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22 I INFECTIOUS DISEASES I BACKGROUND & ANTIBACTERIALS BY DRUG CLASS DOSE OPTIMIZATION The pharmacodynamics of select antibiotics are displayed in the figure below. Drugs with concentration-dependent killing ( such as aminoglycosides) can be dosed less frequently and in higher doses to maximize the...

22 I INFECTIOUS DISEASES I BACKGROUND & ANTIBACTERIALS BY DRUG CLASS DOSE OPTIMIZATION The pharmacodynamics of select antibiotics are displayed in the figure below. Drugs with concentration-dependent killing ( such as aminoglycosides) can be dosed less frequently and in higher doses to maximize the concentration above the MIC. Drugs with time-dependent killing (such as beta -lactams) can be dosed more frequently or administered for a longer duration to maximize the time above the MIC. Examples include extending the infusion time of beta - lactam antibiotics (e.g. from 30 minutes to 4 hours) or administering the drug as a continuous infusion. Studies have documented that extended /continuous infusions of beta -lactams reduce hospital length of stay, mortality and costs, particularly when treating pneumonia caused by MDR Gram - negative pathogens like Pseudomonas . ^ - k Cmax:MIC ( concentration dependant ) Aminoglycosides, quinolones, daptomycin ( toxicity ) Goal: high peak ( T killing), low trough I Dosing strategies: large dose, long interval Concentration AUCtMIC Vancomycin, macrolides, tetracyclines, polymyxins Gool: exposure over time Dosing strategies: variable - Time > MIC ( time dependent ) Belo -lacioms (penicillins, cephalosporins, corbopenems) Goal: maintain drug level > MIC for most of the dosing interval Dosing strategies shorter dosing intervol, extended or continuous infusions Time ( hours) . MIC . AUC = area under the concentration - time curve Cmax = maximum plasma concentration MIC = minimum inhibitory concentration BETA- LACTAM ANTIBIOTICS Beta - lactam antibiotics ( penicillins, cephalosporins and carbapenems) have a chemical structure that is characterized by a beta - lactam ring. They inhibit bacterial cell wall synthesis by binding to penicillin - binding proteins ( PBPs). This prevents the final step of peptidoglycan synthesis in bacterial cell walls. Refer to the Learning Basic Science Concepts chapter for details. PENICILLINS Coverage varies by subgroup, or type, of penicillin. As a class, they are not active against MRSA or atypical organisms. Natural penicillins are active against Gram - positive cocci ( Streptococci and Enterococci ; they do not cover Staphylococci ) and Gram - positive anaerobes ( mouth flora ). They have little Gram - negative activity. Aminopenicillins cover Streptococci , Enterococci and Gram - positive anaerobes ( mouth flora ) plus ( with the addition of the amino group) the Gram - negative bacteria Haemophilus , Neisseria, Proteus , E. coli and Klebsiella ( HNPEK ) . Aminopenicillins combined with beta -lactamase inhibitors (clavulanate, sulbactam and tazobactam ) have added activity against MSSA, more resistant strains of Gram- negative bacteria ( HNPEK ) and Gram - negative anaerobes (B. fragilis ). Extended-spectrum penicillins, combined with a beta - lactamase inhibitor (e.g., piperacillin / tazobactam ) , have broadspectrum activity. They cover the same organisms as aminopenicillin / beta-lactamase inhibitor combinations [Gram positive bacteria ( Streptococci, MSSA, Enterococci ) , Gram- positive anaerobes (mouth flora) , more resistant strains of HNPEK, Gram - negative anaerobes ( B. fragilis )] plus have expanded coverage of other Gram - negative bacteria, including Citrobacter, Acinetobacter, Providencia , Enterobacter, Serratia (CAPES ) and Pseudomonas aeruginosa. Antistaphylococcal penicillins cover Streptococci and have enhanced activity against methicillin -susceptible Staphylococcus aureus ( MSSA ) , but they lack activity against Enterococcus , Gram - negative pathogens and anaerobes. 