Antibiotics 2025 PDF

INTRODUCTION TO ANTI-INFECTIVE THERAPY  Overview  Treat infection by killing (“cidal”) or suppressing (“static”) the offender microorganism (bacteria, mycobacterium, fungi, protozoa, or viruses.  Take advantage of biochemical/biological differences between microorganism and hu...

INTRODUCTION TO ANTI-INFECTIVE THERAPY  Overview  Treat infection by killing (“cidal”) or suppressing (“static”) the offender microorganism (bacteria, mycobacterium, fungi, protozoa, or viruses.  Take advantage of biochemical/biological differences between microorganism and human beings.  Choice of Agent  Patient factors  Spectrum of activity  Pharmacological properties  Institutional antibiogram  INTRODUCTION TO ANTI-INFECTIVE THERAPY 1  Identifying “Bug”  Identify prior to treatment so that proper drug selection can be made (ideally, but empirical treatment is sometimes used initially while awaiting the identification of the infecting microorganism).  Rapid Assessment- Gram stain (sterile body fluid, CSF, synovial fluid, urine, etc)  Conclusive diagnosis -cell culture  Definitive Identification- Detect microbial antigens, microbial DNA or RNA or host human response to microorganism.  INTRODUCTION TO ANTI-INFECTIVE THERAPY 2  Choosing Antimicrobial Therapy:  Minimum Inhibitory Concentration- MIC - lowest concentration of antibiotics to inhibit “visible” bacterial growth. To provide effective antimicrobial therapy, the clinically obtainable antibiotic concentration in body fluids should be greater than the MIC.  Minimum Bactericidal Concentration- MBC- The lowest concentration of antimicrobial agent that results in 99.9% decline in colony count. DETERMINATION OF MIC VALUE: DISK DIFFUSION METHOD DETERMINATION OF MIC VALUE: E-TEST The “E-TEST” consists of a predefined gradient of antibiotic concentrations on a plastic strip. INTRODUCTION TO ANTI-INFECTIVE THERAPY  Empiric Therapy but you may  Even though you may not know the infecting organism(s) sometimes need to treat right away  Serious or life-threatening disease  Treat based on clinical experience  Give Broad-spectrum antibiotic  Multiple Antibiotic Therapy  Combination of drugs- Synergy may result due to different MOAs of the drugs  Clinical experience  Therapy to be more effective  Can increase risk of drug toxicity  Prevention of drug-resistant organisms INTRODUCTION TO ANTI-INFECTIVE THERAPY  Lack of therapeutic effectiveness maybe due to:  Misdiagnosis  Improper drug regimen  Inappropriate choice of antibiotic agent  Microbial resistance (due to mutation, adaptation, gene transfer)  Infection by two or more types of microorganisms  Expectations of patients/clinicians Some Bacteria of Clinical Importance TEN MOST DANGEROUS ANTIBIOTIC-RESISTANT BACTERIA ACCORDING TO THE W.H.O. CLASSIFICATION OF ANTIMICROBIALS Inhibitors of Cell Wall Synthesis:  Fosfomycin  Beta-Lactams:  Penicillins  Cephalosporins  Carbapenems  Monobactams (Aztreonam)  Polypeptides including  Vancomycin, Telavancin, Oritavancin, Dalbavancin  Bacitracin CLASSIFICATION OF ANTIBACTERIALS  Protein Synthesis Inhibitors  Folate Antagonists  Aminoglycosides  Sulfonamides  Macrolides  Trimethoprim  Tetracyclines  Pyrimethamine  Tigecycline  Inhibitors of Nucleic Acid  Clindamycin Function/Synthesis  L Streptogramins:  Fluoroquinolones (Quinupristin/Dalfopristin)  Rifampin  Oxazoladinones: (Linezolid, Tedizolid) Free Radical Generators Metronidazole Nitrofurantoin  lustration of listsabove HOW THE DRUGS WORK ANTIBIOTIC COVERAGES IN A NUTSHELL Acinetobacter BY AKINESIA - OWN WORK, CC BY-SA 4.0, HTTPS://COMMONS.WIKIMEDIA.ORG/W/INDEX.PHP?CURID=64751804 ANTIBIOGRAM ANTIBIOTICS: WHAT DO I NEED TO KNOW FOR EXAMS ? 1. “General” antibacterial spectrum for that class/subclass of agent 2. “Special” or unique use/coverage for an antibiotic where applicable (example: benzathine PenG for syphilis) 3. Administered parenterally only? 4. Adverse effects 5. Mechanism of action / Mechanism(s) of resistance 6. Important pharmacokinetic property(s) of an antibiotic per the course instructor (route of elimination is important!) 7. Contraindications 8. Drug interactions 9. Covers Pseudomonas ? makelist 10. Covers anaerobes (especially Bacteroides fragilis) ? Makelist makelist 11. Covers Atypicals ? makelist 12. Covers Enterococcus ? Covers VRE? 13. Covers Clostridium difficile ? (only 3 agents do cover: vancomycin, metronidazole, fidaxomicin) 14. Covers MRSA/ MRSE or VISA ?? list CELL WALL SYNTHESIS INHIBITORS STRUCTURE OF THE PEPTIDOGLYCAN CELL WALL OF BACTERIA BACTERIAL CELL WALL SYNTHESIS: BUILDING BLOCKS : GLYCANS STAGE I : THE STARTING POINT: UDP-NAG STAGE I: SYNTHESIS OF UDP-NAM FROM UDP-NAG UDP-NAG phosphate UDP-NAG enolpyruvic acid UDP-NAM FOSFOMYCIN (MONUROL®)  Mechanism of action: A phosphonic acid derivative. Inhibits the enzyme enolpyruvate transferase which catalyzes the conversion of UDP-NAG to UDP-NAM. Thus it inhibits cell wall synthesis at its earliest point in Stage I of cell wall synthesis !!  Usually administered as single-dose treatment of uncomplicated UTI  Not effective for pyelonephritis b/c it doesn’t reach effective concentrations  Oral bioavailability is 40% with a T1/2 of 5-8 hrs.  Well tolerated. Side effects include GI distress, HA, dizziness, vaginitis  FOSFOMYCIN (MONUROL®)  Used ORALLY to treat lower urinary tract infections. Its importance has increased dramatically over the past decade b/c it is useful in treating multidrug-resistant organisms that produce cystitis [e.g., VRE and carbapenemase-producing Enterobacteriaceae, SPACE-M, Pseudomonas ?, in addition to the usual culprits that produce UTI’s ( E. coli , S. saprophyticus, Proteus, Klebsiella, enterococci, MSSA/MRSA). Not effective against ESBL- elaborating bacteria. ↑ Fosfomycin Enolpyruvate transferase STAGE II : BACTROPRENOL TRANSPORTS CYTOSOLIC NAG-NAM PENTAPEPTIDE ACROSS THE CYTOPLASMIC CELL MEMBRANE SUMMARY OF STAGE I & STAGE II OF BACTERIAL CELL WALL SYNTHESIS  VANCOMYCIN and CHEMICALLY-RELATED ANTIBIOTICS VANCOMYCIN: A GLYCOPEPTIDE INHIBITOR OF STAGE II CELL WALL SYNTHESIS VANCOMYCIN INHIBITS THE INCORPORATION OF A NAG-NAM-PEPTIDE BUILDING BLOCK (“BRICK”) INTO THE GROWING PEPTIDOGLYCAN CELL WALL INHIBITORS OF STAGE II CELL WALL SYNTHESIS: GLYCOPEPTIDES → VANCOMYCIN  Inhibits cell peptidoglycan polymerization by forming complexes with D- Ala-D-Ala termini of cell wall precursors. The presence of the D-Ala-D- Ala moiety is absolutely required for vancomycin binding, and hence its antibacterial efficacy   Effective ONLY for gram (+) organisms ( covers both aerobes and anaerobes !) resistant  Reserved for serious gram (+) infections (e.g. , endocarditis, C. difficile psueudomembranous colitis, resistant S. pneumoniae, MRSA/MRSE BINDING OF VANCOMYCIN TO THE D-ALA-D-ALA TERMINUS OF A NAG-NAM-PEPTIDE BUILDING BLOCK (“BRICK”) D-Ala-D-Ala  VANCOMYCIN  Poorly absorbed orally but this is beneficial in the oral treatment of pseudomembranous colitis ( C. difficile)  Administered IV  Has become extremely important due to effectiveness against tough-to- treat gram positive organisms. ( e.g. DOC for Clostridium difficile, Corynebacterium jeikeium, ampicillin-resistant enterococci )  A drug of choice for nosocomial MRSA/MRSE hospitalacquired  VANCOMYCIN  Is a DOC for serious infections and endocarditis caused by the following:  Methicillin-resistant S. aureus (MRSA)  Methicillin-resistant coagulase-negative staphylococci (MRSE)  Certain beta-lactam- and multidrug-resistant Streptococcus pneumoniae  Beta-hemolytic streptococci (when beta-lactams cannot be used because of drug allergy or resistance)  Viridans streptococci (when beta-lactams cannot be used because of drug allergy or resistance)  VANCOMYCIN  Enterococcus (when beta-lactams cannot be used because of drug allergy or resistance)  Corynebacterium spp.  