic at high doses, birth defects in first trimester

-Only use if benefits outweigh risks

Neuraminidase inhibitors special concerns

-Hypoglycemia after birth

-Seen with oseltamivir, but likely is acceptable to use

Amphotericin

What antifungal is generally safe in pregnancy?

Azole and Flucytosine

What antifungals are concerns in pregnancy?

Fluconazole specific concerns in pregnancy

-Skeletal, cranial, and functional abnormalities, spontaneous abortion,

-Pregnancy category D (Avoid) except for vaginal candidiasis (C)

-Contraindicated at doses higher than 300 mg

-Avoid even low doses in first trimester

Itraconazole specific concerns with pregnancy

-Spontaneous abortion

-Avoid, especially in first trimester

-Use contraception for 2 months following use

Voriconazole specific conerns in pregnancy

-Reduced fetal weight, skeletal abnormalities

-Lack of human data, so contraindicated in pregnancy unless benefits outweigh risks

Posaconazole specific concerns with pregnancy

-Skeletal malformations (cranial malformations, missing ribs)

-Avoid use in pregnancy

-Use contraception for 2 months following use

Isavuconazole specific concerns with pregnancy

-Increase in perinatal mortality

-Use only in life-threatening situations when benefits outweigh risks

Echinocandins specific concerns with pregnancy

-Embryotoxic in rats and rabbits (ossification of bones, misaligned ribs, retrocaval ureters, dilation of ureter)

-Use only when benefits outweigh risks

Flucytosine specific concerns in pregnancy

-Teratogenic in rats (vertebral fusions, cleft lip and palate, micrognathia)

-Contraindicated, use only if benefits outweigh risks

Piperacillin/Tazobactam

Which antimicrobial would be SAFEST/MOST APPROPRIATE for use in a pregnant patient?

A. Posaconazole

B. Ganciclovir

C. Sulfamethoxazole/trimethoprim

D. Piperacillin/Tazobactam

-plasma protein binding

-lipophilicity

-size impact

What impacts whether the antimicrobial is transferred to breast milk?

decreases; increases

-Higher plasma protein binding ___________ transfer, but higher milk protein binding ___________ transfer.

high

_______ lipophilicity increases milk transfer.

decreases

High molecular weight _______ transfer.

lactation

amount is usually reported as milk to plasma ratio

Metronidazole specific concerns with lactation

discontinue BF for 12-24 hours

Tetracyclines specific concerns with lactation

should not be excreted in huge concentrations but risk of issues with tooth development

-lipoglycopeptides

-oxazolidinones

-polymyxins

What antimicrobials have limited lactation information?

antifungals specific concerns with lactation

-limited information for all antifungals

fluconazole

What is the azole of choice for breastfeeding?

famciclovir specific concerns for lactation

it has limited information

Fluoroquinolone with pediatric use

•Not routinely first-line

•Weight benefits and risks

•Levofloxacin: PI says >50 kg and > 6 months

•Moxifloxacin: PI says no information, drug information resources provide guidelines for > 3 months (anthrax,TB)

Tetracyclines in pediatrics

Use in < 8 years reserved for severe, life-threatening infections or where better alternatives are unavailable

Daptomycin use in pediatrics

Avoid use < 12 months

Chloramphenicol use in pediatrics

Follow serum concentrations, only use when less toxic agents are unavailable or resistant

Posaconazole use in peds

PI provides dosing ≥ 18 years

Baloxavir use in peds

Approved in children >12 years

Zanamivir use in peds

Approved in children > 7 years

hepatic elimination physiologic alterations

fatty infiltration may decrease CYP 3A4 isoforms, increase phase II reactions/metabolism

renal elimination physiologic alterations

some indication that obesity may increase glomerular filtration (increased number or size of nephrons)

volume of distribution physiologic alterations

•no correlative with body weight

-Hydrophilic drugs correlate to lean body mass

-Lipophilic drugs correlate to total body weight

total body weight

assumes everything increases proportionally with weight; overestimates CrCl

ideal body weight

doesnt account for body types

lean body weight

also called adjusted body weight

body mass index

doesnt distinguish fat/muscle/bone

body surface area

non-linear, disproportionate increase in surface area for given increase in total body weight