48 RxPrep Course Book | RxPrep © 2019, RxPrep © 2020 Select Penicillins DRUG SAFETY/ SIDE EFFECTS / MONITORING DOSING Natural Penicillins Penicillin V Potassium ( Pen VK‘ ) Tablet, suspension Penicillin G Aqueous ( Pfizerpen -G ) PO: 125- 500 mg Q6-12H on an empty stomach CONTRAINDICATIONS Augmentin and Unasyn: history of cholestatic jaundice or hepatic dysfunction associated with previous use IV: 2 - 4 million units Q4- 6H Injection Penicillin G Benzathine ( Bicillin L-A) IM: 1.2- 2.4 million units x 1 (frequency varies) Penicillin G Benzathine and Penicillin G Procaine ( Bicillin C- R ) Aminopenicillins Amoxicillin (Moxatag' ) Tablet, capsule, chewable, suspension Amoxicillin /Clavulanate ( Augmentin. Augmentin ES’ 600 ) PO: dosing varies with formulation; 24 - hr ER tablet is taken once daily Injection, capsule, suspension SIDE EFFECTS Seizures (with accumulation), Gl upset, diarrhea, rash (including SJS /TEN) /allergic reactions /anaphylaxis, hemolytic anemia, renal failure, myelosuppression with prolonged use, T LFTs MONITORING Renal function, symptoms of anaphylaxis withl‘l dose, CBC and LFTs with prolonged courses PO: 250- 500 mg Q6H on an empty stomach 1 hr before or 2 hrs after meals NOTES Aminopenicillins Ampicillin PO is rarely used due to poor bioavailability; amoxicillin is preferred if switching from IV ampicillin IV/IM: 1- 2 grams Q4-6H Ampicillin/ Sulbactam ( Unasyn ) Severe renal impairment (CrCI < 30 mL/min): do not use extended- release oral forms of amoxicillin and amoxicillin/ clavulanate ( Augmentin XR ), or 875 mg strength of amoxicillin/clavulanate PO: dosin8 varies with formulation; XR tablet is taken Q12H with food Tablet, chewable, suspension Ampicillin BOXED WARNING Penicillin G benzathine: not for IV use; can cause cardiorespiratory arrest and death IV: 1.5 -3 grams Q6H Amoxicillin/clavulanate: use a 14:1ratio to i diarrhea caused by the clavulanate component Injection |Y ampicillin and ampicillin/ sulbactam must be diluted in Extended- Spectrum Penicillins NS only Piperacillin/ Tazobactam (Zosyn ) IV: 3.375 grams Q6H or 4.5 grams Q6- 8H Injection Prolonged or extended infusions: 3.375 - 4.5 grams IV Q 8H (each dose infused over 4 hours) Extended -Spectrum Penicillins Piperacillin/ tazobactam contains 65 mg Na per 1 gram of piperacillin Antistaphylococcal Penicillins Antistaphylococcal Penicillins Dicloxacillin Preferred for MSSA soft tissue, bone and joint, endocarditis and bloodstream infections PO: 125 - 500 mg Q6H Capsule Nafcillin No renal dose adjustments IV/IM: 1- 2 grams Q4- 6H Nafcillin is a vesicant - administration through a central line is preferred; if extravasation occurs, use cold packs and hyaluronidase injections Injection Oxacillin IV: 250- 2,000 mg Q4- 6H Injection ' Brand discontinued but name still used in practice. See lab interactions , storage requirements and renal dosage information near the end of this chapter. Penicillin Drug Interactions Probenecid can T the levels of beta -lactams by interfering with renal excretion. This combination is sometimes used intentionally in severe infections to t antibiotic levels. Beta -lactams (except nafcillin and dicloxacillin) can Penicillins can T the serum concentration of methotrexate; they can i the serum concentration of mycophenolate active metabolites due to impaired enterohepatic recirculation. enhance the anticoagulant effect of warfarin by inhibiting the production of vitamin K-dependent clotting factors. 