Adverse effects:  “Red man syndrome” is observed when given by too rapid IV infusion b/c of histamine and other cytokine release.  Fever and chills (upon rapid infusion) redden eartoxicity reversible  Ototoxicity and nephrotoxicity (particularly when combined with aminoglycosides). Tends tobereversible RESISTANCE TO VANCOMYCIN  Unfortunately, acquired resistance to vancomycin is increasing (e.g., VRE, VISA, VRSA)  High-level resistance to vancomycin is encoded by different clusters of genes referred to as the vancomycin-resistance gene clusters (e.g., vanA, B, D, and M gene clusters).  These genes encode enzymes which lead to replacement of D-Ala-D-Ala– ending peptidoglycan precursors with D-alanyl-D-lactate termini instead, to which vancomycin binds with significantly lower affinity. The replacement of D- alanine by D-lactate, which disrupts one of the five hydrogen bonds required for the interaction of vancomycin with its target, increases the MIC of this antibiotic almost 1000-fold. RESISTANCE TO VANCOMYCIN  VanA is the most common type of vancomycin resistance, usually mediates higher levels of resistance than other types, and causes cross-resistance to teicoplanin.  The VanB phenotype, the second most common type, is less frequently encountered than VanA. The major phenotypic difference between VanA- and VanB-producing strains is that teicoplanin is not a good inducer of expression of the genes in the VanB cluster INHIBITORS OF STAGE II CELL WALL SYNTHESIS: LIPOGLYCOPEPTIDES INHIBITORS OF STAGE II CELL WALL SYNTHESIS: LIPOGLYCOPEPTIDES  Telavancin (Vibativ®) Oritavancin (Orbactive®) Dalbavancin (Dalvance®)  Are semi-synthetic lipoglycopeptide derivatives of vancomycin which like vancomycin, are reserved for treatment of serious gram positive infections only.  Telavancin is dosed QD. Dalbavancin and Oritvancin have extremely long T1/2 allowing once–weekly dosing (dalbavacin); single injection for skin infections (oritavancin)  Half-life of dalbavancin = 8 days  Half-life of oritavancin = 16 days  LIPOGLYCOPEPTIDES: TELAVANCIN ORITAVANCIN DALBAVANCIN  MOA: In addition to inhibition of cell wall synthesis by the same mechanism attributed to vancomycin, lipoglycopeptides add a second mechanism of action: depolarization of bacterial cell membrane potential and hence disruption of bacterial cell membrane integrity.  Furthermore, oritavancin has additional interactions with the D-glutamine elavancin and pentaglycyl bridge of newly-incorporated NAG-NAM-peptidyl cell wall precursors. These extra interactions apparently allow oritavancin to be an effective inhibitor of transpeptidases and thus precursor cross-linking !! RSAMSSA avancin  Telavancin is used for acute bacterial skin and skin structure infections (ABSSSI) and hospital-acquired or ventilator-acquired pneumonia (MSSA and MRSA)  Dalbavancin and Oritavancin are FDA approved for ABSSSI  FUNCTIONS RELATED TO BACTERIAL MEMBRANE POLARIZATION Bymembrane depolarizing cell youinhibit all ofthese  INHIBITORS OF STAGE II CELL WALL SYNTHESIS: LIPOGLYCOPEPTIDES  Lipoglycopeptides are broadly active against gram-positive bacteria including:  Streptococci vancomycin  Enterococcus faecalis and Enterococcus faecium ( including some VRE reefetticus Vana with ortivancin) ritavanan  Staphylococcus aureus, including MSSA, MRSA and VISA  Listeria van B  Corynebacterium jeikium OD  Oritavancin is active against vancomycin-resistant enterococci (VRE) strains that harbor the vanA gene; but dalbavancin and telavancin are not.  All three have activity against vanB VRE. LIPOGLYCOPEPTIDES: TELAVANCIN ORITAVANCIN DALBAVANCIN  The most common adverse reactions occurring in patients using telavancin have been taste disturbance, nausea, vomiting, and foamy urine.  QTc prolongation has occurred with telavanicin in a small percentage of patients. Telavancin has been classified as category C (risk cannot be ruled out) for use during pregnancy.  Warning: Severe hypersensitivity (anaphylactic) and skin reactions have been reported with dalbavancin  Red-man syndrome with too fast infusion of ortitavancin  Nephrotoxicity: telavancin more than vancomycin??  Nephrotoxicity has not been associated with oritavancin and dalbavancin  STAGE III: TRANSPEPTIDASE-CATALYZED CROSSLINKING OF NAM-PEPTIDE STRANDS ONCE THEY HAVE BEEN INCORPORATED INTO THE CELL WALL NAM iterisentianon NAM -----------NAG----------- lastD Ahhhhe NAG I disease peace 1cm - -------NAG------- 5 STAGE III: CHEMISTRY OF THE CROSS-LINKING STEP CATALYZED BY TRANSPEPTIDASE i PBP Lys Glu Ala Lys Glu Ala Lys Glu Ala Lys Glu Ala peptideis an amidegroup FYI STAGE III: CROSSLINKING OF THE PEPTIDOGLYCAN CELL WALL CROSS-LINKING LENDS MECHANICAL STABILITY TO THE CELL WALL  BETA-LACTAM ANTIBIOTICS RESEMBLE D-ALA-D-ALA a β betalactamase cleavesamide bondonce ringisopen free rotationof swore will lactam cyclicamide nhibiteffect ANTIBIOTIC 7 MECHANISM OF TRANSPEPTIDASE INHIBITION BY A BETA-LACTAM ANTIBIOTIC (PENICILLIN)  INHIBITORS OF STAGE III OF CELL WALL SYNTHESIS: BETA-LACTAM ANTIBIOTICS laidal causes  Four chemical classes of beta-lactam antibiotics: 1. Penicillins MET 2. Cephalosporins 3. Carbapenems 4. Monobactams (Aztreonam) cleave that the beta lactamring enzyme a inhibitors (BLIs) do possess a  Note: Three of the marketed beta-lactamase beta-lactam ring in their chemical structure, but essentially have no intrinsic anti-bacterial activity of their own:  Clavulanic acid  Sulbactam ( exhibits modest intrinsic activity against Acinetobacter)  Tazobactam BETA-LACTAMS: PROTOTYPIC STRUCTURES Gnoringfusedto it BETA-LACTAM ANTIBIOTICS: THE BIG PICTURE PENICILLINS  PENICILLINS Penicillins (PCNs):  Oldest class of β-lactam antibiotics  Bactericidal (all beta-lactam antibiotics are)  Bacteriostatic against Enterococcus spp.  Selective toxicity b/c mammalian cells do not make a cell wall  Side effects- hypersensitivity reactions, and diarrhea  ALL PCNs are cross-reacting and cross-sensitizing. Furgito onepenicillinassumeyou'reallergicto all PENICILLINS  CLASSIFICATION OF PENICILLINS  Classification of Penicillins: Four groups: memorize category sdrugs 1. Natural penicillins (Pen G and Pen V) 2. Penicillinase-resistant penicillins (aka “antistaphylococcal penicillins”): Nafcillin, Oxacillin, Dicloxacillin 3. Aminopenicillins (Ampicillin and Amoxicillin) 4. Antipseudomonal penicillins ( Piperacillin and Ticarcillin) PENICILLINS: MECHANISM OF ACTION Mechanism of Action:  Gram positive and Gram negative bacteria possess a cell wall- a polymer known as “a peptidoglycan” (glycan subunits bonded to peptides).  