The Beta-Lactam Antibiotics

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The Beta-Lactam Antibiotics. Cell wall active agents Prevent the final step in the synthesis of the bacterial cell wall Range from very narrow spectrum to very broad spectrum. β -lactam ring. β -Lactams. How do they work?. The β -lactam binds to Penicillin Binding Protein (PBP) - PowerPoint PPT Presentation

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  • The Beta-Lactam Antibiotics

    Cell wall active agentsPrevent the final step in the synthesis of the bacterial cell wall

    Range from very narrow spectrum to very broad spectrum

  • -Lactams

  • How do they work?The -lactam binds to Penicillin Binding Protein (PBP)PBP is unable to crosslink peptidoglycan chainsThe bacteria is unable to synthesize a stable cell wallThe bacteria is lysed

  • Peptidoglycan Synthesis

  • PK/PDThe -lactams are time-dependent killersThe effect is directly proportional to the amount of TIME the concentration of the antibiotic at the site of infection is ABOVE the MIC of the organism.

    The -lactams are BACTERIOCIDAL (at therapeutically attainable levels)

  • Time DependantH Derendorf

  • Time DependantWA Craig

  • So many choices which one to pick?

    What is the likely organism?Whats its major mode of resistance?Wheres the infection?Whats my local environment?the UNC Hospital antibiogramWhat does the micro lab say?in vitro sensitivity testing

  • ClassificationPenicillinsNatural penicillinsPenG, PenVK, Benzathine Pen, Procaine PenAminopenicillinsAmpicillin, AmoxicillinAnti-Staph penicillinsOxacillin, DicloxacillinAnti-Pseudomonal[Carboxy] Ticarcillin[Ureido] Piperacillin

  • ClassificationCephalosporins1st GenerationCephalexin, Cefazolin2nd GenerationCefoxitin, Cefuroxime, Cefotetan3rd GenerationCefotaxime, Ceftriaxone, Ceftazidime4th GenerationCefepime

  • Penicillin GAvailable PO, IM, IV (dosed in units)Drug of Choice (DoC) [2-4 MU IV q4h]T. pallidum, N. meningitidis, Group A Strep, and ActinomycosisLong-acting formsProcaine PenG (12 hrs)Benzathine Pen (5 days) [2.4 MU IM for syphilis]Adverse Reactions other than skin rashPenicillin serum sickness/drug feverJarisch-Herxheimer reaction (1 and 2 syphilis)Hemolytic anemia, pancytopenia, neutropenia

  • Ampicillin/AmoxicillinAmp (IV, PO)Amox (PO)Spectrum: PenG + H. flu and some E. coliDoC: Listeria monocytogenes and Enterococcus [Amp 2g IV q4h]Dental ProphylaxisAmox 1 gram PO x 1 prior to appt.Integral in H. pylori regimensADRsNon-allergic rashes (9%) esp. when associated with a viral illness (mononucleosis - EBV)Amox better tolerated PO and better absorbed (Amp must be taken on empty stomach)

  • OxacillinIVDoC MSSA, MSSE [2g IV q4h]Actually less active against Pen susceptible isolates than PenMore active than Vanc vs. MSSASignificant hepatic metabolismNo need to dose adjust for renal impairmentADRsHepatotoxicity (cholestatic hepatitis)NeutropeniaKernicterus in neonates

  • DicloxicillinOralNOT equivalent to IV Ox (therapeutically)Poor oral absorption~50% (better on empty stomach)Dose: 250-500mg po QID

  • PiperacillinIVDoC: PseudomonasSpectrum: most Enterobacteriaceae (E. coli, Proteus, Klebsiella, Enterbacter, Serratia, Citrobacter, Salmonella and Shigella)Most active penicillin vs. PseudomonasOften used in combination with Aminoglycoside or Cipro/LevofloxacinADRsBleeding (platelet dysfunction)Neutropenia/Thrombocytopenia

  • -Lactamase Inhibitors

    How do you evade a -lactamase?Use a non--lactam agentSteric InhibitionPenicillins with large side chainsCephalosporins-lactam + -lactamase inhibitorsNot all -lactamases are inhibitable (!)

  • Clavulanic Acid

    Augmentin (Amox/Clav) POSpectrum: MSSA and upper respiratory infections (S. pneumo, H. flu, M. catarrhalis) and most anaerobesClav is responsible for most of the GI side-effects seen with Amox/ClavVariable ratios of Amox/Clav in liquids/tabs/chewtabs

  • SulbactamUnasyn (Amp/Sulbactam)Spectrum: Amp + most anaerobes + many enteric Gm (-) rods, OSSADoC: for GNR mixed infection E.coli, Proteus, anaerobes when Pseudomonas is not implicatedDiabetic foot (once Pseudomonas ruled out)Wound infections

    Sulbactam alone is very active against Acinetobacter spp.

