PA Lecture Fall - Oct 2024 Antibiotic Review and Overview (Oct 14, 2024) PDF

Objectives  Review Antibiotic Principles  Terminology  Bacteria Review  Coverages  Analyze Antimicrobial Stewardship Concepts  Review Antibiotic Classes  Note trends in coverage by various classes  Assess Appropriate Antibiotic Coverage  Apply Coverage...

Objectives  Review Antibiotic Principles  Terminology  Bacteria Review  Coverages  Analyze Antimicrobial Stewardship Concepts  Review Antibiotic Classes  Note trends in coverage by various classes  Assess Appropriate Antibiotic Coverage  Apply Coverage to Clinical Scenarios Cell Wall Matrix  Simplified Microbiology 101 Gram Positive  Staphlococcus (MSSA, MRSA)  Streptococcus (PCN Resistant Strep Pneumo)  Enterococcus (VRE) Gram Negative  Simple/Piddly  Haemophilus, Moraxella, Salmonella, Shigella, Morganella, Neisseria)  FENCE BUGS (PEK)  Proteus, Ecoli, Klebsiella  SPACE  (Serratia, Pseudomonas, Acinetobacter, Citrobacter, Enterobacter) Simplified Microbiology 101 Atypicals  Chlamydia  Mycomplasma  Legionalla Anaerobes  Peptostreptococcus  Bacteroides  Clostridium  Terminology  Broad/Narrow Spectrum  Synergy  Time Dependent Kill/Concentration Dependent Kill  Post Antibiotic Effect  Bacteriostatic versus Bacteriocidal  Mechanisms of Action  (Cell wall inhib, Protein Synthesis (50 S or 30S), DNA gyrase, Folic acid metabolism)  Mechanisms of Resistance  {Decreased Permeability into cell, Inactivating enzymes (b-lactamases, AG modifying enzymes), Altered target sites (PCP, DNA gyrase), Active Efflux}  Origins of Extended spectrum Beta Lactamases (ESBL) Carbapenem Resistant Enterobacteriaceae (CRE)  Penicillinase was the first beta lactamase –hydrollized the B lactam ring (1940)  Gram negatives most commonly produce resistance via:  Chromosomal Class C (may hyperproduce)  Naturally produce AmpC enzymes in new bacteria that didn’t normally produce it  ESBL  Common expression of resistance is plasmid encoded (TEM-1, TEM-2, SHV-11) –spared expanded cephalosproins  First saw ESBL production 1979—Oxyimino side chain hydrolyze these expanded cephalosporins  TEM B lactamases (TEM-1 is most common)  SHV-1 similar to TEM-1 (most common Kleb)  CTX-M (most active against cefotaxime, ceftaz, ceftriaxone, cefepime)  OXA (most active against oxacillin)  Largest Threat are Five Carbapenemases (CRE)  Klebsiella pneumonia carbapenemase (KPC)  New Delhi metallo-beta-lactamase (NDM)  Verona integrin encoded metallo-beta-lactamase (VIM)  Imipenemase (IMP)  Oxacillinase-48-like-carbapenemase (OXA-48) Extended spectrum Beta Lactamases (ESBL) Carbapenem Resistant Enterobacteriaceae (CRE)  Central Line associated blood stream infections (CLABSIs)  Catheter associated urinary tract infections (CAUTIs)  Most common pathogens seen with this resistance  E.coli***  Klebsiella oxytoca & pneumonia**  Enterobacter*  Citrobacter  Serratia  MRSA Coverage  Traditional Coverages  Vancomycin IV to treat MRSA (PO is Cdiff only),  Oral Options: Doxy/TCN, Bactrim, Clindamycin  Newer Kids on the Block–  IV or PO: Linezolid  IV only: Quinupristin/Dalfopristin, Tigecycline, Daptomycin, Ceftaroline  Newest Kids on the Block –  IV or PO: Tedizolid  IV only: Telavancin, Oritavancin, Dalbavance, Delafloxacin*  SPACE Bug ABX Coverage  Which ABX cover SPACE bugs?  