ALL beta-lactam antibiotics (including penicillins) interfere with the last step ( Stage 3) of bacterial cell wall synthesis i.e., the transpeptidation (cross-linking) step. This leads to cell lysis.  All beta-lactam antibiotics are only effective against organisms with a peptidoglycan (PG) cell wall. Thus, ineffective against atypical bacteria, mycobacteria, protozoa, fungi and viruses. PENICILLINS: MECHANISM OF ACTION  Penicilllins, like all β-lactam antibiotics, work by binding to select Penicillin Binding Proteins (PBPs)- these are bacterial enzymes involved in the cross- linking of the cell wall and in maintaining morphological features of the cell wall. By interfering with cell wall synthesis PCNs ultimately cause lysis of susceptible bacteria.  Alterations in some of these PBPs have resulted in resistance to the PCNs: e.g., Methicillin -resistant Staphylococcus aureus (MRSA) and MRSE hIa arose because of alteration (mutation) of PBP2 to PBP2a ettaralin.ee In penicillin-resistant Enterococcus faecium PBP5 is mutated to a low- affinity form In penicillin-resistant Enterococcus faecalis PBP4 is mutated to a low- affinity form  PENICILLINS: MECHANISM OF ACTION  There are several PBPs that the penicillins may simultaneously inactivate.  Inhibition of certain PBPs may be related to the activation of a bacterial autolytic process (by inactivation of endogenous inhibitors of these autolysins). a These enzymes normally cleave parts of the cell wall to make room for peptidoglycan synthesis for cell wall expansion.  With inhibition of cell wall synthesis, bacterial lysis can occur due to increased osmotic pressure. This autolysis may be cell cycle dependent, that is, most likely to occur while the cell is dividing.  Certain “tolerant” species of staphylococci and streptococci have been isolated which are autolysin-deficient. These organisms are inhibited, but not killed by penicillins SOME PENICILLIN-BINDING PROTEIN CLASSES AND THEIR ASSOCIATED FUNCTIONS & ROLES NATURAL PENICILLINS: PEN G & PEN V  Penicillin G (benzylpenicillin) is classified as a “Natural” PCN: obtained from fermentation of the mold Penicillium chrysogenum. Poor oral bioavailability (30%) so it is used i.m. or i.v. Parentalang  Pen V ( the phenoxy analog of Pen G) is the p.o. choice since it is more stable to degradation in the GI tract  General Spectrum:  Aerobic and anaerobic gram (+) cocci (streptococci: S.pyogenes, S.pneumoniae; viridans group streptococci (+/-); Enterococcus sp., oral anaerobes, and certain gram (+) anaerobic bacilli (Clostridium perfringens, e Iremembetg.mg Propionibacterium). Does NOT cover Clostridium difficile  Neisseria meningitidis and Treponema pallidum (syphilis = DOC). → THINK Gram Positive AEROBES and ANAEROBES (minus staphylococci) + Neisseria meningitidis + syphilis  9 NATURAL PENICILLINS: PEN G PEN V betalactamase  NOT EFFECTIVE for staphylococci (b/c many harbor a penicillinase) !! u mtnotcovee.ua f  NOT EFFECTIVE for nearly all (important) gram negative bacilli !!  Important coverages:  Neisseria meningitidis  Streptococcus pneumoniae (+/-)  Streptococcus pyogenes (strep throat): Pen V  Clostridium perfringens (+ clindamycin)  Syphilis ( use long-acting benzathine salt of Pen G) esiingieiectiin exceptiftheirs  Oral anaerobes (peptococcus/ peptostreptococcus/ actinomyces) penicillinallergy  Enterococcus  The natural penicillins are hydrolyzed (inactivated) by beta-lactamases produced by resistant organisms (e.g., the penicillinases of staphylococci.) PLASMA CONCENTRATION PROFILE OF VARIOUS FORMULATIONS OF PEN G adm 04hr5 prophylaxis s txforsyphilis longactingsalt PLASMA CONCENTRATION PROFILE OF VARIOUS FORMULATIONS OF PEN G 30daylevelsmaintaine  intrinsic4 resistant PENICILLINASE-RESISTANT PENICILLINS: AKA “ANTI-STAPHYLOCOCCAL PENICILLINS”  PENICILLINASE-RESISTANT PENICILLINS: NAFCILLIN, OXACILLIN, DICLOXACILLIN  Often referred to as “ANTI-STAPHYLOCOCCAL” or “Beta-lactamase-resistant” PCNs. Gaping This is the only PCN class that is intrinsically stable to most staphylococcal penicillinases.  Dicloxacillin Oxacillin Nafcillin (Diclox. is p.o. choice) blcis morelipophilic  Uses: Think STAPH INFECTIONS especially S. aureus = MSSA (Methicillin- Susceptible Staph Aureus) oxacillin  Coagulase-negative Staph ( S. epidermitis, S. saphrophyticus, S. haemolyticus, S. hominis) are also covered  Streptococci (decreased activity against streptococci compared to their activity against staphylococci, but MICs are acceptable in certain cases)  Cross the blood brain (1st generation cephalosporins, which have a similar antibacterial spectrum, do NOT)  Useful for bacteremia and endocarditis NOnephrons needsNafcillin usestaphinfections MSSAI streptococci bacteremia endocarditis canbeusedin Dtn DOES'TWORKAGAISTMRSA w renalfailure PENICILLINASE-RESISTANT PENICILLINS onlytxbyceftraline I  Do NOT cover MRSA/MRSE (by definition)  ** No dose reduction is needed in renal failure b/c there is a significant biliary component to their elimination (especially nafcillin) in addition to the renal component ***.  Original drug from this class was i.v. METHICILLIN (toxic: caused interstitial nephritis); it has/can be used in laboratory susceptibility testing protocols to identify resistant strains of S. aureus (i.e., MRSA) and S. epidermitis (i.e.,MRSE), but oxacillin is used more often for this purpose in laboratories now. STRUCTURE OF CELL WALL OF GRAM NEGATIVE BACTERIA Tothroughporin intimate fantata Forgram thebetalactamas areconfinedtothe periplasmicspace whereas gram for theyaresecretedinto theenvironment Gram beta lactamases are tougherbetheyare concentratedinone STRUCTURE OF GRAM NEGATIVE BACTERIA  AMINOPENICILLINS: AMPICILLIN bolismAMOXICILLIN 897nA si  Ampicillin (PO/IV)  Amoxicillin (PO) → amoxicillin is the p.o. choice  Aminopenicillins retain/exceed much of the good gram (+) spectrum of the “Natural” PCNs:  Streptococcus spp.  S. pneumoniae  S. pyogenes  Oral anaerobes 1141   Viridans group strep (+/-) Enterococcus spp. (DOC) o  Propionibacterium more  Heliobacter pylori  Listeria sp. (DOC = ampicillin +/- gentamicin)  Neisseria meningitidis AMINOPENICILLIN + BETA-LACTAMASE INHIBITOR: AMPICILLIN/ SULBACTAM AMOXICILLIN/ CLAVULANIC ACID  Ampicillin/sulbactam (Unisyn®) → IV  Amoxicillin/clavulanic acid (Augmentin®)→ PO  When combined with a beta-lactamase inhibitor, amoxicillin and ampicillin expand the spectrum of aminopencilllins to include MANY of the clinically-important gram negative bacilli (i.e., enterobacteriaceae & Haemophilus influenzae): Salmonella, Shigella, Haemophilus influenzae, E.coli, Moraxella catarrhalis Proteus mirabilis (DOC) + Klebsiella, Bacteroides spp. = SS HEMP + BK area of dominatesthe THINK: Amp/Amox coverages + SS HEMP + BK gut choice  “SP-CE-M” and Pseudomonas aeruginosa are NOT covered !!  