Pharmacology Antibiotics

Front 1

Antibiotic Selection Process

Back 1

I. Antibiotic Selection Process
a. Establish the Presence of an Infection
i. Signs and sxs
ii. Predisposing Factors
iii. R/O malignancy, autoimmune, med rxn
b. Identify the Site of Infection
i. Burning and frequency of urination- UTI
ii. Cough and sputum production- URI
iii. Redness and swelling on skin- cellulitis
c. Direct Empiric Antibiotic Therapy Towards Likely Organism
i. Identify the primary pathogens
1. Gram Stain: - or + stain, shape
2. Cultures and Sensitivities will tell you what they are susceptible or resistant to, indentify the organism and the minimum inhibitory concentration (MIC)

Front 2

Factors in Choosing an Antibiotic

Back 2

i. Choose appropriate antibiotic for the pathogen, site of infection and the patient
1. Pathogen: antimicrobial spectrum of activity, susceptibility testing, local susceptibility patterns
2. Drug Factors: clinical efficacy, pharmacokinetics of drug
3. Patient Factors: age, hepatic/renal fx, allergies, pregnancy, cost

Front 3

Fever

Back 3

a. Fever:
i. Hallmark of infectious dz, but not always present (URI)
ii. Other causes: autoimmune dz, malignancy, drugs/drug fever
1. Any drug can cause a fever- B-lactam abx, anticonvulsants, fever will disappear 48hrs once medication is stopped
2. Antipyretics can mask response to therapy

Front 4

WBC

Back 4

a. WBC:
i. Increased WBC- but can increase in other situations (major surgery, MI, leukemia, ccstds)
ii. WBC may be normal (UTI) or low (neutropenia)
iii. Left shift presence of immature WBCs indicates bone marrow response to infections

Front 5

Other Signs/Symptoms of Infection

Back 5

a. Other
i. Bilateral infiltrates on CXR
ii. Copious amounts of yellow-green secretions from ET tube
iii. Erythema surrounding CVC
iv. Increased ESR (not specific to infection)- inflammatory response
v. Confusion
vi. WBCs found in urinalysis

Front 6

Sepsis/Septic Shock

Back 6

Decreased BP, Glucose intolerance, tachypnea, tachycardia, DIC- increased PIT count and increased thrombin tone, decreased urine output

Front 7

Identification of a Pathogen

Back 7

I. Identification of Pathogen
a. Obtain samples prior to abx therapy, perform blood cultures in all acutely ill/febrile pts
b. Gram Stain: gram - = red, gram + = violet

Front 8

Special Considerations for Culture Results

Back 8

a. Special Considerations for Culture Results
i. Colonization: the isolated organisms are from the specimen, but are not causing sxs
ii. Infection: the isolated organisms are from the specimen and causing the infection
iii. Contamination: the isolated organisms came form the pt’s skin or environment
iv. Presence of epithelial cells= probably a bad sample, skin contaminants if S. epidermidis or Corneybacterium
v. Cultures and Sensitivities:
1. Provide final identification and effectiveness of antimicrobials
2. Results in 24-48 hours

Front 9

Pathogen Considerations

Back 9

I. Pathogen:
a. Must consider spectrum of activity, susceptibility testing, local susceptibility patterns
b. Minimum Inhibitory Concentration (MIC)- lowest antimicrobial concentration that prevents visible growth of an organism
c. Susceptible: you can get enough drug into the patient to treat the infection (MIC < attainable serum levels)
d. Intermediate: you may or may not be able to tx infx – if drug is safe enough to give in high doses or if drug concentration works well at infection site (MIC = attainable serum levels)
e. Resistant: you cannot get enough drug in this pt to treat the infx (MIC > attainable serum levels)

Front 10

Drug Factors

Back 10

I. Drug Factors:
a. Clinical efficacy- can it actually reach the infx
b. Pharmacokinetics and dynamics will determine dose and dosing intervals
i. Time Dependent Killers: killing is dependent on time organism is in contact with the drug (B-lactams, vancomycin)
ii. Concentration Dependent Killers: killing is dependent on concentration of drug (fluroquinolones, aminoglycosides)
c. Synergy- use of two antibiotics together provides synergistic effects
d. Post antibiotic Effect- organism growth is suppressed for a period of time after the drug concentration falls below MIC
e. Also: antimicrobial spectrum of the antibiotic, available routes of administration, cost, drug interactions, evidence of efficacy with type of infection, safety in certain populations (renal failure, pregnancy)