Pick one of the Cell Wall Inhibitors  Penicillins, Cephalosporins, Carbapenems  Anaphylaxis PCN allergy = Aztreonam  Combine with one of the two below for different MOA  DNA gyrase = FQN (Cipro, Levaquin)  30 S = Aminoglycosides (Gent, Tobra, Amikacin)  NEW SPACE Bug ABX Coverage  Cell Wall Inhibitors  Penicillins (Pip&Ticar)  Cephalosporins (Ceftaz & Cefepime ***Ceftaz-avibactam: Avycaz *** Ceftolozane-tazobactam: Zerbaxa),  Carbapenems (Imipenem, Meropenem, Doripenem, *** Meropenem-vaborbactam: Vabomere)  Anaphylaxis PCN allergy = Aztreonam  Combine with one of the two below for different MOA  DNA gyrase = FQN (Cipro, Levaquin & *** Delafloxacin)  30 S = Aminoglycosides (Gent, Tobra, Amikacin) Utilizing Local Antibiograms for Resistance  ANTIMICROBIAL STEWARDSHIP (AMS) Bottomline: Utilizing antibiotics for the optimal duration to treat the infection while minimizing resistance and toxicities  Multi-factorial Focus on AMS Programs  Educational Campaigns  Local Facility Education  Patients/Family Members education  The Joint Commission new standards effective January 1, 2017  Implementation and Evaluations of Sites  ***Data Feedback to Providers***  ***Resistance Patterns***  Key Stewardship Focus  Timely collection of urine, blood, and sputum cultures  Prior to ABX administered ideally  Knowing when an ABX is held  NO IV access, ptn off floor for procedure  Esp with antibiotics that are given 1-2 times/day  Monitor patients BP and temperature closely: if excessive low or high  Monitor urine output significantly decreases  ABX dose most likely needs adjusted for increase/decreased clearance  Outpatient Pearl: don’t collect urine samples in asymptomatic patients  Color change, smell do NOT rush to treat  Do not use the urine collection bag for urine cultures to send to lab.  Clean catch, midstream urine collections are imperative  Pharmacokinetic Optimization:  Monitor patient admin times with Vancomycin and Aminoglycosides (Tora/Gentamicin)  Consistent administration times to allow accurate Trough assessments  Key Stewardship Focus  Allergy screening in CPRS (#1 documented allergy is to antibiotics)  Hx of allergy to assist in providing clear documentation of allergy  Dose Optimization  Assess for treatment of disease (Osteomyelitis/Endocarditis) and patient parameters  Screening Patient Parameters  Renal function via SCR and Acute Kidney Injury (AKI) (other nephrotoxic meds; Bactrim with AKI/HyperK+)  Drug-Drug Interactions (watch Fe or MVI with oral FQN/TCNs binding; SSRI + Linezolid)  EKG review of QTc close to 500msec (Fluoroquinolones and Macrolides; Anti-nausea or Antipsychotics)  Appropriate Duration /Stopping when Inappropriate or Cultures Clear  Ensure duration is long enough and not excessive  Ensure dose is high enough to penetrate and not too low to avoid promoting resistance  Monitoring Patient Clinical Progress  Renal function recovery (all antibiotics for CrCl or Acute Kidney Injury)  New Rash or Eosinophilia (indicative of allergic reactions)  Hyperkalemia (i.e. Bactrim)  Restricted use of class of antibiotics (Daptomycin, Linezolid, Carbapenems, etc)  Recommend best antibiotics for disease state per Guidelines (idsociety.org)  Review Local Antibiogram for Resistance Patterns  Classes Of Antibiotics  PCN class  Pen V and Pen G  Antistaphlococcal (Methacillin, Nafcillin, Ox, Clox, Diclox)  AminoPCN (Ampicillin, Amoxicllin)  CarobxyPCN (Ticarcillin, Carbenacillin)  UreidoPCN (Piperacillin)  Beta-lactamase Inhibitors (Clauvulanate, Sulbactam, Tazobactam)  Unasyn, Augmentin, Timentin, Zosyn  