The Beta-Lactam Antibiotics

32
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

description

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

Transcript of The Beta-Lactam Antibiotics

Page 1: The Beta-Lactam Antibiotics

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

Page 2: The Beta-Lactam Antibiotics

β-Lactams

β-lactam ring

Page 3: The Beta-Lactam Antibiotics

How do they work?

1. The β-lactam binds to Penicillin Binding Protein (PBP)

2. PBP is unable to crosslink peptidoglycan chains

3. The bacteria is unable to synthesize a stable cell wall

4. The bacteria is lysed

Page 4: The Beta-Lactam Antibiotics

“Penicillin binding protein”

Peptidoglycan Synthesis

Page 5: The Beta-Lactam Antibiotics

PK/PD

The β-lactams are “time-dependent” killers The 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 β-lactams are BACTERIOCIDAL… (at therapeutically attainable levels)

Page 6: The Beta-Lactam Antibiotics

“Time Dependant”

H Derendorf

Page 7: The Beta-Lactam Antibiotics

“Time Dependant”

WA Craig

Page 8: The Beta-Lactam Antibiotics

So many choices… which one to pick?

What is the likely organism? What’s its major mode of resistance? Where’s the infection? What’s my local environment?

the UNC Hospital antibiogram

What does the micro lab say? in vitro sensitivity testing

Page 9: The Beta-Lactam Antibiotics

Classification

Penicillins Natural penicillins

PenG, PenVK, Benzathine Pen, Procaine Pen Aminopenicillins

Ampicillin, Amoxicillin Anti-Staph penicillins

Oxacillin, Dicloxacillin Anti-Pseudomonal

[Carboxy] Ticarcillin [Ureido] Piperacillin

Page 10: The Beta-Lactam Antibiotics

Classification

Cephalosporins 1st Generation

Cephalexin, Cefazolin 2nd Generation

Cefoxitin, Cefuroxime, Cefotetan 3rd Generation

Cefotaxime, Ceftriaxone, Ceftazidime 4th Generation

Cefepime

Page 11: The Beta-Lactam Antibiotics

Penicillin G

Available PO, IM, IV (dosed in units) Drug of Choice (DoC) [2-4 MU IV q4h]

T. pallidum, N. meningitidis, Group A Strep, and Actinomycosis

Long-acting forms Procaine PenG (12 hrs) Benzathine Pen (5 days) [2.4 MU IM for syphilis]

Adverse Reactions – other than skin rash Penicillin “serum sickness”/drug fever Jarisch-Herxheimer reaction (1° and 2° syphilis) Hemolytic anemia, pancytopenia, neutropenia

Page 12: The Beta-Lactam Antibiotics

Ampicillin/Amoxicillin

Amp (IV, PO)Amox (PO) Spectrum: PenG + H. flu and some E. coli DoC: Listeria monocytogenes and

Enterococcus [Amp 2g IV q4h] Dental Prophylaxis

Amox 1 gram PO x 1 prior to appt. Integral in H. pylori regimens ADRs

Non-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)

Page 13: The Beta-Lactam Antibiotics

Oxacillin

IV DoC – MSSA, MSSE [2g IV q4h]

Actually less active against Pen susceptible isolates than Pen

More active than Vanc vs. MSSA Significant hepatic metabolism

No need to dose adjust for renal impairment ADRs

Hepatotoxicity (cholestatic hepatitis) Neutropenia Kernicterus in neonates

Page 14: The Beta-Lactam Antibiotics

Dicloxicillin

OralNOT equivalent to IV Ox (therapeutically)

Poor oral absorption ~50% (better on empty stomach)

Dose: 250-500mg po QID

Page 15: The Beta-Lactam Antibiotics

Piperacillin

IV DoC: Pseudomonas Spectrum: most Enterobacteriaceae (E. coli,

Proteus, Klebsiella, Enterbacter, Serratia, Citrobacter, Salmonella and Shigella)

Most active penicillin vs. Pseudomonas Often used in combination with Aminoglycoside

or Cipro/Levofloxacin ADRs

Bleeding (platelet dysfunction) Neutropenia/Thrombocytopenia

Page 16: The Beta-Lactam Antibiotics

β-Lactamase Inhibitors

How do you evade a β-lactamase?1. Use a non-β-lactam agent

2. Steric Inhibition Penicillins with large side chains Cephalosporins

3. β-lactam + β-lactamase inhibitors Not all β-lactamases are inhibitable (!)

Page 17: The Beta-Lactam Antibiotics

Clavulanic Acid

Augmentin (Amox/Clav) POSpectrum: MSSA and upper respiratory

infections (S. pneumo, H. flu, M. catarrhalis) and most anaerobes

Clav is responsible for most of the GI side-effects seen with Amox/Clav

Variable ratios of Amox/Clav in liquids/tabs/chewtabs

Page 18: The Beta-Lactam Antibiotics

Sulbactam

Unasyn (Amp/Sulbactam) Spectrum: Amp + most anaerobes + many

enteric Gm (-) rods, OSSA DoC: for GNR mixed infection – E.coli, Proteus,

anaerobes when Pseudomonas is not implicated Diabetic foot (once Pseudomonas ruled out) Wound infections

Sulbactam alone is very active against Acinetobacter spp.

