Antibiotics for PAs - Part I

Antibiotics for Physician Assistants - Part I

Updated: 08/07/2016

• Empiric therapy is defined as the initiation of treatment prior to firm diagnosis, and knowing the specific organism causing the infection
• Started only after cultures have been obtained
• Targets likely pathogens and must use local antibiogram
• Broad spectrum means covering both gram positive and gram negative bacteria
• Pharmacokinetics: what the body does to a drug
• Absorption: described in terms of bioavailability (F)
• 100% bioavailable drugs (PO = IV): Linezolid, Fluoroquinolones, Tetracyclines, Azithromycin, Metronidazole, Trimethoprim/Sulfamethoxazole (Bactrim), Rifampin
• Distribution: affected by protein binding, blood flow, molecular size, lipophilicity, inflammation, and fluid status
• Metabolism: occurs primarily in the liver via multiple mechanisms
• Phase I: oxidation/reduction (CYP 450), hydrolysis
• Phase II: glucuronidation, sulfonation, methylation, acetylation, glutathione
• Elimination: primarily renal (glomerular filtration and tubular secretion)
• Most antibiotics require dose adjustment for creatinine clearance (CrCl) <50 mL/min

Cell Wall Synthesis Inhibitors

Beta Lactams

(Penicillins, Cephalosporins, and Carbapenems)

Penicillins

• MOA: binds to penicillin binding proteins on surface of cell wall and inhibits cell wall synthesis
• Variable PO absorption, short half lives (frequent dosing), primarily renally eliminated

	Indications	Dose	Pearls
Penicillin G	Streptococcal infections Syphilis Staph aureus (susceptible)	IM/IV: 3-4 million units q 4 hours	Continuous infusion over 24 hours if normal renal function
Penicillin G Benzathine	Syphilis	IM: 2.4 million units x 1 (primary, secondary, early latent) IM: 2.4 million units weekly (late latent, latent of unknown duration)	IM injection Longer acting
Penicillin V Potassium (VK)	Actinomycosis Erysipelas Streptococcal Pharyngitis	PO: 250-500 mg q 6 hours
Anti-staphylococcus or Penicillinase Resistant Oxacillin (IV), Nafcillin (IV), Dicloxacillin (PO)	Methicillin-susceptible staph aureus (MSSA) Narrow spectrum gram (+) coverage Staphylococcal skin/soft tissue infections (mastitis)	2 grams q 4 hours	Continuous infusion over 24 hours if normal renal function May increase warfarin requirement (drop INR)

Aminopenicillins: gram negative and positive coverage

	Indications	Dose	Pearls
Ampicillin	E. coli Proteus (K. pneumoniae intrinsically resistant) Listeria Enterococcus: gram (+) cocci in pairs; faecalis Streptococcus: gram (+), viridans, pyogenes, pneumoniae, agalactiae	IV: 2 grams q 4-6 hours PO:	Gram positive and negative coverage (limited)
Ampicillin/Sulbactam [Unasyn]	Similar to Ampicillin Better Gram (-) coverage Acinetobacter Anaerobes: E. coli Skin/soft tissue infections, intraabdominal and peritonitis	IV: 3 grams q 4-6 hours
Amoxicillin	Similar to Ampicillin UTI in pregnancy, AOM	PO: 500-1000 mg q 8-12 hours	Lower bioavailability than IV ampicillin (greater than PO ampicillin) Gram positive and negative coverage (limited)
Amoxicillin/ Clavulanate [Augmentin]	Similar to Amoxicillin Better Gram (-) coverage Anaerobes (not Acinetobacter): E. coli, Salmonella, Shigella, Campylobacter, H. pylori, Klebsiella AOM, sinusitis, dental infections, bites	PO: 250-500 q 8 hours OR PO: 875 mg q 12 hours