AMINOPENICILLIN + BETA-LACTAMASE INHIBITOR: AMPICILLIN/ SULBACTAM AMOXICILLIN/ CLAVULANIC ACID  These two combination aminopenicillin/beta lactamase inhibitors also cover:  Staphylococci (MSSA only) not MRSA  Pasturella multocida (DOC) = animal bites  Acinetobacter ( the sulbactam component of Unisyn® exhibits activity against Acinetobacter)  Prevotella ( gram negative oral anaerobe often recovered from anaerobic lung abscesses)  Borrelia burgdoferi (early Lyme disease)  ANTIPSUEDOMONAL PENICILLINS: PIPERACILLIN/TAZOBACTAM TICARCILLIN/CLAVULANIC ACID DC  Piperacillin and Ticarcillin  Are combined with a beta-lactamase inhibitor: Piperacillin/tazobactam (Zosyn®) , Ticarcillin/clavulanic acid (Timentin®)  Broad spectrum: AEROBIC and ANAEROBIC gram positive & gram negative organisms  Expand the gram negative spectrum beyond that of the aminopenicillins to include some of the SPACE-M** organisms: Serratia, Pseudomonas & Providencia, Acinetobacter, Morganella (all per susceptibility testing). ** Enterobacter cloacae, Citrobacter freundii, and Klebsiella aerogenes (“ECK”) are at moderate-to-high risk for producing an inducible chromosomal beta-lactamase, AmpC, that may be difficult to detect on initial susceptibility testing but can mediate resistance to all currently available beta-lactams other than carbapenems and, in some cases, cefepime. Carbapenems (i.e., meropenem) are the DOC’s to treat these three species. Cefepime monotherapy can be used if MIC < 2  ANTIPSUEDOMONAL PENICILLINS: PIP/TAZO  Good activity against Bacteroides spp. & other ANAEROBES (cefepime, which has a similar antibacterial spectrum to that of Pip/tazo does not)  Otherwise (in general) they cover most of the same bacteria (both gram positive and gram negative) that amoxicillin/clavulanic acid or ampicillin/sulbactam do THINK: Ampicillin/sulbactam coverages + serious infections due to many of the Enterobacteriaceae (including SPACE-M, but caution if using as definitive therapy for “ECK”) + Pseudomonas + Bacteroides fragilis  Used to treat serious or complicated infections including Pseudomonas aeruginosa ( +/- an aminoglycoside): complicated UTI, pyelonephritis, pneumonia, SSSTI infxns, intrabdominal infxns.  Can be used empirically pending identification of the infecting organism. ANTIPSUEDOMONAL PENICILLINS  Pip/tazo exhibits excellent activity against most Klebsiella spp. while Ticar/clavulanic acid does NOT  Ticarcillin/clavulanic acid (but not Pip/tazo) is one of the few antibiotics that covers Stenotrophomonas multophilia  * The use of ticarcillin/clavulanic acid has dropped dramatically b/c it is simply too hard to obtain the drug commercially. It’s basically unavailable anymore. So forget about this antibiotic.  PENICILLINS: SUMMARY  Pen G/PenV  Use: oropharyngeal S. pyogenes, Clostridium perfringens ( + clindamycin), Neisseria meningitidis, syphilis = DOC (IM benzathine salt Bicillin LA®), oral anaerobes: peptococcus/peptostreptococcus/actinomycetes  Oxacillin/Nafcillin/Dicloxacillin  Use: Staphylococci (“ MSSA” = “methicillin-susceptible staphylococcus aureus” → by definition this means they DON’T cover MRSA/MRSE); in  Also cover S. pyogenes so can be used for uncomplicated cellulitis PENICILLINS: SUMMARY  Amoxicillin or Ampicillin (or Amp/sulbactam: Amox/clavulanic acid):  Use: Covers same gram (+) organisms as Pen G (e.g., S. pneumoniae & other Streptococcus spp. , Enterococcus spp., Listeria).  Combination with the beta-lactamase inhibitors clavulanic acid or sulbactam are used to expand activity to many gram negatives: E.coli, Proteus mirabilis, H. influenzae, M. catarhhalis, Shigella, Salmonella, Klebsiella, and the (anaerobe) Bacteroides fragilis.  Do not cover the “SP-CE-M” organisms. Covers most spirochetes including Borrelia burdoferi (early Lyme disease), covers H. pylori, N. meningitidis; animal bites (DOC for Pasturella multocida) PENICILLINS: SUMMARY  Piperacillin/tazobactam (Zosyn®)  Coverages:  Streptococcus spp. & Enterococcus (Probably less potent against gram positive cocci than aminopenicillins though)  Many nosocomial gram negative bacilli (including Bacteroides fragilis; Pseudomonas aeruginosa and other “SPACE-M” organisms → per susceptibility testing)  Caution if used for serious infections of “ECK” organisms → treatment with a carbapenem or cefepime preferred  Enterobacter cloacae  Citrobacter freundii  Klebsiella aerogenes PENICILLINS AND AMINOGLYCOSIDES  PCNs and aminoglycosides have synergistic effects- The PCN alters cell wall permeability facilitating the entry of aminoglycosides into the bacterium to reach their target ribosomes. The combination is used clinically but not added in the same mixture (the negatively-charged) PCN and (positively-charged) aminoglycoside would form an inactive complex! PENICILLINS: OVERVIEW OF ANTIBACTERIAL SPECTRUM PENICILLINS: RESISTANCE MECHANISMS  Expression of beta-lactamases: resistance has developed to PCN’s (and other beta-lactam antibiotic classes) due to acquired resistance (bacteria attain the ability to cleave open the β lactam ring by acquiring enzymes with β- lactamase activity). This is the major cause of resistance to all classes of beta-lactam antibiotics Clavulanic acid, sulbactam, and tazobactam are beta-lactamase inhibitors that are marketed in combination with select PCNs to increase the effectiveness E of the PCN component  Decreased permeability of the drug: certain PCNs inherently cannot penetrate the outer envelope of the gram negative organism to target its PBPs. Porin- deficient bacterial mutants have also been identified PENICILLINS: RESISTANCE MECHANISMS  Some bacteria develop efflux pumps (expels drug)  Altered PBPs so that the PCN binds with less affinity :  MRSA/MRSE: PBP 2 altered to PBP 2a (MecA resistance gene)  PCN-resistant S. pneumoniae: mutation to PBP2b and PBPx E  PCN-resistant Enterococccus faceium : mutation of PBP 5 to a low-affinity form  PCN-resistant Enterococcus faecalis: mutation of PBP 4 to a low affinity form  Organism Resistant to: PBP (alteration) S. aureus Methicillin, β-lactams (except 2a (decreased binding) ceftaroline) S.epidermidis Methicillin, β-lactams (except 2a (decreased binding) ceftaroline) S. pneumoniae Ampicillin 1a, 2x, 2a, or 2b (decreased binding) E. faecalis Most β-lactams 1, 3 (decreased binding) 3 (overproduced) E. faceium Most β-lactams 1, 2 (decreased binding) E. coli Cephalexin 3 (decreased binding) P. aeruginosa Piperacillin 3 (decreased binding) Acinetobater calcoaceticus β-lactams 1,3 (decreased binding) N. gonorrhoeae β-lactams 1, 2 (decreased binding) N. meningitidis β-lactams 2 (decreased binding) H. influenzae Ampicillin 4 (decreased binding) β-lactams 3, 4, 5 (decreased binding) B. fragilis Cefoxitin 1 (decreased binding) Cefotetan 1, 2 (decreased binding) ADVERSE EFFECTS OF THE PENICILLINS  GI effects :  Leukopenia,neutropenia,thrombocyto-  Nausea, Diarrhea (most common side penia with prolonged therapy (> 2-4 effects); potential for superinfections, weeks) including C. difficile-related  A decrease in WBC counts is occasionally pseudomembranous colitis seen with all PCNs  Hypersensitivity Reactions  Neutropenia/ Bone-marrow suppression → highest incidence with nafcillin  Skin Rash: macropapular with puritis (higher incidence with ampicillin?)  