  • TazobactamZosyn (Pip/Tazo)THE most broad-spectrum penicillinTazobactam may improve the activity of piperacillin vs. gram-negative rods, including anaerobes4.5g IV q8h = 3.375g IV q6h4.5g IV q6h for Pseudomonas

  • The Cephalosporins (generalized)*Not effective vs. Enterococcus or Listeria

  • Cephalexin/CefazolinPO/IVStable vs Staph penicillinaseSpectrum: MSSA, PSSP, most E. coli, and some KlebsCan be dose thrice weekly in HD pts[1.5 grams IV TIW]DoC: surgical prophylaxis, bacterial peritonitis in CAPD pts [1 gm in the dwell bag]ADRsPositive Coombs test (though, hemolytic anemia is rare)

  • CefuroximeIV/POExtensive use in pediatricsSpectrum: Strep pneumo, Viridans Strep, most H. flu, N. meningitidisDoC: uncomplicated CAP (esp. H. flu), UTI/pyelo

  • CefotaximeIVSpectrum: Strep pneumo, Neisseria spp., most Gram (-) enterics, M. catarrhalis and H. flu (including -lactamase +)DoC: bact meningitis (esp. in peds + amp if < 4 weeks), CAP, complicated UTI/pyelonephritis, Bacterial Peritonitis

  • CeftriaxoneIVOnce daily dosing (95% protein bound = long half-life)Spectrum: Strep. pneumoniae, most Enterbacteriaceae, Excretion: 50% urine, 50% bile = no need to adjust for renal insufficiencyCSF penetration: 5-15% in meningitis, 1.5% with out inflammationDoC: bacterial meningitis, CAP, Strep. viridans endocarditis (+ gent)ADRsCholestasisElevated bilirubin (displacement)Diarrhea

  • CeftazidimeIVSpectrum: Enteric GNR (including Pseudomonas; some Acinetobacter)No anaerobic activity (same for cefotaxime and ceftriaxone)DoC: Pseudomonas infx

  • Third Generation Cephs: Issues

    -lactamase induction?ESBLsDe-repression of chromosomal -lactamases

    Selective pressure for VRE?

  • CefepimeIVNON-Spectrum: MRSA, C. diff, Burkholderia, Stenotrophomonas, gram-negative anaerobesStable vs. de-repressed chromosomal -lactamases, but not ESBLLess -lactamase induction than 3rd CephsDoC: HAP, febrile neutropenia

  • CarbapenemsImipenem, Meropenem, ErtapenemBroad-spectrum coverage:Gram positive: PSSP, MSSA, VSEGram negative: most gram-negative organisms (Acinetobacter sp., Pseudomonas sp.) Lack of coverage: Ertapenem: Pseudomonas sp., Acinetobacter sp.All: Stenotrophomonas, Legionella sp., MRSA, VRE

  • CarbapenemsDistribution: similar to penicillinsExcretion: renal clearanceAdverse reactions: Hypersensitivity: rash, urticaria, cross-reactivityImipenem: seizures (rare)High dosesRenal dysfunctionMost likely can occur with all carbapenems at high doses

  • CarbapenemsResistance:Gram negative: usually combination of mechanisms (Carbapenemase production + decreased entry)Imipenem Decreased production of OprD (outer membrane protein for carbapenems)Imipenem utilizes OprD > meropenem, ertapenemPseudomonas, EnterobacterSusceptible to efflux system in EnterobacterMeropenem: substrate for multi-drug efflux systemsMay have increased MIC for meropenem but not imipenemAll: low affinity PBPs

  • MonobactamsMonobactams: AztreonamSpectrum: ONLY Gram negative aerobic bacteria Lack of Coverage: Some resistant P. aeruginosa, E. cloacae, and C. freundii Acinetobacter sp., Stenotrophomonas sp. Pharmacokinetics:Well distributed into tissues, esp. inflamed tissuesExcretion: renal clearanceAdverse reactions: Skin rash No cross-reactivity with Beta-Lactam class

  • What about penicillin allergies?Literature reports a ceph/pen cross-reactivity of 1 10%The cross-reactivity of aztreonam/pen or ceph is essentially 0%The cross-reactivity of carbapenems/penicillins is also around 10% (similar to that of ceph/pen)Decision making:Severity of reactionEos

    Note the D-ala-D-ala vancomycin binding siteThis crosslinking gives stability and strength to the cell wallListeria monocytogenes Imipenem: usually has better activity against enterococcus than meropenem or ertapenem. It is bacteriostatic not cidal. Cilastatin:reversible, competitive inhibitor of dehydropeptidase-1 (DHP1) (enzyme found in the brush border of the proximal tubular cells of the kidneys) Prevents the breakdown of imipenem to inactive metabolites

    OprD: is different than the one used for cephalosporins