Antipseudomonal Penicillins

	Indications	Dose	Pearls
Piperacillin/ Tazobactam (Zosyn)	MSSA Empiric or definitive therapy for Pseudomonas aeruginosa Anaerobes Enterococcus: gram (+) cocci in pairs; faecalis Streptococcus: gram (+), viridans, pyogenes, pneumoniae, agalactiae	IV: 3.375-4.5 g q 6-8 hours	Can be given extended infusion (over 4 hours) or continuous infusion Zosyn and Cefepime are the empiric broad spectrum agents of choice at most institutions No atypical coverage (Legionella, Mycoplasma, Chlamydia)

Cephalosporins

• As you increase generation, you generally add greater gram negative coverage, but lose gram positive coverage
• Cross-reactivity in patients with penicillin allergy: 10%
• If patient has had true IgE mediated (anaphylaxis) reaction, avoid all B-lactams including Carbapenems (Exception: can give aztreonam)

	Indications	Dose	Pearls
First Generation Cefazolin (Ancef) Cephalexin (Keflex)	Staphylococcus: aureus, epidermidis, haemolyticus, saprophyticus Streptococcus: gram (+), viridans, pyogenes, pneumoniae, agalactiae Aerobic GRN: M. catarrhalis, E. coli, K. pneumoniae Skin and soft tissue infections, surgical prophylaxis, ENT: Streptococcal pharyngitis GU: UTI Pediatric osteomyelitis	IV: Cefazolin 1-2 g IV q 8 hours PO: Cephalexin 250-500 mg q 6 hours (good absorption)	No CSF penetration
Second Generation Cefuroxime (Ceftin PO, Zinacef IV/IM) Cefoxitin (Mefoxin)	Aerobic GNR: H. flu, M. cat, N. meningitidis Anaerobes: E. coli Skin/soft tissue infections GU: UTI Pulm: Mild CAP (3rd Gen preferred), acute chronic bronchitis exacerbation ENT: sinusitis, AOM Surgical prophylaxis (GI/GU) Abdominal infections	PO: Cefuroxime axetil 250-500 mg q 12 hours IV: Cefuroxime 1.5 g q 8 hours IV: Cefoxitin 1-2 grams q 4-6 hours
Third Generation Ceftriaxone (Rocephin) Cefotaxime (Claforan) Ceftazidime (Fortaz, Tazicef)*	Improved Anaerobic GNR: E. coli, Klebsiella, P. mirabilis, S. pneumoniae MSSA coverage *Ceftazidime: Pseudomonas Ceftriaxone: Meningitis Gonorrhea, CAP	IV/IM: Ceftriaxone 1-2 g q 24 hours (2 g q 12 for meningitis) IV: Cefotaxime 1-2 g q 4-8 hours IV: Ceftazidime 1-2 g q 8 hours	Ceftriaxone - good CNS penetration (higher dose)
Fourth Generation Cefepime (Maxipime)	Empiric or definitive therapy against Pseudomonas aeruginosa Febrile neutropenia	IV: 1-2 grams q 8-12 hours	Unlike Zosyn, no anaerobic or enterococcus activity Less gram positive coverage than lower generations
Fifth Generation Ceftaroline (Teraflo, Zinforo)	GN coverage similar to ceftriaxone Streptococcus Staphylococcus (MRSA)	IV: 600 mg q 8-12 hours

Monobactams

Aztreonam

Gram negative only Pseudomonas

IV: 2 grams q 6-8 hours

No cross-reactivity with other beta-lactams

Carbapenems

Ertapenem	Gram negative coverage: ESBL producing Enterobacteriaceae Streptococcus MSSA Anaerobes	IV: 1 g q 24 hours
Meropenem	Same as Ertapenem Pseudomonas aeruginosa Acinetobacter Enterococcus	IV: 1 g q 8 hours IV: 2 g q 8 hours (CNS)	Broad spectrum activity, limit activity
Imipenem/Cilastatin Primaxin	Similar to Meropenem Nocardia Nontuberculous mycobacterial organisms	IV: 500 mg q 6 hours	Imipenem is rapidly inactivated by renal dehydropeptidase I (DHP-1), cilastatin is a DHP-1 inhibitor that allows for a prolonged half life and increased tissue penetration