Front 11

Patient Factors

Back 11

I. Patient Factors:
a. Age
i. Elderly- decrease in functioning nephrons leads to decrease in renal function
ii. Neonates- may experience kernicterus after sulfonamide administration
b. Hepatic/Renal impairment- may require dosage adjustment
c. Allergies- confusion, usually PCN or related, if allergic rxn was anaphylaxis – best to avoid cephalosporins and carbapenems also if possible
d. Pregnancy- medications may be cleared 50% faster (increase dose), also chek for teratogenic medications
e. Cost- newer antibiotics are more expensive but not more effectives, some meds require more monitoring (more expensive)
f. Route of Administration- PO is preferred, IV if severe, most can switch to PO once stable
g. Concomitant medications- for drug interactions (warfarin, OCP)
h. Compliance Considerations: # of doses per day can affect

Front 12

Antibiotic Resistance

Back 12

I. Antibiotic Resistance
a. Intrinsic: naturally occurring based on the nature of the drug
b. Acquired Resistance: normally sensitive organism becomes resistant
i. Detoxifying enzymes can alter abx structure and function (ex. Beta-lactamase breaks down beta-lactam ring of PCN abx)
ii. Alteration in abx target site (ex. Alteration of PCN binding protein
iii. Decreased cellular accumulation of antibiotic (impaired influx- decreased permeability, enhanced efflux)

Front 13

IV Administration

Back 13

I. IV Administration
a. IV most often used for severe infx (meningitis, sepsis, osteomyelitis)
b. When can’t tolerate PO or has non-functioning GI tract
c. Many oral abs have great bioavailability and should be given PO

Front 14

Advantages to Oral Antibiotics

Back 14

I. Advantages to Oral Administration
a. Decreased cost, pts prefer it
b. Utilizes less resources, decreases personnel time
c. Reduce exposure of nosocomial pathogens through IV site
d. Reduced risk of phlebitis, better pt mobility and discharge

Front 15

Beta Lactams

Back 15

Penicillins, Cephalosporins, Monobactams

MOA: bind to PCN binding proteins and inhibit cell wall synthesis causing cell death

Front 16

Penicillins- Adverse Reactions

Back 16

i. Adverse Reactions: rash (maculopapular or uticarial, usually with mono), anaphylaxis, angioedema, interstitial nephritis (esp methicillin and nafcillin- reversible), Positive Coombs test with hemolytic anemia, leukocytopenia/thrombocytopenia, C. diff with colitis, Jarish Herxheimer Rxn (spirochetal infx- toxins released when bacteria die- flu like sxs), Augmentin- GI upset, nafcillin/oxacillin- reversible hepatitis

Front 17

PCN Allergy

Back 17

i. Penicilin Allergy: few that are claimed have positive skin test, obtain detailed description (should be a quick reaction) and what has been tolerated in the past
1. Management:
a. Administer cephalosporin if rxn was non-life threatening
b. Prescribe/recommend a non beta-lactam antibiotic (macrolide, quinolone, sulfonamides, vancomycin)
c. Penicilin Desensitization: in ICU, up dose slowly until full dose
d. Perform PCN skin test

Front 18

PCN Special Considerations

Back 18

a. Penicillins
i. Special Considerations: monitor renal/hepatic fx and CBC, administer PCN, Amp and dicloxacillin on empty stomach,
1. Interactions with probenicid and methotrexate (higher levels)
2. OCP interaction is unsure- definitely with Rifampin

Front 19

Natural PCN (PCN VK-oral, PCN G- IV)

Back 19

Gram Positive

MC for pharyngitis, erysipelas, syphillis (not effective for staph because they produce PCNase)

Front 20

Aminopenicillins (ampicillin, amoxicillin- MC)