Prolonged Bleeding Time  Acute anaphylactic shock (10% mortality  Ticarcillin interferes with platelet function by but incidence is only 0.05%) binding to ADP receptors on the platelet  Serum sickness (rare)→ highest incidence with Pen G  Seizures  Pen G (benzyl penicillin) can weakly block GABA-A receptors in the CNS DRUG ROUTE HALF-LIFE RENAL EXCRETION PROTEIN % (HOURS) BINDING Pen G IM, IV 0.5 97-85 60% Pen V Oral 0.5 20-40 80% Benzathine IM 14 days Pen G Nafcillin IV 0.8 -1.2 31-38 90% Oxacillin IV 0.4 - 0.7 39-36 92% Dicloxacillin Oral 0.6 - 0.8 35 -50 96% Ampicillin Oral, IV 1.1 – 1.5 40 -92 16 -20% Amoxicillin Oral 1.4 – 2.0 86 15 – 25% Ticarcillin IV 1.0 – 1.4 95 45% Piperacilllin IV 0.8 -1.1 74 - 89 30% HAPTEN FORMATION VIA SPONTANEOUS ISOMERIZATION OF PENICILLINS LEADS TO PENICIILLIN HYPERSENSITIVITY CEPHALOSPORINS STRUCTURES OF cephalexin SELECT CEPHALOSPORINS cefazolin CEPHALOSPORINS  “ Generations” are classified based on common antibacterial spectrums shared by members of a particular generation and beta- lactamase resistance  ALL cephalosporins are stable to the staphylococcal beta-lactamase (penicillinase)  NO cephalosporin covers Enterococcus, Listeria, or atypical bacteria  IMPORTANT NOTE: The antimicrobial spectrum discussed for the various cephalosporins in these slides are generalizations. Selection of a particular cephalosporin ( or any antibiotic for that matter) for the treatment of a serious infection is contingent on laboratory susceptibility testing, institutional antibiograms, community/institutional resistance patterns, etc. CEPHALOSPORINS: ANTIMICROBIAL SPECTRUM GENERALIZATIONS CEPHALOSPORINS: GENERALIZED ANTIBACTERIAL SPECTRUM 1ST GENERATION CEPHALOSPORINS: OVERVIEW 1st Generation  Staph. (MSSA) and Strep.  PEcK  Cefazolin  Cephalexin (p.o.)  Cephadroxil (p.o)  ALL generations of cephalosporins are stable against staphylococcal beta-lactamases (i.e., penicillinase) 1ST GENERATION SPECTRUM  Gram positive: Staphylococci (MSSA) & Streptococci [Note: NO cephalosporin covers Enterococcus sp.]  Gram negative: PEcK: * = variable coverage due to current prevalence of resistance genes Proteus mirabilis E. coli * Klebsiella *  Ineffective against MRSA/MRSE, enterococci, or Listeria  Limitations (don’t cover): most respiratory tract infections, animal bites, oral & colon/abdominal anaerobes (Bacteroides fragilis), CNS infections (don’t cross the blood-brain barrier) SELECT 1ST GENERATION AGENTS  Cephalexin (Keflex®) PO: oral treatment of uncomplicated skin infections and UTI  Cefazolin (Ancef®) IV: surgical prophylaxis !! , staph (MSSA), strep, cellulitis, folliculitis, orthopedics (penetrates bone) SELECT CEPHALOSPORINS: 2ND GENERATION SPECTRUM  SECOND GENERATION SPECTRUM: THINK same coverages as 1st generation agents, but adds these gram negatives: Haemophilus influenzae, Neisseria, Moraxella catarrhalis → so gram negative coverages = HeNPEcK + M  Cefuroxime IV ; Cefuroxime axetil PO (prodrug of cefuroxime); Cefprozil PO  Uses: Sinusitus & Otitis (cefuroxime axetil, cefprozil), Respiratory infections including community-acquired pneumonia since it covers S. pneumoniae, H. influenzae, M. catarrhalis  Limitations (don’t cover): many enteric organisms/abdominal anaerobes; should not be used for CNS infections (even though cefuroxime does cross the blood-brain barrier) 2ND GENERATION CEPHALOSPORINS: OVERVIEW 2nd Generation  Gram positive coverage: slightly less, but similar to 1st generation agents  Increased coverage of gram-negative organisms compared to 1st gen. agents: HeNPEcK + M  Cefuroxime  Cefuroxime axetil (p.o.)  Cefprozil (p.o.)  The following two agents are more correctly termed “cephamycins”. They are unique because they cover anaerobes (Bacteroides spp ? → resistance is increasing). However, these agents are not as popular as they once were:  Cefoxitin  Cefotetan ( no longer marketed in USA → has MTT side chain in its chemical structure → may F cause bleeding) SPECIAL SUBCLASS OF 2ND GENERATION CEPHALOSPORINS: THE “CEPHAMYCINS”  Cefoxitin (IV), Cefotetan (IV) ✓Add activity against Bacteroides spp. (reliable coverage??) and oral anaerobes  Stable to many cephalosporinases including ESBLs, but NOT the AmpC beta-lactamases of SPACE-M organisms or carbapenemases (e.g., KPC)  Biggest use is prophylaxis of intra-abdominal and gynecologoical surgeries (so-called “dirty-surgery” e.g., colorectal, appendectomy, OB/GYN) b/c mixed aerobe/anaerobe organisms may be present  Note: Bacteroides fragilis is the most common cause of anaerobic infections in humans. Abdominal infections are usually polymicrobial and result from a disruption in tissue barriers.  Also have been used in the treatment of lung abscess and hospital acquired pelvic inflammatory disease (PID)  Cefoxitin (not cefotetan) has some activity against certain non-TB mycobacteria  Limitations: staph and certain other gram positives Bacteroides spp. can cause infections in various parts of the human body. They have been isolated from numerous patients suffering from meningitis and brain abscesses. After entry into the blood stream during extraintestinal infections, these microbes may enter the CNS by penetration of the blood brain barrier via olfactory and trigeminal cranial nerves. They have also been associated with oral infections and abscesses in the neck. In 90% of the cases of lung abscesses, polymicrobial Sites of infection and diseases caused by infection occurs, and Bacteroides fragilis has been the predominant anaerobe isolated. Bacteroides spp. Bacteroides vulgatus and Bacteroides fragilis have been reported to be the two main isolates from patients suffering from Crohn’s disease, while the latter has been associated with intra- abdominal abscesses, appendicitis, and IBD. 3RD GENERATION CEPHALOSPORINS: OVERVIEW 3rd Generation  GOOD activity against gram negative bacilli. Also effective for treatment of moderately PCN-resistant pneumococcus; gonorrhea; bacterial meningitis (especially ceftriaxone)  Ceftriaxone  Cefotaxime  Ceftazidime +/- avibactam (only 3rd generation agent that covers Pseudomonas)  Cefdinir (p.o.)  Cefixime (p.o.) E  Cefpodoxime (p.o.)  Avoid use of 3rd generation agents for SPACE-M (disputed) and ESBL- or carbapenemase- elaborating organisms  The ones with a “t” in their name cross the blood-brain barrier and are useful in treating meningitis→ ceftriaxone, cefotaxime, and ceftazidime CEPHALOSPORINS: 3RD GENERATION  Parenteral 3rd generation cephalosporins (those with a “t” in their name) display excellent activity against gram negative bacilli (e.g., Haemophilus influenzae, Salmonella, Serratia, Klebsiella, E.Coli, Proteus) These agents are widely used in the treatment and prophylaxis of infections in hospitalized patients.  The parenteral 3rd generation cephlosporins are also active against:  Gram negative cocci (Moraxella catarrhalis and Neisseria spp.)  Avoid using for “SPACE-M” (b/c these bacteria may harbor the AmpC beta- lactamase which is alleged to be induced/derepressed by 3rd generation agents. Also do NOT use for ESBL-elaborating, or carbapenem-resistant Enterobacteriaceae ( = CRE).  