Add Staph coverage and Anaerobes  Will help with organisms who produce Beta lactamases  Classes Of Antibiotics  Cephalosporins  1st Generation (Cephalexin, Cefazolin)  2nd Generation (True (Cefuroxime) and Cephamycins (Tan Fox))  3rd Generation (True (Ceftriaxone, and Anti-pseudomonal Ceftaz)  4th Generation (Cefepime)  Carbapenems  Imipenem/Cilastain  Meropenem  Doripenem  Ertapenem  Monobactam  Azactam  Classes Of Antibiotics  Aminoglycosides  Gentamicin  Tobramycin  Amikacin  Neomycin  Vancomycin  Linezolid (Zyvox)  Quinipristin/Dalfopristin (Synercid)  Mupirocin (Bactroban)  Classes Of Antibiotics  Colistin  Fosfomycin  Tigecycline (Tygacil)  Daptomycin (Cubicin)  Televancin (Vibativ)  Classes Of Antibiotics  Sulfonamides (MOA, SJS, Nephrotoxicity)  Trimethoprim (Solo and Combo Product)  Nitrofurantoin  Macrolides ((E-mycin, Clarithromycin, Azithromycin)  Clindamycin  Chloramphenicol (ADRs– Aplastic anemia)  Classes Of Antibiotics  Fluoroquinoloes  Ciprofloxacin  Levofloxacin  Moxifloxacin  Gemafloxacin  Tetracyclines  Tetracycline  Minocycline  Demeclocycline  Penicillins General Structure Beta-lactam Structures  Penicillin Acid Stability  Acid-Stable  Acid-Labile  Penicillin VK  Penicillin G  Oxacillin  Methicillin  Cloxacillin  Carbenacillin  Dicloxacillin  Ticarcillin  Nafcillin  Mezlocillin  Ampicillin  Piperacillin  Amoxicillin  Penicillin Adverse Effects  Eosinophilia  Interstitial Nephritis  Methicillin  Pseudomembranous Colitis  Penicillin Hypersensitivity Reactions  Most common adverse effect in chart  All penicillins have equal potential for inducing allergic reaction  Hypersensitivity to one means probable hypersensitivity to all penicillins  Hypersensitivity may not occur on re- exposure or may occur without previous reaction  Immediate Reaction (anaphylaxis) - IgE mediated  Delayed Reaction (i.e. rash) - IgM or IgG mediated  Penicillin G/VK - Microbiology  Gram positive organisms  Staph. produce B-lactamases - 99% resistant  Streptococcus pneumoniae resistance  PBP changes  Gonorrhea resistance occurring  Some Enterococcus and Peptococcus (used for dental prophylaxis procedures)  Penicillinase Resistant Penicillins  Antistaphylococcal penicillins  Staph and Strep (no Enterococcus)  IV - Methicillin, Oxacillin, Nafcillin  Nafcillin - hepatic elimination  PO - Cloxacillin, Dicloxacillin  Aminopenicillins  Ampicillin (QID)/Amoxicillin(TID)  Amino group allows for penetration into gram negative cell wall.  Spectrum includes :  Strep/ ***Enterococcus***  Piddly  +/- Fence (PEK)  Serratia  Carboxypenicillins  Carbenicillin/Ticarcillin  Watch Sodium load  Increased permeability to cell wall.  Activity includes:  Streptococcus  Piddly  Fence  SPACE  Ureidopenicillin  Piperacillin  Less Sodium load (still present though)  Activity includes:  Streptococcus/ **Enterococcus**  Piddly  Fence  SPACE  B-Lactamase Inhibitor/ Penicillin Combinations  Augmentin-amoxicillin/clavulanic acid  Unasyn -ampicillin/sulbactam  Timentin -ticarcillin/clavulanic acid  Zosyn -piperacillin/tazobactam  Use will depend upon incidence of b-lactamase production Cephalosporin Structure R1 – Spectrum of Activity, PBP affinity, B-lactamase susceptibility R2 – Stability, metabolism, adverse effects, drug interactions, protein binding, t1/2  Cephalosporin Generations Generation Common Oral Products Common Parenteral Products First Cephalexin (Keflex) Cefazolin (Ancef) Cefadroxil (Duricef) Second Cefuroxime (Ceftin) Cefuroxime (Zinacef) Cefprozil (Cefzil) Cefaclor (Ceclor) Second N/A Cefoxitin (Mefoxitin) (Cephamycins) Cefotetan (Cefotan) Third Cefixime (Suprax) Ceftriaxone (Rocephin) Cefdinir (Omnicef) Cefotaxime (Claforan) Cefopodoxilme (Vantin) Third N/A Ceftazidime (Fortaz) (Antipseudomonal) Cefoperazone (Cefobid) Fourth N/A Cefepime (Maxipime) Fifth Ceftaroline (Teflaro) Ceftaz-avibactam (Avycaz) Ceftolozane/tazo (Zerbaxa)  Spectrum of Activity  As generations increase, gram negative coverage increases  New agents coverage have renal restrictions due to outcomes variability (see slides below)  Cephalosporins generally DO NOT COVER  Enterococcus (except Ceftaroline)  MRSA (except Ceftaroline)  Chlamydia, Mycoplasma, Legionella  Spectrum of Activity Generation Gram + Gram - Anaerobes (No Enterococcus) (Bacteroides) First Staph, Strep Piddly, Ecoli* No Second Staph, Strep Yes (H. flu, M. No cat, Proteus, E. coli,Kleb -PEK) Second Staph, Strep Yes (H. flu, M. Yes (cephamycins) cat, PEK) Third Strep Yes (SACE) No Third Poor Yes (SPACE) No (Antipseudomonal) Fourth Staph, Strep Yes (SPACE) No Fifth Staph, Strep SCE No *Enterococcus SPACE – Serratia, Pseudomonas, Acinetobacter, Citrobacter, Enterobacter  Cephalosporins Adverse Effects  Gastrointestinal  Diarrhea  Pseudomembranous colitis  Renal  Interstitial nephritis (rare)  Immunologic  Serum sickness in children- Cefaclor (Ceclor-2nd generation)  Cephalosporin Adverse Effects  Hypersensitivity reaction:  5-15% cross-reactivity with Penicillins  Generally safe in non-IgE-mediated (anaphylaxis) penicillin allergic patients (DO NOT USE IN THIS SITUATION!!!)  Rash, drug fever  Hematology  Bleeding  N-Methylthiotetrazole (NMTT) side chain  Cefamandole & cefoperazone due to hypoprothrombinemia (disturbance in vitamin K dependent clotting factors)  Alcohol, disulfiram-like intolerance  Agents with NMTT side-chain (Cefamandole & Cefaperazone)  Ceftolozane/tazobactam (Zerbaxa)  Cephalosporin with Beta lactamase inhibitor  Approved for complicated Urinary Tract Infections including Pyelonephritis  Combined with Metronidazole, complicated intra-abdominal infections  Covers: Strep anginosus/salivarius/constellatus, Proteus mirabilis, E.coli, Klebsiella oxytoca &pneumoniae, Pseudomonas aeruginosa  In vitro activity against ESBL and SOME Beta-lactamases (trials E.coli/Kleb pneumoniae when MIC 2 Vanc) and VRE  Complicated skin and soft tissue infections  4mg/kg daily (requires renal adjustment)  Staph aureus and MRSA bacteremia/Right sided Endocarditis  6mg/kg daily (requires renal adjustment)  DOES NOT cover Pneumonia  Inactivated by pulmonary surfactant  ADR:  Rhabdomyolysis  Monitor CPK baseline and weekly (DC if above 5x ULN)  Eosinophilic pneumonia (RARE) 72 Telavancin (Vibactiv)  Glycolipopeptide  Semi-synthetic derivative of Vancomycin  Watch cross sensitivity with Vanc  May cause red man syndrome or nephrotoxicity like Vanc  FDA approved in 2009 for skin and soft tissue infections  FDA approved in June 2013 for bacterial HAP/VAP  Covers gram positive organisms (SSI)  Staph (including MRSA), Strep and Enterococcus  Dose: 10mg/kg/day  ADR:  May falsely elevated INR (doesn’t increase bleeding risk)  Contraindication: Concomitant IV unfractionated heparin infusions  Nephrotoxicity  Red man syndrome with infusion  QT prolongation- avoid in patients with congenital long QT or known prolonged