34 22 | INFECTI 0 U 5 DISEASES I; BACKGROUND & ANTIBACTERIALS BY DRUG CLASS KEY FEATURES OF PENICILLINS CLASS EFFECTS All penicillins should be avoided in patients with a beta- lactam allergy (exception: pregnant patients with syphilis) All penicillins increase the risk of seizures if accumulation occurs (e.g. with renal failure) f OUTPATIENT (ORAL) INPATIENT ( PARENTERAL) Penicillin VK Penicillin G Benzathine ( Bicillin L- A ) A first- line treatment for strep throat and mild nonpurulent skin infections (no abscess) Amoxicillin (Moxatag ) First -line treatment for acute otitis media (80-90 mg/kg/day) Drug of choice for infective endocarditis prophylaxis before dental procedures ( 2 grams PO x 1, 30-60 minutes before procedure) Used in H. pylori treatment * Amoxicillin/ Clavulanate ( Augmentin ) Drug of choice for syphilis (2.4 million units IM xl) Not for IV use: can cause death Piperacillin /Tazobactam (Zosyn ) Only penicillin active against Pseudomonas Extended infusions (4 hours) can be used to maximize T > MIC Nafcillin, Oxacillin and Dicloxacillin Cover MSSA only (no MRSA) No renal dose adjustment needed First -line treatment for acute otitis media (90 mg/kg/day) and for sinus infections (if an antibiotic is indicated) Use the lowest dose of clavulanate to i diarrhea * See the Gastroesophageal Reflux Disease <5 Peptic Ulcer Disease chapter CEPHALOSPORINS Coverage varies by cephalosporin generation. As a class, they are not active against Enterococcus spp. or atypical organisms. First generation: excellent coverage of Gram - positive cocci (e.g., Streptococci and Staphylococci ) and preferred when a cephalosporin is used for MSSA infections. They have some activity against the Gram - negative rods Proteus , E. coli and Klebsiella ( PEK ) , but in general , Gram - negative activity is decreased compared to 2nd, 3rd and 4 th generation cephalosporins. Second generation: there are two types. Drugs such as cefuroxime cover Staphylococci , more resistant strains of S. pneumoniae plus Haemophilus , Neisseria, Proteus, E. coli and Klebsiella (HNPEK ) . Cefotetan and cefoxitin have added coverage of Gram negative anaerobes ( B. fraqilis ) . Third generation: there are two groups. Group 1: includes ceftriaxone, cefotaxime and oral drugs, which cover more resistant Streptococci ( S. pneumoniae and viridans group Streptococci ) , Staphylococci ( MSSA ) , Gram- positive anaerobes ( mouth flora ) and more resistant strains of HNPEK. J Group 2: includes ceftazidime, which lacks Gram - positive activity but covers Pseudomonas , and the newer beta lactamase inhibitor combinations, ceftazidime /avibactam and ceftolozane / tazobactam, which have added activity against MDR Pseudomonas and other MDR Gram - negative rods. Fourth generation: only includes cefepime, which has broad Gram- negative activity ( HNPEK, CAPES and Pseudomonas ) and Gram - positive activity similar to ceftriaxone. f only includes ceftaroline, which has Gram - negative activity similar to ceftriaxone, but broad Gram positive activity; it is the only beta - lactam that covers MRSA. Fifth so generation: RxPrep Course Book | RxPrep > 2019, RxPrep © 2020 DRUG DOSING SAFETY/ SIDE EFFECTS /MONITORING Cefazolin ( Ancef * ) IV/IM:1-1.5 grams