No useful activity against MRSA or Bacteroides spp. (anaerobes) CEPHALOSPORINS: 3RD GENERATION  Most 3rd-generation cephalosporins, including ceftriaxone and cefotaxime, have good activity against Streptococcus pneumoniae (including some strains with reduced penicillin susceptibility) and Streptococcus pyogenes; this activity against streptococci is comparable to that of 1st generation agents. On the other hand, ceftazidime has NO useful activity against gram positive organisms, but is the only 1st, 2nd, or 3rd generation cephalosporin with activity against Pseudomonas CEPHALOSPORINS: 3RD GENERATION 3rd Generation (cont’d)  Ceftazidime is the only 3rd generation cephalosporin that is active against Pseudomonas aeruginosa. Unfortunately, ceftazidime has no appreciable gram positive activity. Adding avibactam to ceftazidime increases its spectrum to include Enterobacteriaceae that elaborate AmpC, ESBL, and (non –metallo) carbapenemases such as the KPC  Third generation agents are not so great against staphylococci (amongst the parenteral 3rd generation cephalosporins, only ceftriaxone has useful activity against staphylococci). The oral agents, cefdinir and cefpodoxime do exhibit modest activity against staphylococci. SELECT CEPHALOSPORINS: 3RD GENERATION CEPHALOSPORIN: CEFTRIAXONE  Ceftriaxone (Rocephin®): IV “ superstar” 3rd gen. ceph (QD, 60% biliary and 40% renal elimination), crosses BBB.  Ceftriaxone is the 3rd generation parenteral agent used most often for susceptible organisms b/c it is dosed QD and can be used in renal failure without dose reduction. penetrates the CNS and is useful in the treatment of bacterial meningitis (susceptible organisms only).  Activity against staphylococci (modest), but good activity against streptococci (e.g., pneumococci); broad gram negative coverage (but don’t for use “ECK”, or carbapenemase- or ESBL-elaborating organisms)  Uses: Pulmonary, head & neck, endovascular, and GI infections.  Single-dose ceftriaxone is the drug of choice (usually in combination with another antibiotic such as azithromycin) to treat urethral, cervical, rectal, and pharyngeal gonorrhea  Ceftriaxone is also useful in treating late Lyme Disease with neurologic complications, carditis, or arthritis SELECT CEPHALOSPORINS: 3RD GENERATION: CEFTRIAXONE (CONT’D)  Limitations: does NOT cover Pseudomonas or Bacteroides spp.  Ceftriaxone can cause biliary sludging (crystallization of drug) which limits its utility in treating biliary tree infections  Ceftriaxone has also associated with kernicterus in neonates  The dose of ceftriaxone does not need to be reduced in patients with either renal or liver dysfunction ! SELECT CEPHALOSPORINS: 3RD GENERATION  Cefotaxime (Claforan®) IV  Very similar in coverages to that of ceftriaxone including staphylococci and streptococci (but can be used in neonates, while ceftriaxone cannot b/c of risk of kernicterus)  Requires administration BID or TID for efficacy; dose reduction required in renal disease  Generally speaking, ceftriaxone has replaced this agent for most indications SELECT CEPHALOSPORINS: 3RD GENERATION: CEFTAZIDIME  Ceftazidime (Fortaz®): IV  Is unique amongst the 3rd generation cephalosporins in that it covers Pseudomonas aeruginosa  Stenotrophomonas maltophilia (very few antibiotics cover this organism)  Limitations: little activity against gram positives, oral anaerobes, no Bacteroides spp.  Ceftazidime/avibactam (Avycaz®): IV  Use: Addition of the beta-lactamase inhibitor ,avibactam, confers activity against gram negative bacilli (Enterobacteriaceae) that express AmpC, ESBL, and carbapenemases (non-metallo carbapenemases only)  Above coverages includes Pseudomonas aeruginosa and CNS infections → useful for Pseudomonal meningitis, but cefepime or meropenem are preferred agents due to cost considerations) SELECT CEPHALOSPORINS: ORAL 3RD GENERATION AGENTS (FYI)  Select oral agents: Cefdinir (Omnicef®) Cefixime(Suprax®) Cefpodoxime (Vantin®)  Cefdinir (Omnicef®) :  Approved Uses: Acute bacterial exacerbation of chronic bronchitis, acute maxillary sinusitis, community-acquired pneumonia, otitis media, pharyngitis and/or tonsillitis. Skin and skin structure infections. SELECT CEPHALOSPORINS: ORAL 3RD GENERATION AGENTS (FYI)  Cefpodoxime (Vantin®):  Approved uses: Acute ano-rectal infections in women, acute bacterial exacerbation of chronic bronchitis, community-acquired pneumonia, acute maxillary sinusitis, otitis media, pharnygitis and/or tonsillitis. Skin and skin structure infections, uncomplicated gonorrhea, urinary tract infections  Cefixime (Suprax®)  Approved Uses: Uncomplicated gonorrhea, acute bacterial exacerbations of chronic bronchitis, otitis media, pharyngitis and/or tonsillitis, urinary tract infections CEFEPIME: THE ONLY 4TH GENERATION CEPHALOSPORIN 4th Generation: Cefepime (Maxipime®) IV  Broad spectrum against Gram (+) and Gram (–) organisms including (SPACE-M), Pseudomonas, but NOT Bacteroides spp. or ESBL/carbapenemase-expressing bacteria  Re-establishes the good coverage of staphylococci and other gram positive cocci that was declining in the transition from 1st to 3rd generation agents; but NO MRSA, Listeria, Enterococcus (cephalosporins don’t cover these organisms anyway)  Use: Enterobacter, Citrobacter and Serratia, Pseudomonas aeruginosa  Used in neutropenic fever, CNS infections (crosses blood-brain barrier) and multi-drug resistant infections; Better gram positive activity (staphylococci and streptococci) than 3rd generation agents (no MRSA) 4TH GENERATION CEPHALOSPORIN (CEFEPIME) OVERVIEW 4th Generation  ↑ Gram (+) and Gram (-) including SPACE-M  Covers Pseudomonas  Crosses the blood brain barrier  Usually reserved for multi-drug resistant organisms  NOT stable to ESBL- or KPC-elaborating agents 4TH GENERATION CEPHALOSPORIN: CEFEPIME  The 4th generation agent, Cefepime (Maxipime®) is designated to target organisms with multiple-drug resistance, including SPACE-M. (however, NOT useful for organisms that elaborate ESBLs, carbapenemases).  Extended spectrum of activity:  Relatively good gram-positive activity (not Enterococcus spp.). This is an important point: Cefepime brings back the good coverage of staphylococci (and streptococci) that was declining in the transition from 1st to 3rd generation cephalosporins  Good gram negative coverage including Pseudomonas aeruginosa; and SPACE-M (per in-vitro susceptibility testing)  Lacks coverage of ANAEROBES → add metronidazole to expand coverage  Cefepime crosses the blood-brain barrier → useful for meningitis 5TH GENERATION CEPHALOSPORINS: OVERVIEW 5th Generation Ceftaroline:  ↑ Gram (+) including MRSA (other coverages similar to ceftriaxone) Ceftolozane/tazobactam  No MRSA coverage, but covers Pseudomonas, Bacteroides, SP-CE-M) CEPHALOSPORINS 5th Generation  Ceftaroline (Teflaro®): Improved gram + activity; other coverages similar to that of ceftriaxone (THINK “CTX + MRSA”)  Ceftaroline is the ONLY beta lactam antibiotic that covers MRSA/MRSE because unlike other beta-lactam antibiotics it can bind to, and inactivate PBP 2a  Ceftolozane/tazobactam (Zerbaxa®)  Newer agent with spectrum similar to a 3rd generation cephalosporin with the added advantage of good coverage of Pseudomonas aeruginosa and modest