Back 20

Gram Positive and Gram Negative

Amox- URI, H.pylori, drug choic for suscepticble enterococcal infections

Augmentin- skin infx, UTI, CA Pneumonia, lymphadenitis

Front 21

PCN resistant PCN

Back 21

Dicloxacillin, Nafcillin-IV, Oxacillin- IV

Gram Positive- staph & strep

Drug of choice for B-lactamase producing staph

Tx cellulitis, mild-mod diabetic foot infx, septic arthritis, endocarditis

Front 22

Extended-spectrum PCNs

Back 22

Ticarcillin/clavulanate and Piperacillin/tazobactam

Gram positive & gram negative & anaerobes

nosocomial pneumonia, intra-abdominal infx, skin and soft tissue infx

Front 23

Cephalosporins

Back 23

i. 1st Gen- Cephalexin (oral), Cefazolin (IV)
ii. 2nd Gen- Cefuroxime (oral), Cefoxitin (IV)
iii. 3rd Gen- Cefpodoxime (oral), Ceftriaone (IV)
iv. 4th Gen- Cefepime (IV)
v. Newer Gen- ceftaroline (IV)- only B- Lactam that covers MRSA
vi. Cephalosopirn Activity- less susceptible to B-lactamases (broader spectrum, includes Staph), earlier stages are better for gram positive, later generations are better for gram negative
vii. Special Considerations: similar adverse reactions to PCN, monitor renal fx, take with food, probenicid may increase concentrations, use with caution in pts with PCN allergy

Front 24

First Generation Cephalosporins

Back 24

Cephalexin (oral), Cefazolin (IV)

Gram positive, gram negative

UTI, pharyngitis, mild skin/soft tissue infx, lower respiratory infx

Front 25

Second Generation Cephalosporins

Back 25

Cefuroxime (oral), Cefoxitin (IV)- has anaerobic coverage

Gram positive and negative, falling out of favor

sinusitis, pharyngitis, OM, lower respiratory infx

Front 26

Third Generation Cephalosporins

Back 26

Cefpodoxime (oral), Ceftriaone (IV)

Gram positive and negative

CA pneumonia, OM, URI, meningitis, febrile neutropenia

Ceftrazidime has Pseudomonas coverage

Front 27

Fourth Generation Cephalosporins

Back 27

Cefepime (IV)

Gram positive (strep), Gram NEgative, Anaerobes

Meningitis, febrile neutropenia, pneumonia, nosocomial infx, pyelonephritis

Front 28

Monobactams (Aztreonam)

Back 28

i. Gram – coverage only (includes pseudomonas)
ii. Good for resistant infections, resistant to many beta-lactamases,
iii. No cross sensitivities with allergies to PCN
iv. IV or IM admin, doses adjusted for renal function, low incidence of adverse effects (diarrhea)

Front 29

Carbapenems

Back 29

ICarbapenems (imipenem/cilastatin, meropenem, doripenem, ertapenem)

a. Resistant to most beta-lactamases, drug of choice for infectiosn caused by extended spectrum b-lactamases

b. Coverse strep, staph, listeria, gram -, anaerobes, pseudo (except ertapenem)

c. Dose adjust for renal function, cross sensitivity with PCN allergy, adverse effects like N/V and seizures (imipenem with renal failure)

d. UTI, Lower RI, intra-abdominal, gyno infx, skin, soft tissue, bone, joint

e. Imipenem is combined with cilastatin to prevent breakdown by renal enzymes

Front 30

Glycopeptide Antibiotics

Back 30

(Vancomycin and Telavancin- out of favor)
a.1st line for MRSA, gram + only, sepsis, endocarditis, meningitis, skin/soft tissue

b. Oral is not absorbed (C. diff only), dose based on body weight and renal function

c. Monitor serum levels (should be 10-20, < 10 is bad)

d. Adverse rxns: ototoxicity, nephrotoxicity (increased with other nephrotoxic drugs), injection site reaction

e. Red Man Syndrome: infusion related reaction caused by release of histamine, urticarial rxn, flushing, tachycardia and hypotension (NOT an allergic reaction)
Treat by stopping, wait for rxn to subside, then slow infusion rate down 1gm/hr or less, may administer Benadryl before

Front 31

Other Cell Wall/Membrane Active Agents

Back 31

Datptomycin, Fosfomycin, Bacitracin, Cycloserine

Front 32

Daptomycin (IV)