Adverse Effects of Beta Lactams

• Hypersensitivity
• Cross reactivity of cephalosporins is <10%
• Avoid all beta-lactams for anaphylactic reactions, including carbapenems
• Exception: can give aztreonam
• Seizures: higher risk with carbapenems
• Highest when not renally-dosed
• Nafcillin, oxacillin, and ceftriaxone - only beta-lactams that do not require renal adjustment
• Electrolyte Imbalance (Na and K): most often with salts (penicillin G potassium or nafcillin sodium)

Other Bacterial Cell Wall Agents

• Binds to the D-ala-D-ala terminus of the peptidoglycan molecule preventing cross linking of the chains by penicillin binding protein → weakens cell wall and causes osmotic lysis

Vancomycin (Vancocin)

Aerobic gram (+): MRSA, MSSA, S. pneumoniae Anaerobic gram (+) Empiric therapy when MRSA suspected, MDRS in CA meningitis, severe infections with MRSA, CoNS, Enterococcus resistant to ampicillin Sepsis, meningitis, pneumonia, infective endocarditis

Loading dose of 25 mg/kg in critically ill patients Maintenance dose: 15 mg/kg based on TBW Frequency based on renal function (most q 12)

No gram (-) activity PO formulation for C. difficile due to poor absorption Bactericidal, slower than B-lactams Bacteriostatic against Enterococcus Trough levels used to determine efficacy and nephrotoxicity (goal: 15-20) SCr: baseline and every 3-4 days

Bacitracin (BACiiM, Bacitracin)

Gram (+) and Gram (-) activity Staphylococcal pneumonia, aureus, epidermidis Streptococcus pyogenes

IM Topical

Decreased incidence of cross reaction with sulfa drugs when not combined with polymyxin B and neomycin

Cyclic Lipopeptide

• Calcium-dependent insertion of lipid tail leading to disruption of cell membrane and cell death

Daptomycin (Cubicin)

MDRS and gram (+) MRSA, MSSA, VRE, S. pneumoniae, another streptococcal spp. Must have failed or had intolerant response to vancomycin

IV (skin/soft tissue): 4 mg/kg daily All other: 6-8 mg/kg daily, based on TBW

No gram negative activity Not for use in pneumonia (lung surfactant binds the drug) Monitor CPK at baseline and weekly

Phospholipid Membrane Inhibitor

• MOA: Bind to outer membrane of GN bacteria leading to disruption of membrane instability and leakage of cellular contents

Polymyxin Colistin (colistimethate sodium)

Highly resistant GNR, including Pseudomonas and Klebsiella Acinetobacter CRE: Carbapenem resistant Enterobacteriaceae Multidrug resistant GN infections: pneumonia, bacteremia, sepsis, complicated UTIs

IM, IV Ophthalmic Topical

Poor gram (+) coverage and anaerobic coverage

Question 1: What determines if a bacterial organism is gram negative or gram positive?

Question 2: Why isn’t a beta lactam antibiotic or other agent that inhibits cell wall synthesis used for young healthy people with community acquired pneumonia?

Question 3: Which of the following antibiotics provides the best activity against gram negative bacteria?

1. Daptomycin (Cubicin)
2. Clindamycin (Cleocin)
3. Rifampin
4. Aztreonam

Question 4: Which pair of medications does not have cross-reactivity?

1. Linezolid and SSRIs
2. Aztreonam and Penicillin G
3. Daptomycin and Statin
4. Erythromycin and Warfarin

Answer 1: Gram positive organisms have a peptidoglycan layer

• Gram negative organisms have a thick polysaccharide layer

Answer 2: Atypicals do not have a cell wall

• See Introduction to MIB

Answer 3: D, the rest have gram positive coverage

Answer 4: B, both are Beta lactams