Page 19: The Beta-Lactam Antibiotics

Tazobactam

Zosyn (Pip/Tazo)THE most broad-spectrum penicillinTazobactam may improve the activity of

piperacillin vs. gram-negative rods, including anaerobes

4.5g IV q8h = 3.375g IV q6h4.5g IV q6h for Pseudomonas

Page 20: The Beta-Lactam Antibiotics

The Cephalosporins (generalized)

1st Generation Gram (+)

2nd GenerationDecreasing Gram (+) and Increasing Gram (-)

3rd GenerationGram (-), but also some GPC

4th Generation Gram (+) and Gram (-)

*Not effective vs. Enterococcus or Listeria

Page 21: The Beta-Lactam Antibiotics

Cephalexin/Cefazolin

PO/IV Stable vs Staph penicillinase Spectrum: MSSA, PSSP, most E. coli, and some

Klebs Can 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]

ADRs Positive Coombs’ test (though, hemolytic anemia is

rare)

Page 22: The Beta-Lactam Antibiotics

Cefuroxime

IV/POExtensive use in pediatricsSpectrum: Strep pneumo, Viridans Strep,

most H. flu, N. meningitidisDoC: uncomplicated CAP (esp. H. flu),

UTI/pyelo

Page 23: The Beta-Lactam Antibiotics

Cefotaxime

IVSpectrum: Strep pneumo, Neisseria spp.,

most Gram (-) enterics, M. catarrhalis and H. flu (including β-lactamase +)

DoC: bact meningitis (esp. in peds + amp if < 4 weeks), CAP, complicated UTI/pyelonephritis, Bacterial Peritonitis

Page 24: The Beta-Lactam Antibiotics

Ceftriaxone

IV Once daily dosing (95% protein bound = long half-life) Spectrum: Strep. pneumoniae, most Enterbacteriaceae, Excretion: 50% urine, 50% bile = no need to adjust for

renal insufficiency CSF penetration: 5-15% in meningitis, 1.5% with out

inflammation DoC: bacterial meningitis, CAP, Strep. viridans

endocarditis (+ gent) ADRs

Cholestasis Elevated bilirubin (displacement) Diarrhea

Page 25: The Beta-Lactam Antibiotics

Ceftazidime

IVSpectrum: Enteric GNR (including

Pseudomonas; some Acinetobacter)No anaerobic activity (same for cefotaxime

and ceftriaxone)DoC: Pseudomonas infx

Page 26: The Beta-Lactam Antibiotics

Third Generation Cephs: Issues

β-lactamase induction? ESBLs De-repression of chromosomal β-lactamases

Selective pressure for VRE?

Page 27: The Beta-Lactam Antibiotics

Cefepime

IVNON-Spectrum: MRSA, C. diff,

Burkholderia, Stenotrophomonas, gram-negative anaerobes

Stable vs. de-repressed chromosomal β-lactamases, but not ESBL

Less β-lactamase induction than 3rd CephsDoC: HAP, febrile neutropenia

Page 28: The Beta-Lactam Antibiotics

Carbapenems

Imipenem, Meropenem, ErtapenemBroad-spectrum coverage:

Gram positive: PSSP, MSSA, VSE Gram negative: most gram-negative organisms

(Acinetobacter sp., Pseudomonas sp.)

Lack of coverage: Ertapenem: Pseudomonas sp., Acinetobacter

sp. All: Stenotrophomonas, Legionella sp., MRSA,

VRE

Page 29: The Beta-Lactam Antibiotics

Carbapenems

Distribution: similar to penicillinsExcretion: renal clearanceAdverse reactions:

Hypersensitivity: rash, urticaria, cross-reactivity Imipenem: seizures (rare)

High doses Renal dysfunction Most likely can occur with all carbapenems at high

doses

Page 30: The Beta-Lactam Antibiotics

Carbapenems

Resistance: Gram negative: usually combination of mechanisms

(Carbapenemase production + decreased entry) Imipenem

Decreased production of OprD (outer membrane protein for carbapenems)

Imipenem utilizes OprD > meropenem, ertapenem Pseudomonas, Enterobacter Susceptible to efflux system in Enterobacter

Meropenem: substrate for multi-drug efflux systems May have increased MIC for meropenem but not

imipenem All: low affinity PBPs

Page 31: The Beta-Lactam Antibiotics

Monobactams

Monobactams: Aztreonam Spectrum: 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 tissues Excretion: renal clearance

Adverse reactions: Skin rash No cross-reactivity with Beta-Lactam class

Page 32: The Beta-Lactam Antibiotics

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 reaction Eos