QT  Pancreatitis (*rare)  REMS program – Increased mortality for ptn with pre-existing renal function & risk of fetal development toxicity 73  Oritavancin (Orabactive)  Glycolipopeptide: approved in Aug 2014  Single dose regimen: 1200mg IV x dose  Coverage: Staph (incl MRSA, Strep, Enterococcus)  Not studied in patients with CrCl < 30ml/min  Approved for skin and soft tissue infections  Infusion related reaction (red man syndrome)  Monitor: LFTS and SCr  Unique pearl:  ***Do not use IV unfractionated Heparin for 5 days post oritavancin admin d/t interference with aPTT results.  Oritavancin :  Weak INHIBITOR of 2C9 and 2C19  Weak INDUCER of 3A4 and 2D6  Oritavancin may increase bleed risk with warfarin– weak 2C9 inhibition  Dalbavance (Dalvance )  Glycolipopeptide: approved in May 2014  Coverage: Staph (include MRSA), Strep, and Enterococcus  Single dose regimen: 1500mg IV x 1 dose  Two dose regimen: 1000mg IV x 1 dose then 500mg x1 dose a week later  May use with CrCl < 30ml/min, but NOT dialysis  Approved for skin and soft tissue infections  Unique pearl:  (Dalbavance does not interfere like Oritavancin)  Can use IV unfractionated Heparin as it does NOT inter with aPTT.  Dalbavance ok to use with Warfarin  (Oritavancin may increase bleed risk with warfarin– weak 2C9 inhib)  Sulfonamides Structure and Chemistry -All sulfonamides are similar in structure to para-aminobenzoic acid (PABA). -PABA is a precursor required by bacteria for folic acid synthesis. H2N COOH H2N SO2NHR PABA SULFONAMIDE NUCLEUS  Folic Acid Pathway Dihydropteroate Dihydrofolate Synthetase Reductase PABA Folic Acid Tetrahydrofolic Acid AA Sulfonamides Trimethoprim  Sulfonamides Adverse Reactions  Anaphylaxis  Nephrotoxicity  Crystalluria with less soluble compounds  Cutaneous (Sulfadiazine and Reactions Sulfathiazole)  Morbilliform Rash  Administer with fluids-  Steven Johnson check hydration status Syndrome of patients prior to use  Erythema Multiforme  Kernicterus  Photosensitivity Rash  When given in last months of pregnancy  Hematologic Rxns  Compete for bilirubin binding sites on plasma albumin  Hypersensitivity  Results in increased Rxns fetal blood levels of  Drug Fever, Rash S  SMZ/TMP (Bactrim) Spectrum of Activity Gram Positive Gram Negative Other Staph. spp. Haemophilus influ Nocardia asteroides Streptococcus spp. Neisseria Chlamydia gonorrhoeae trachomatis Bacillus anthracis Salmonella Toxoplasma gondii Shigella Plasmodium falciparum Providencia spp. Pneumocystis carinii Protues mirabilis/ vulgaris E.coli Klebsiella pneumo Citrobacter spp. Enterobacter spp.  Nitrofurantoin Spectrum of Activity Gram PositiveOrganisms Gram NegativeOrganisms Staphylococcus aureus Escherichia coli Staphylococcus Klebsiealla pneumonia saprophyticus Enterococcus faecalis Citrobacter spp. Enterococcus faecium Enterobacter aerogenes **Resistance does not develop readily to nitrofurantoin.  Methenamine Mechanism of Action  No antibacterial effect alone.  At adequate urine pH (< 5.5), it is hydrolyzed to formaldehyde, which kills bacteria by denaturing proteins. 6 H2O Methenamine 6 Formaldehyde NH4+ Kills Bacteria  Methenamine Factors Affecting Formaldehyde Concentrations  Methenamine concentrations in the urine affected by:  Rate of hydrolysis of methenamine to formaldehyde  Rate of urine loss from bladder by voiding or drainage  PEARL: *Frequent voiding of bladder (indwelling catheters or intermittent cath) will decrease effects by removing formaldehyde and by reducing the time of exposure of bladder bacteria to formaldehyde.  