Back 32

a. Daptomycin (IV): similar to vanco, but covers VRE and VRSA, used for skin/soft tissue, bactremia and endocarditis,
i. Dose adjust for renal function
ii. Adverse effects: injection site rxn, fever, chills, diarrhea, N/V
iii. Muscle cramps and weakness may occur- check CPK and d/c if CPK >5x ULN

Front 33

Fosfomycin

Back 33

a. Fosfomycin: oral, gram – and +, used for UTis in women, 3 g dose

Front 34

Bacitracin

Back 34

a. Bacitracin: highly nephrotoxic so only used topically, used to treat surface lesions on skin or irrigation of wounds, joints

Front 35

Cycloserine

Back 35

a. Cycloserine: covers gram + and -, but is mainly used for resistant TB (serious adverse events: headaches, tremors, acute psychosis)

Front 36

Tetracyclines- drugs, MOA

Back 36

Tetracycline • Minocycline • Doxycycline
• Mechanism of action:
• Tetracyclines bind to the 30 S ribosomal subunit, which prevents binding of tRNA to the mRNA- ribosome complex, thus interfering with protein synthesis

Front 37

Tetracyclines- coverage and uses

Back 37

Gram positive, gram negative, atypicals

Respiratory infections, community acquired MRSA, acne

doxy- anthrax, chlamydia, lyme

demeclocycline- used for SIADH not bacterial infx

Front 38

Tetracycline Adverse Effects

Back 38

GI intolerance
Photosensitivity
Tooth discoloration and abnormal bone growth (not during pregnancy or < 8yrs)
Vestibular toxicity with minocycline (dizziness, ataxia, N/V)- goes away after d/c

Front 39

Special Considerations

Back 39

Admin separate from Al, Mg, Ca & Fe by 1-2 hrs

Food- tetra (empty), doxy (food, bad GI)

Monitor: renal, hepatic, CBC, hematology if long term

Front 40

Tigecycline

Back 40

IV only, Glycylcycline antibiotic, Derivative of minocycline

Covers Gram positive, Gram negative and anaerobes

Indicated for complicated skin and skin structure infections and complicated abdominal infections, community acquired pneumonia.

Has efficacy vs. MRSA, MRSE (staph epidermidis), VRE, and penicillin resistant Streptococcus pneumoniae

Phase 3 and 4 clinical trials have shown and increase in all cause mortality- mainly used for salvage therapy (last ditch)

Front 41

Macrolides- drugs and MOA

Back 41

• Erythromycin • Clarithromcyin • Azithromycin • Fidaxomicin

Mechanism of action • Bind to the 50 S ribosomal subunit, inhibiting
bacterial protein synthesis

Front 42

Macrolides- coverage and uses

Back 42

Erythro, Clarithro, Azithro-
Gram + strep, Gram negatives, atypicals
Alt for PCN allergy, CA Pneumonia, skin/soft tissue
azithro- urethritis, decreased COPD exacerbations, but increased resistance

Fidaxomicin- just for C. Diff

Front 43

Macrolides Adverse Rxns

Back 43

Nausea/vomiting (25% with erythromycin) • Abdominal pain • Diarrhea • Renal failure
• QT prolongation (risk erythromycin > clarithromycin > azithromycin)
• Azithromycin- Cardiovascular risk? • 2012 NEJM study being evaluated for potential risk

Front 44

Fidaxomicin Adverse Rxns

Back 44

Gastrointestinal most common – Nausea 11% – Gastrointestinal hemorrhage 4% – Vomiting
– Abdominal pain •

Hematologic (rare)
– Anemia, neutropenia

Front 45

Macrolides Special Conciderations

Back 45

Pregnancy B/C for clarithro

Azithro before or after meal

azithro has best compliance- once daily, erythro 4x/day

lots of drug interactions for erythro and clinda (cyp450)

Front 46

Clindamycin- coverage and uses

Back 46

Gram positive (MSSA and MRSA), Anaerobes

Skin and soft tissue (MRSA- rapid resistance), anaerobic infx, aspiration pneumonia, alt for dental prophylaxis if PCN allergic,