coverage of the ANAEROBE Bacteroides fragilis. Covers SP-CE-M (no Acinetobacter). Also useful for PCN-resistant Strep. pneumoniae SELECT CEPHALOSPORINS: 5TH GENERATION 5th generation: 0  Ceftaroline (Telflaro®) IV : ONLY beta-lactam antibiotic that covers MRSA/MRSE; other coverages resembles those of ceftriaxone  Uses: Community acquired pneumonia (OK against MSSA-related pneumonia, but should NOT be used for MRSA-related pneumonia)  Complicated skin and skin structure infections (MRSA approval is for the skin only, not for pneumonia) O  Ceftolozane/tazobactam (Zerbaxa®) IV:  Approved in combination with metronidazole for intra-abdominal infxns (Proteus, Pseudomonas, Bacteroides fragilis). Useful for complicated UTI, pyelonephritis. Covers SP-CE-M (no Acinetobacter). Also useful for PCN-resistant Strep. pneumoniae ADVERSE EFFECTS OF THE CEPHALOSPORINS  Hypersensitivity reactions ( cross-sensitivity in ~ 1-5 % of patients with penicillin allergy)  Serum-like sickness with prolonged parenteral administration  Moderate-to-severe diarrhea, especially with cefixime  Cefotetan (has the MTT sidechain): Hypoprothrombinemia, bleeding (antidote: vitamin K) and disulfiram-like reactions with ethanol  Superinfection  Kernicterus (ceftriaxone)  Biliary sludging with ceftriaxone (but not with other cephalosporins)  CEFIDEROCOL (FETROJA®): THE UNIQUE NEW CEPHALOSPORIN FOR THE MANAGEMENT OF MULTI- DRUG RESISTANT GRAM NEGATIVE ORGANISMS  Cefiderocol is a first in its class, an injectable siderophore cephalosporin with potent in vitro activity against carbapenem-resistant Enterobacteriaceae (CRE) and drug- resistant non-fermenting Gram-negative bacilli.  FDA-approved for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis  Being evaluated for the treatment of nosocomial pneumonia and carbapenem-resistant infections.  Its unique mechanism of action allows for high intracellular penetration into the periplasmic space and increased stability to many β-lactamases including both serine- type (KPC, OXA) and Ambler class B metallo-β-lactamases (VIM, IMP, NDM).  Cefiderocol has an important place in therapy for complicated UTI, but further data are necessary to determine its place in therapy for other systemic infections, such as pneumonia and bloodstream infections.  CEFIDEROCOL (FETROJA®): MECHANISM OF ACTION  Similar to humans, microorganisms require iron for important cellular redox processes. In order to survive under iron-depleted conditions in human hosts, pathogens possess various pathways for heme uptake and non-heme iron-acquisition mechanisms. One such mechanism is the production and subsequent extracellular release of molecules called siderophores that scavenge for free ferric ( Fe3+) iron and undergo re-uptake into the cell as a siderophore–iron complex via iron transporter channels. Siderophores are classified into three general types: hydroxamate, carboxylate, and catecholate. Hydroxamate- and carboxylate-type siderophores are commonly produced by fungi and some bacteria, while catecholate siderophores are primarily produced by bacteria. For example, the enteric Gram-negative bacteria, Escherichia coli, produces enterobactin, a catechol siderophore with a high affinity for Fe3+, while P. aeruginosa produces a combination of pyoveridine, a hydroxamate-type, and pyochelin, a catecholate-type, siderophore.  Cefiderocol is a novel combination of a catechol-type siderophore and a cephalosporin antibiotic which utilizes the siderophore–iron complex pathway to penetrate the outer membrane of Gram-negative organisms in addition to normal passive diffusion through membrane porins.  CEFIDEROCOL (FETROJA®): MECHANISM OF ACTION (CONT’D)  The chemical structure of cefiderocol contains a cephalosporin core with side chains similar to ceftazidime and cefepime. A catechol 2-chloro-3,4-dihydroxybenzoic acid moiety on the 3-position of a side chain functions as the siderophore mimic, by chelating extracellular iron and by facilitating enhanced uptake into bacterial periplasmic space via iron transporter channels in the outer membrane. Additionally, a pyrridoline ring bound to the catechol moiety confers zwitterionic properties, similar to those of cefepime, that enhance water solubility of the molecule.  Once within the periplasmic space, cefiderocol dissociates from the iron and binds to penicillin-binding proteins (PBP), primarily PBP3, to inhibit peptidoglycan synthesis. Compared to ceftazidime, cefiderocol has demonstrated significantly lower IC50’s (50% inhibitory concentrations) and a higher affinity for PBP3 in strains of E. coli, Klebsiella pneumoniae, P. aeruginosa and A. baumannii. Furthermore, the combined structure of a cephalosporin and a catechol moiety appears to confer enhanced stability against hydrolysis by many β-lactamases, including extended spectrum β-lactamases (ESBLs) such as CTX-M, and carbapenemases, such as KPC, NDM, VIM, IMP, OXA-23, OXA-51-like and OXA-58  SOME CLINICALLY IMPORTANT BACTERIAL SPECIES THAT MAY BE WITH TREATED CEFIDEROCOL (FETROJA®) Gram positive bacteria : NONE  Anaerobes: NONE  Gram Negative Bacteria: Acinetobacter baumannii E. coli Enterobacter cloacae Klebsiella pneumoniae E Serratia marcescens Pseudomonas aeruginosa Stenotrophomonas maltophilia Burkholderia cepacia CHEMICAL STRUCTURE OF CEFIDEROCOL PHARMACOKINETICS OF SELECT 1ST AND 2ND GENERATION CEPHALOSPORINS PHARMACOKINETICS OF SELECT 3RD , 4TH & 5TH GENERATION CEPHALOSPORINS CARBAPENEMS CARBAPENEMS  CARBAPENEMS coverage  Carbapenems (“Gorilla-cillins”): IV, no oral formulations  Imipenem-cilastatin  Meropenem  Ertapenem*  Doripenem  CARBAPENEMS  Carbapenems have the broadest anti-bacterial spectrum amongst the beta- lactam antibiotics !!:  Many, many gram positive and negative organisms (including “tougher” to treat ones)  ANAEROBES including Bacteroides spp.  Pseudomonas aeruginosa  Acinetobacter **Effective against Enterococcus faecalis ( but not E. faecium)**.  Often the DOCs for “SPACE-M” or ESBL-expressing bacteria.  Carbapenems (except ertapenem) are drugs of choice for Acinetobacter (although resistance is becoming troublesome) CARBAPENEMS  Imipenem is always co-formulated with cilastatin = (Primaxin®) to protect it from degradation by renal brush border dehydropeptidases (which otherwise rapidly metabolize imipenem to an inactive, potentially nephrotoxic metabolite)  combination with cilastatin also allows for tx. of serious UTIs  Imipenem lowers the seizure threshold especially in patients with renal failure. TDI seizures Peng s imipenem  CARBAPENEMS  Meropenem (Merrem®)  Similar coverages as imipenem  Reduced seizure risk  Meropenem/Vaborbactam (Vabomere®) is effective against organisms that produce ESBLs, AmpC and carbapenemases (e.g., KPC ), but is NOT stable to metallo-beta lactamases)  Ertapenem (Invaz®) it  “Monkey-cillin” b/c no activity against : Acinetobacter, Pseudomonas, Enterococcus)  IV/IM once daily  Use for: gangrene, sepsis, pneumonia, abdominal infections  Useful in patients requiring home IV (QD 30 minute infusion) CARBAPENEMS  Doripenem (Doribax®):  Has a spectrum of activity very similar to that of meropenem  More potent