Q8 H Cephalexin ( Keflex ) PO: 250- 500 mg Q6 -12H CONTRAINDICATIONS Ceftriaxone: hyperbilirubinemic neonates (causes biliary sludging, kernicterus); concurrent use with calcium -containing IV products in neonates 28 days old Cefadroxil PO: 1- 2 grams Q12 - 24H 1st Generation WARNINGS I Anaphylaxis/hypersensitivity reactions 2nd Generation Cefuroxime (Ceftin* ) PO/IV/IM: 250-1,500 mg Q8 -12H Cefotetan (Cefotan ) IV/IM: 1- 2 grams Q12H Cefaclor PO: 250- 500 mg Q8H Cefoxitin IV/IM: 1- 2 grams Q 6-8H Cefprozil PO: 250- 500 mg Q12- 24H 3,d Generation Group 1 Some drugs can ? INR in patients taking warfarin Cross sensitivity (< 10%) with PCN allergy - do not use in patients who have a type 1 PCN allergy (swelling, angioedema, anaphylaxis) Cefotetan contains a side chain [N- methylthiotetrazole (NMTT or 1-MTT) ] which can T the risk of bleeding and cause a disulfiram- like reaction with alcohol ingestion SIDE EFFECTS Seizures ( with accumulation) Gl upset, diarrhea, rash/allergic reactions/anaphylaxis, acute interstitial nephritis, myelosuppression with prolonged use, T LFTs, drug fever, serious skin reactions (SJS/TEN) . Cefdinir (Omnicef * ) PO: 300 mg Q12H or 600 mg daily Ceftriaxone ( Rocephin* ) IV/IM: 1- 2 grams Q12 - 24H Cefotaxime IV/IM: 1- 2 grams Q4 -12H MONITORING Cefditoren (Spectracef ) PO: 200-400 mg Q12H with food Renal function, signs of anaphylaxis with l* dose, CBC, LFTs Cefixime (Suprax ) PO: 400 mg divided Q12 - 24H Cefpodoxime PO: 100-400 mg Q12H Ceftibuten PO: 400 mg daily on an empty stomach 3rd Generation Group 2 Ceftazidime ( Fortaz , Tazicef ) IV/IM: 1- 2 grams Q8-12H Ceftazidime/ Avibactam ( Avycaz ) IV: 2.5 grams Q8H Ceftolozane /Tazobactam (Zerbaxa ) IV: 1.5 gram Q8H NOTES Ceftriaxone - no renal adjustment Cefixime available in a chewable tablet Ceftazidime/avibactam covers some carbapenemresistant Enterobacteriaceae (CRE) , 4 h Generation Cefepime ( Maxipime ) IV/IM: 1- 2 grams Q8-12H , 5 h Generation Ceftaroline fosamil (Teflaro ) IV: 600 mg Q12H * Brand discontinued but name still used in practice. See lab interactions, storage requirements and renal dosage information near the end of this chapter. Cephalosporin Drug Interactions Drugs that decrease stomach acid can decrease the bioavailability of some cephalosporins. Cefuroxime , cefpodoxime, cefdinir and cefditoren should be separated by two hours from short -acting antacids. H 2RAs and PPIs should be avoided. 3! 22 | INFECTIOUS DISEA 5 E 5 I: BACKGROUND & ANTIBACTERIALS BY DRUG CLA 5 S KEY FEATURES OF CEPHALOSPORINS CLASS EFFECTS Due to a small risk (< 10%) of cross - reactivity, do not choose a cephalosporin on the exam if the patient has a penicillin allergy (exception: pediatric patients with acute otitis media) Risk of seizures if accumulation occurs (e.g., with renal failure) OUTPATIENT (ORAL) INPATIENT (PARENTERAL) 1st Generation: Cephalexin ( Keflex ) 1st Generation: Cefazolin Common uses: skin infections (MSSA), strep throat 2nd Generation: Cefuroxime Common uses: acute otitis media, community- acquired pneumonia (CAP), sinus infection (if an antibiotic is indicated) 3rd Generation: Cefdinir Common uses: CAP, sinus infection (if an antibiotic is indicated) Common use: surgical prophylaxis 2nd Generation: Cefotetan and Cefoxitin Anaerobic coverage ( B. fragilis ) o Common use: surgical prophylaxis (colorectal procedures) Cefotetan can cause a disulfiram-like reaction with alcohol ingestion 3rd Generation: Ceftriaxone and Cefotaxime Common uses: CAP, meningitis, spontaneous bacterial peritonitis, pyelonephritis