Front 47

Clindamycin Adverse Effects & Special Considerations

Back 47

Adverse effects •
GI:Diarrhea,nausea,dyspepsia • Skin rashes • Higher incidence of Clostridium difficile vs other antibiotics • Hepatotoxicity • Back pain: vaginal clindamycin

Food: • AdministrationwithfooddecreasesGIupset • Administrationwithafullglassofwaterdecreases
esophageal ulceration

Pregnancy Category B

Front 48

Linezolid- coverage and use

Back 48

Gram positive only (includes vanco and methacillin resistant)

resistant infx like MRSA or VRE, skin/soft tissue infx, bone/joint infx, bacteremia, pneumonia

Front 49

Linezolid Special COnsiderations

Back 49

Pregnancy category C
Good pulmonary penetration •

Exhibits weak reversible inhibition of monoamine oxidase

Use caution when giving to patients taking SSRI- close monitoring is required

Avoid high tyramine containing foods

Thrombocytopenia 30% (reversible) and peripheral or
optic neuropathy (not or only partially reversible)

Thrombocytopenia more common in patients with renal failure and prolonged treatment durations (> 2weeks) •

Oral formulation has 100% bioavailability (expensive)

May be preferable in PVL producing CA-MRSA strains

Front 50

Aminoglycosides (IV only)- drugs and MOA

Back 50

• Gentamicin- IV • Tobramycin- IV • Amikacin-IV • Streptomycin-IV- rarely used • Neomycin- topical only except as prep for bowel surgery (PO) and hepatic encephalopathy (PO)(second line) • Kanamycin- topical only

• Mechanism of action- inhibits protein synthesis by binding to the 30S ribosomal subunit

Front 51

Aminoglycosides- coverage and uses

Back 51

Genta, tobra, amkacin

gram positive, aerobic gram negative bacilli

UTI, pneumonia, meningitis, synergy with PCN or vanco for bacterial endocarditis

Front 52

Aminoglycosides- Adverse Rxns

Back 52

•
Ototoxicity-vestibular(vertigoandataxia) and auditory (tinnitus and high frequency hearing loss)- usually not reversible
•
Nephrotoxicity- rise in Scr –although an increase in trough concentration will be the first sign.
•
Ototoxicity and nephrotoxicity usually only occur when duration of therapy is > 5 days, in the elderly, or in patients with impaired renal function.

Front 53

Aminoglycosides- Dosing

Back 53

•
Dosing and dosing intervals are variable- depends on indication and renal function- Doses are weight based
•
Two dosing methods- – conventional (usually q8 or q12h) or – traditional and extended interval dosing (q24, q36h)
•
Both methods require monitoring of renal function and serum drug concentrations at least every few days.

Front 54

Benefits of Extended Interval Dosing

Back 54

Benefits of extended interval dosing:
– probable reduced nephrotoxicity
– decreased lab monitoring- do not need to measure peaks
– no risk of having a sub-therapeutic peak level – decreased pharmacy time for preparation – decreased nursing time for administration – easier for home care doses

Extended interval dosing can be used for most Gram negative infections and some Gram positive.

Front 55

Sulfonamides- rxs and MOA

Back 55

• Sulfisoxazole • Sulfamethoxazole/ trimethoprim (bactrim) • Sulfadiazine • Sulfasalazine
•
MOA
• Competitive antagonists of para-aminobenzoic acid (PABA)- which prevents formation of folic acid
• Only works on bacteria that synthesize their own folic acid

Front 56

Sulfonamides (coverage and uses)

Back 56

Sulfisoxazole, sufla/trim (bactrim)

Gram positive, gram negative, atypical

UTI, toxoplasmosis, sulfa-tri= 1st line for CA MRSA, PCP pneumonia (tx and prophylax), URI, UTI

Sulfasalazine- UC, enteritis, IBS

Front 57

Sulfonamides- ADR

Back 57

Both need Cr testing, Bactrim BAD if low Cr <15, Pregnancy Category C

Photosensitivity

Nausea/vomiting/diarrhea

Dermatologic Rash – Steven -Johnsons syndrome or toxic epidermal necrosis (TENS)- fever and flu like symptoms, blistering and rash on skin and mucous membrane- very rare