Quinolones Mechanism of Action  Target: DNA gyrase (topoisomerase II)  DNA gyrase is essential for Supercoiling of cellular DNA by a nicking, pass through, and resealing process.  Quinolones inhibit bacterial DNA gyrase and topoisomerase IV  Bactericidal  Postantibiotic Effect  After exposure to inhibitory concentrations of quinolones, continued killing occurs.  The postantibiotic effect averages ~ 1-2 hrs.  Tends to increase with increasing concentrations and length of exposure.  Quinolones Ciprofloxacin  Wide range of FDA approved indications.  Ciprofloxacin is most potent of the quinolones against gram negatives.  Specifically most potent against pseudomonas  Excellent bioavailability – Use oral form if possible  Functioning GI tract required (Do not use if Ileus or SBO)  Gram positive activity variable- consider newer FQN  Quinolones Levofloxacin/Gemifloxacin/Moxifloxacin  Gram positive coverage  All three are good for Staph and Strep  Coverage includes PCN Resistant Strep Pneumo  Gram negative coverage (SACE)  Levofloxacin potency is less than ciprofloxacin  No Pseudomonas for Gemifloxacin or Moxifloxacin  Atypical respiratory pathogens  Excellent bioavailability – use oral agent  Quinolones Levofloxacin/Gemifloxacin/Moxifloxacin  Levofloxacin is a hybrid between Ciprofloxacin and the newer agents Gemifloxacin and Moxifloxacin  Moxifloxacin Unique Characterisitcs  Anaerobes (Complicated Intra-abdominal infections)  Moxifloxacin dose NOT cover UTI’s  Poor urinary concentrations Delafloxacin (Baxdela)  New Fluoroquinolone: FDA approved June 2017  Approved acute bacterial skin and skin structure infections  Available IV 300mg BID or PO 450mg BID  CrCl= 15-29ml/min 200mg IV BID or 450mg PO BID (Not recommend ESRD)  Coverage: Staph/Strep/MRSA & E.coli Enterobacter, Klebsiella, Pseudomonas  Approval studies compared itself against Vanc/Aztreonam  Pearls Differentiating from other FQNs  Delafloxacin has not demonstrated QT prolongation or phototoxicity to date  No markers of ADRs to liver, kidneys or glucose control  *Retained warning for: Tendon ruptures/Neuropathy/CNS  *All FQNs may exacerbate muscle weakness with myasthenia gravis  Assessment Question  What are two potential benefits from utilizing Delafloxacin over the traditional fluoroquinolones?  A. Less Cation binding and Less Neuropathy  B. Less C.diff and Less Neuropathy  C. Less Tendonitis and Less Neuropathy  D. Less QTc prolongation and Less Phototoxcity  What the unique pair of bacterial coverage Delafloxacin exhibits?  A. VRE and CRE  B. CRE and ESBL  C. MRSA and VRE  D. MRSA and Pseudomonas  Assessment Question  What are two potential benefits from utilizing Delafloxacin over the traditional fluoroquinolones?  A. Less Cation binding and Less Neuropathy  B. Less C.diff and Less Neuropathy  C. Less Tendonitis and Less Neuropathy  D. Less QTc prolongation and Less Phototoxcity  What the unique pair of bacterial coverage Delafloxacin exhibits?  A. VRE and CRE  B. CRE and ESBL  C. MRSA and VRE  D. MRSA and Pseudomonas  TETRACYCLINES  Members  Doxycycline (Vibramycin)  Minocycline (Minocin, Vectrin)  Demeclocycline (Declomycin)  Oxytetracycline (Terramycin)  Chlortetracycline (Aureomycin)  Tetracycline (Achromycin, Panamycin)  Tetracyclines Take Home Points  Do not use in Pregnancy/kids