Transcript RTC ANTIBIOTICS CEPHALOSPORINS AND PENICILLINS

Antibiotic Therapy in the Critically
Ill Surgical and Trauma Patient
Part I: Penicillins,
Cephalosporins, Troleandomicins
Justin Chandler, MD
1/5/11
Pharmacokinetics
• Quantifies the course of the drug through the body
• Goal is effective response with no toxicity
– Must understand drug absorption, distribution, and elimination
• Influence plasma drug concentration
• Bioavailability - percentage of an administered dose that reaches the
circulation
• Half-life – time required for halving of blood concentration
– Function of clearance and volume of distribution
• Volume of distribution – proportion of drug in plasma compared to
body
– Derived factor, may be altered by 3rd space volume, fluid overload, or
hypoalbuminemia potentially altering dosing
• Clearance – refers to volume of liquid from which the drug is
removed per unit time (distribution to tissues, metabolism, or
elimination)
Pharmacodynamics
• Attempts to quantify the heterogenous responses to drug
administration
– Drug-patient, drug-microbe, and microbe-patient interactions are found
when dealing with antibiotics
– Knowledge of how patient characteristics influence absorption,
distribution and elimination, along with how the antibiotic interact with
the microbe can improve intended response
– Microbial pathology, inoculum size, groth phase, resistance, pt milieu
(pH, site of infection, immune response) are important factors
• Pharmacodynamics is a laboratory analysis, and can be difficult to
translate to actual pt care
• In vitro studies include minimal inhibatory concentration (MIC)
– Provides useful information about drug levels needed for inhibition of
bacterial growth
– May miss “subpopulations” of resistance
– “Postantibiotic effect” is inhibition of bacterial growth despite nontheraputic blood levels seen with aminoglycosides and β-lactams
Penicillin
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Prototype drug
– Discovered by Alexander Fleming
in 1928
• Group of antibiotics derived from
Penicillium fungi
– Florey, Chain, and associates
made possible the commercial
production of penicillin G (by the
end of the 1940s) initiating the
modern antibiotic era
– Classified as β-lactam antibiotics
– Are bacteriocidal, and act by
inhibiting the synthesis of the
peptidoglycan layer of cell walls
• An important for cell wall structural
integrity (esp G+)
• The final transpeptidation step in
the synthesis is facilitated by
transpeptidases known as
penicillin-binding proteins (PBPs)
β-lactams
• Divided into five classes on the basis of antibacterial
activity (considerable overlap)
– Natural penicillins
• Penicillin G and penicillin
– Penicillinase-resistant penicillins
• Methicillin, nafcillin, and isoxazolyl penicillins
– Aminopenicillins
• Ampicillin and amoxicillin
– Carboxypenicillins
• Carbenicillin and ticarcillin
– Acyl ureidopenicillins
• Azlocillin, mezlocillin, and piperacillin
• Carboxypenicillins and ureidopenicillins are also referred
to as antipseudomonal penicillins
β-lactams
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Natural Penicillins
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Penicillinase-Resistant Penicillins
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Addition of amino group
Retain G+ and antistreptococcal activity, poor against staph
Effective against E faecalis (including VRE but not E faecium), Neisseria, Moraxella, some E
coli and Klebsiella, Salmonella, Shigella, & Proteus and some H influenza
Extended-Spectrum Penicillins (carboxypenicillins, acyl ureidopenicillins)
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Useful for strep, C diphtheriae, some staphylococci (resistance: S aureus 60%, S epi 90%,
and almost all enterococci)
Aminopenicillins
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Do not have G- activity
Mostly used for aerobic and anaerobic streptococci, Enterococcus faecalis (but not E
faecium), Corynebacterium, Listeria, Neisseria m, Proteus m, Pasturella m, Bacteroides (not
B fragilis) and Clostridium (not C diff)
Enhances activity against G- and P aeruginosa
Ureidopenicillins have increased intrinsic activity against Pseudomonas
Effective against S aureus, Listeria m, Salmonella, Proteus, Providentia spp, P multocida,
many anerobes (cocci, B fragilis, Bacteroides, Prevotella and Clostridium spp (not C diff)
Pip/taz widest coverage (esp P aeruginosa), Amp/sul poor againt nosocomial pathogens
β-lactamase inhibitors (clavulanate, sulbactam, tazobactam)
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Have marginilized use of ureidopenicillins
Cephalosporins
• Consist of >40 drugs with a
wide variety of activities
• Split into 5 generations
• G+ coverage best with 1st gen
and decreases with 2nd to 4th
gen
• G- coverage best with 3rd gen,
poor with 1st gen
• 4th gen has antipseudomonal
activity and better G+ than 2nd
or 3rd gen, but poor MRSA
coverage
• 5th gen has increased MRSA
coverage
First Generation
• Strong G+ coverage
– Some G- coverage with
parenteral route
– Used orally as outpt tx
– Major role in surgical
prophylaxis
– Strong action against
methacillin sensitive staph
(MSSA) and strep
• Poor at anerobes
• Some activity againt E Coli,
Klebsiella, H influenza, P
miriabilis
• Cefadroxil (Duricef)
– Oral (peak serum
concentrations 16 and 28
mcg/mL )
• Cefazolin (Ancef)
– Parenteral
• Cephalexin (Keflex)
– Oral
• Cephalothin (Keflin)
– IV
• Cephapirin (Cefadyl)
– IV
• Cephradine (Velosef)
– Oral & IV
Second Generation
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Of interest to the abdominal surgeon
Stronger G- Coverage, still retain
some G+ coverage (between 1st and
3rd gen)
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Retain activity against aerobic and
anaerobic strep, lose some
effectiveness against MSSA