Blood dycrasias aplastic anemia, granulocytopenia, thrombocytopenia, hemolytic anemia (in patients with G6PD deficiency)

Nephrotoxicity can occur but is rare (drink water)

“Sulfa” allergies are common

Front 58

Sulfa Allergies

Back 58

Sulfa Allergies
• Cross sensitivity of sulfa allergy with sulfonamide antibiotic and non-antibiotics (e.g. glyburide, celecoxib) being criticized
• Structure that causes the hypersensitivity response in sulfonamide antibiotics (N1 heterocyclic ring) is absent in sulfonamide non- antibiotics
• Association between the two now thought to be due to a predisposition to allergic reactions rather than cross-reactivity

Front 59

Sulfonamides Special Considerations

Back 59

Administration
• Instruct patient to drink plenty of fluids while taking sulfonamides

Numerous drug interactions •
Warfarin- can potentiate the effects (increased
INR) • Methotrexate, phenytoin, digoxin

Front 60

Fluoroquinolones- rxs, MOA

Back 60

• Ciprofloxacin • Ofloxacin • Norfloxacin • Levofloxacin • Moxifloxacin
• MOA: Inhibit bacterial topoisomerase II (DNA gyrase) and IV thereby blocking DNA synthesis

Front 61

Fluoros- Cipro, Oflo, Norflo- coverage and uses

Back 61

Gram negative, atypicals (cipro and oxflo)

Norflox- uncomplicated UTIs

Cipro and oxflo- complicated UTIs, gastroenteritis, prostatitis, STDs, skin infx,

Cipro- anthrax PEP

Front 62

Fluoros- Levo, Moxi, Gatiflox

Back 62

gram positive, gram negative

similar to 2nd generation + CA pneumonia, URI

Moxi is only one not for UTIs

Front 63

Fluoros- ADR

Back 63

Fluoroquinolones- Adverse Reactions •
Nausea/ vomiting/ diarrhea/ constipation
• Tendonitis or tendon rupture- higher risk in elderly, renal insufficiency, and concurrent steroid use
• Photosensitivity • Hepatotoxicity • Hypoglycemia/ hyperglycemia • QT prolongation

Front 64

Fluoros- Special Considerations

Back 64

monitor Cr for all but moxiflxacin, pregnancy category C

Separate from Ca, Mg, Al, Fe, Zn by 2hrs

Wafarin- increases INR, monitor

avoid use with anything that might prolong QT intervals as well (cipro is least likely to be a problem)

Front 65

Metronidazole- coverage and use

Back 65

protozoa and anaerobes

intra abdominal infx, gynecologic infx, pseudomembranous colitis (C.diff), eradicates Hpylori (in combo with others)

Front 66

Metronidazole- Special Considerations

Back 66

no renal adjustment, pregnancy category B

Adverse reactions
• GI: nausea/vomiting, xerostomia (dry mouth), dysgeusia (usually manifest as a metallic taste), anorexia and abdominal pain
• CNS: peripheral neuropathy, seizures, encephalopathy- requires discontinuation of metronidazole

Administration – Extended-release tablets: Administer on an empty stomach at least 1 hour before or 2 hours after meals.

Front 67

Nitrofurantoin- coverage and uses

Back 67

gram positive, gram negative

UTI

Front 68

Nitrofurantoin- ADR/special consideration

Back 68

Do not use in CrCl less than 60mL/min, pregnancy category B

Administration
• Food or milk may enhance GI tolerance •

Adverse effects
• GI- nausea and vomiting • Serious AE with long term therapy- hepatotoxicity and pulmonary toxicity- avoid in elderly •

Drug interactions
– Probenicid increases serum concentrations •

Efficacy
96% of E. coli show susceptibility in vitro to nitrofurantion vs. 87% with Bactrim

Front 69

General Treatment of TB

Back 69

• A minimum of two drugs and usually three or four must be used simultaneously to prevent resistant strains
• Treatment duration is, at minimum, six months and up to two to three years for multidrug-resistant (MDR)TB • Isoniazid and Rifampin are preferred first line agents

Example of regimen:
– Isoniazid x 6 months
– Rifampin x 6 months
– Ethambutol continue for the first 2 months then d/c
– Pyrazinamide continue for the first 2 months then d/c