Ceftriaxone No renal dose adjustment Do not use ceftriaxone in neonates (age 0- 28 days) Ceftazidime (3rd Generation) and Cefepime (4th Generation) Active against Pseudomonas Ceftolozane / Tazobactam and Ceftazidime/Avibactam Used for MDR Gram - negative organisms (including Pseudomonas) Ceftaroline Only beta-lactam active against MR 5A •2 RxPrep Course Book | RxPrep © 2019, RxPrep © 2020 CARBAPENEMS Carbapenems are very broad -spectrum antibiotics that are generally reserved for MDR Gram - negative infections. They are active against most Gram - positive, Gram - negative ( including ESBL- producing bacteria ) and anaerobic pathogens. They provide no coverage of atypical pathogens, MRSA , VRE, C. difficile and Stenotrophomonas. Ertapenem is different from other carbapenems as it has no activity against Pseudomonas, Acinetobacter or Enterococcus. DRUG DOSING SAFETY/ SIDE EFFECTS / MONITORING Doripenem IV: 500 mg Q8H Injection CrCI < 50 mL/min: dose CONTRAINDICATIONS Anaphylactic reactions to beta- lactam antibiotics adjustment required Imipenem /Cilastatin ( Primaxin I V.) . Injection IV: 250-1,000 mg Q6- 8H CrCI < 70 mL/min: dose adjustment required Meropenem ( Merrem ) IV: 500-1,000 mg Q8H Meropenem / Vaborbactam (Vabomere) IV: 4 grams Q8H Injection CrCI < 50 mL/min: dose adjustment required Vabomere approved only for complicated UTI (including WARNINGS CNS adverse effects, including states of confusion and seizures Doripenem: do not use for the treatment of pneumonia, including healthcareassociated pneumonia (HAP) and ventilator-associated pneumonia (VAP) Do not use in patients with PCN allergy; cross- reactivity has been reported to be as high as 50%, but more recent studies show rates < 10% SIDE EFFECTS Diarrhea, rash/severe skin reaction (DRESS), seizures with higher doses and in patients with impaired renal function (mainly imipenem), bone marrow suppression with prolonged use, T LFTs MONITORING Renal function, symptoms of anaphylaxis with lft dose, CBC, LFTs NOTES Imipenem is combined with cilastatin to prevent drug degradation by renal tubular dehydropeptidase pyelonephritis) Ertapenem ( Invanz ) IV/IM: 1 gram daily Injection CrCI < 30 mL/min: dose adjustment required Stable in NS only As above plus NOTES No coverage of Pseudomonas Acinetobacter or Enterococcus . Commonly used for diabetic foot infections See lab interactions , storage requirements and renal dosage information near the end of this chapter . Carbapenem Drug Interactions Carbapenems can i serum concentrations of valproic acid, leading to a loss of seizure control. Use with caution in patients at risk for seizures, or in combination with other drugs known to lower the seizure threshold (e.g., ganciclovir, quinolones, bupropion, tramadol ) . See the Seizures / Epilepsy chapter for a complete list . KEY FEATURES OF CARBAPENEMS Class effects: All cover ESBL- producing organisms All except ertapenem cover Pseudomonas Do not use with penicillin allergy Seizure risk (with higher doses, renal failure, or use of imipenem /cilastatin) Remember what they do not cover: Atypicals, VRE, MRSA, C. difficile , Stenotrophomonas Ertapenem does not cover Pseudomonas, Acinetobacter or Enterococcus (ErtAPenem does not cover PEA) Common uses: Polymicrobial infections (e.g., moderate- severe diabetic foot infection) Empiric therapy when resistant organisms are suspected | 0.9% | B Sodium I Resistant Pseudomonas or I Chloride 1 Acinetobacter infections (except I Irijoction, I USP 1 ertapenem) All are IV only. Ertapenem must be diluted in normal saline. 31