against Psuedomonas aeruginosa than other carbapenems  Has greater stability in solution which allows the use of prolonged infusions  Doripenem has a black box warning stating that when used to treat patients with ventilator-associated bacterial pneumonia, it has an increased risk of death compared with imipenem-cilistatin. Also, clinical response rates were lower with doripenem. Doripenem is not approved for the treatment of pneumonia. CARBAPENEMS: SUMMARY AND SPECTRUM  Carbapenems are parenteral bactericidal beta-lactam antibiotics that have an extremely broad spectrum. They are active against:  Most Enterobacteriaceae including those that produce AmpC beta- lactamase (SPACE-M) and extended-spectrum beta-lactamases (ESBL’s); Haemophilus influenzae, Acinetobacter, Pseudomonas (except ertapenem)  Methicillin-sensitive staphylococci (MSSA), and streptococci including Streptococcus pneumoniae (except possibly strains with reduced penicillin sensitivity)  Anaerobes (including Bacteroides fragilis) CARBAPENEMS: SUMMARY AND SPECTRUM  Most Enterococcus faecalis and many Pseudomonas aeruginosa strains, including those resistant to broad-spectrum penicillins and cephalosporins, are susceptible to imipenem, meropenem, and doripenem but are resistant to ertapenem. However, meropenem and doripenem are less active against E. faecalis than imipenem. Carbapenems are active synergistically with aminoglycosides against Pseudomonas aeruginosa.  *** Carbapenems are the beta-lactam antibiotics of choice for treatment of ESBL-producing gram negative bacteria. Until proven otherwise, laboratory-confirmed ESBL-producing isolates should be reported as resistant to all penicillins, cephalosporins, and aztreonam. *** CARBAPENEMS: SUMMARY AND SPECTRUM  Enterococcus faecium, Stenotrophomonas maltophilia, and methicillin- resistant staphylococci (MRSA, MRSE) are resistant to carbapenems  Many multidrug-resistant hospital-acquired bacteria are sensitive only to carbapenems.  Imipenem and meropenem penetrate into CNS when meninges are inflamed. Meropenem is used for gram-negative bacillary meningitis including Pseudomonal meningitis; imipenem is not used in meningitis because it may cause seizures. Most seizures occur in patients who have CNS abnormalities or renal insufficiency and who are given inappropriately high doses.  CARBAPENEMS: PHARMACOKINETICS DRUG Route Half-life Renal Protein (hours) Excretion % Binding % Imipenem/ IV 1.0 60 – 70 20 cilistatin Meropenem IV 1.0 70 2 Ertapenem IV 4.0 38 85 – 90 Doripenem IV 1.0 70 – 80 8 MONOBACTAMS (AZTREONAM) MONOBACTAMS: AZTREONAM  Monobactams: 0  Aztreonam (Azactam®) IV, no oral formulation  β-lactamase resistant, except ESBLs, KPC, derepressed AmpC  Somewhat stable to metallo-beta lactamases, but will require combination with other antibiotics for potentially successful treatment of such bacteria  Covers SP-CE-M (i.e., except Acinetobacter)  Narrow spectrum:  AEROBIC Gram Negative Bacteria ONLY (no gram positive coverage !!!)  NO anaerobes !!!  Covers Pseudomonas aeruginosa.  Usually reserved for serious gram negative aerobic infections of the lung, bone, urinary tract, and blood  MONOBACTAMS: AZTREONAM  Exhibits the least immunological cross-sensitivity with other beta lactam antibiotics. on Exam  Given IV, IM  Pharmacokinetics: Half-life = 2.0 hours, Renal excretion = 75%, Protein Binding 56% Remember: NO GRAM POSITIVES AND NO ANAEROBES !! ANTIBIOTICS CONSIDERED TO HAVE GOOD ACTIVITY AGAINST ANAEROBES BETA-LACTAMASE INHIBITORS STRUCTURES OF BETA-LACTAMASE INHIBITORS Note: all three structures in the first row bear a beta-lactam ring Clavulanic Acid Sulbactam Tazobactam Avibactam Vaborbactam Relebactam BETA-LACTAMASES AND THEIR SUBSTRATES BETA LACTAMASES OF CLINICAL IMPORTANCE BETA-LACTAMASES OF CLICICAL IMPORTANCE (cont’d) ACTIVITY OF SOME MARKETED BETA-LACTAMASE INHIBITORS AGAINST SELECT BETA-LACTAMASES Pip/tazo (S/R) POLYMYXIN B & POLYMYXIN E (COLISTIN)  Used IV as a last resort to treat multi-drug resistant Gram Negatives (e.g., ESBL or KPC- producing E.coli, Klebsiella, Acinetobacter, Pseudomonas )  Also can be inhaled to treat exacerbations of cystic fibrosis  Mechanism of action: act basically as “cationic detergents”. Interact strongly with envelope and cytoplasmic membrane phospholipids of gram negative organisms causing leakage of cellular contents. Bactericidal.  Polymyxin B and colistin differ by just one amino acid in the peptide ring. There are 2 major components for colistin (colistin A and B) and for polymyxin B (polymyxin B1 and B2), the difference arising from the length of the fatty acyl chain.  Antimicrobial spectrums of polymyxin B and colistin are identical.  Adverse effects: Significant nephrotoxicity !! , and neurotoxicity (paresthesia)  POLYMYXIN B & POLYMYXIN E (COLISTIN)  The chemistry of the polymyxins is critical to their antibacterial activity. The primary amines of the α,γ-diaminobutyric acid (Dab) residues are ionized at physiological pH and thus the polymyxin molecules carry a net-positive charge, a critical property for their interaction with negatively charged phosphate groups of the lipid A of lipopolysaccharide (LPS). In addition, polymyxins possess hydrophobic regions, the most recognizable being the fatty acyl chain, and these domains are able to interact with the corresponding hydro- phobic regions of LPS. As a result of these electrostatic and hydrophobic interactions, the bacterial outer membrane is disrupted. Although this permeabilizing effect on the outer membrane led to the proposing of the “self-promoted” uptake of polymyxins , the ultimate mechanism of bacterial killing is still unknown. POLYMYXIN B & POLYMYXIN E (COLISTIN)  Colistin is administered as colistimethate (CMS). This is the prodrug form of colistin used for parenteral administration and inhalation. Hydrolyzed in the bloodstream to colistin. Unlike colistin, it is renally eliminated so dose adjustment is needed in patients with impaired renal function.  Polymyxin B is administered as its sulfate salt and is not a prodrug  The most common way in which gram-negative bacteria become resistant to these antibiotics is through chemical modification or loss of the initial polymyxin target lipopolysaccharide (LPS). “SIMPLIFIED” SPECTRUMS OF KEY ANTIBIOTICS  FOCUS ON THE TREATMENT OF ACINETOBACTER BAUMANNII  First line options:  Ceftazidime , Cefepime  Carbapenems: Imipenem/cilastatin, Meropenem)  Piperacillin/tazobactam  Ampicillin/sulbactam  Fluoroquinolones (FQ’s) : ciprofloxacin, levofloxacin → both can be administered p.o.  Aminoglycosides: gentamicin, tobramycin, amikacin → 1st line only for UTI’s w/o associated bacteremia  SMX/TMP (mostly resistant) → 1st line only for UTI’s w/o associated bacteremia when isolate is reported susceptible  Second-line options (in the setting of resistance)  Tigecycline, Minocycline Multidrug-resistant – Isolate is nonsusceptible to at least one agent in three or more antibiotic groups (ie,  Colistin, Polymyxin B third- or fourth-generation cephalosporins, fluoroquinolones, aminoglycosides, Exam until here carbapenems, piperacillin-tazobactam, ampicillin- sulbactam)