Effective against N gonorrhea,
cefuroxime for N meningitidis
Activity against Enterobacteriaceae
except Enterobacter
No activity against Acinetobacer,
Pseudomonas, or Stenotrophomonas
All are strong against E Coli & K
pneumoniae
Cepamycins and Carbacephems have
activity against G- anerobics, including
B fragilis
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Cefaclor (Ceclor, Distaclor, Keflor, Raniclor)
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Cefamandole
Cefminox
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Oral, IV, IM
Cefuzonam
Cephamycin (Cefoxitin [Mefox], Cefotetan,
Cefmetazole)
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Oral
Cefbuperazone
Cefuroxime (Ceftin)
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IV,IM
Cefprozil (Cefzil)
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IM, IV
Cefotiam
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IV
Ceforanide
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IV
Cefonicid
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Oral
IV ; IV
Carbacephem (Loracarbef)
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Oral
Third Generation
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Extremely popular choices for parenteral
abx
Are relatively resistant to β-lactamases
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Have extended spectrum against GNR
Lack activity against G+ (except ceftriaxone)
and anaerobes
Effective againt Enterbacteriaceae,
(Enterobacter, Citrobacter, Providencia,
Morganella), Aeromonas
Variable against Acinetobacter,
Pseudomonads,
No activity against S maltophilia
Cefoperazone and ceftazidime useful againt B
burgdorferi
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Because resistance can be transmitted to
staphyloccci, GISA and VRSA are emerging
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Cefixime (Suprax)
Cefapene
Cefdinir (Omnicef)
Cefditoren (Meiact)
Cefpodoxime
Cefetamet
Cefteram
Ceftibuten (Cedax)
Parenteral
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Have a role in induction of ESBL organisms
(esp Enterbacteriaceae) and along with
vancomycin, VRE
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Oral
Cefotaxime
Ceftazidime (Cefzim, Fortum, Fortaz)
Ceftriaxone (Rocephin)
Cefmenoxime
Cefpiramide
Cefodizime (Cefazone)
Cefoperazone (Kefotex, CEfoTaX, Claforan)
Cefsulodin
Ceftizoxime
Oxacephem (Flomoxef, Latamoxef)
Cefdaloxime
Cefpimizole
Ceftiolene
Fourth Generation
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Excellent penetration (brain)
Broadest spectrum of activity of
any cephalosporins
– G- is broader than 3rd gen with
good activity againt
Pseudomonads
– G+ coverage comparable to 1st
generation
– More resistant to hydrolysis by βlactamase
• Also less risk of ESBL induction
– Little activity for Enterococci or
enteric anerobes
• Cefepime
– IV, IM
• Cefozopran
• Cefpirome (Cefrom,
Keiten, Broact, Cefir)
“Fifth” Generation
• Combines the activity of the 3rd
and 4th generation
cephalosporins
• Best in vitro activity of any βlactam agent against CAMRSA
– Designed to bind to and
inactivate PBP2a, which
confers resistance in MRSA to
β-lactam agents
• Ceftobiprole may be FDA
approved, however Ceftaroline
is already approved
• Ceftobiprole
– Active against MRSA,
penicillin-resistant S
pneumoniae, P aeruginosa,
and Enterococci
– Non-inferior to the
combination of vancomycin
and ceftazidime for skin and
soft tissue infections
• Ceftaroline
– Activity against MRSA and G+
– Retains broad spectrum
activity against G– Being investigated for CAP
and complicated skin and soft
tissue infection
β-lactam Allergy
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Less common than generally believed (~7-40/1000)
4 distinct types
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Immediate hypersenitivity due to preformed IgE
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Cytotoxic reactions occur when β-lactam-specific IgG or IgM bind to RBCs or renal intersitiail
cells
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Contact dermatitis is the usual manifestation as well as exanthematous reactions and photosenitivity
Other reactions include pruritis, maculopapular reactions, erythema multiforme,
erythema nodosum, photosenitivity, and exfoliative dermatitis
Mechanism involves PCN binding to tissue proteins forming hapten-protein complex
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Most common is penicilloyl derivative or major determinant
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Can lodge in tissue resulting in serum-sickness-like reactions or drug fever
Typically occur 1-2 weeks after exposure
Cell-mediated hypersenitivity results from β-lactam specific T-cells causing cytokine release
and lymphocyte proliferation
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Results in complement dependent cell lysis (hemolysis, purpura)
Immune complex (Arthus) reaction occurs when IgG or IgM complexes fix complement
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Results in uticaria, angioedema, and anaphylaxis
Results in accelerated and late reactions
Minor determinant responsible for anaphylactic reaction
Cephalosporins share a 5-10% cross reactivity, with 1st generation being higher
Anaphylaxis will occur in approximately 0.01% of patients
Question?
• What the hell are Troleandomicins?
• Troleandomycin is a macrolide antibiotic
only sold in Italy and Turkey
Macrolides, Ketolides
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Macrolides
– FDA approved: Azithromycin,
Clarithromycin, Dirithromycin,
Erythromycin, Roxithromycin,
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Ketolides
– FDA approved: Telithromycin,
Cethromycin
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Are all characterized by the
macrolide ring
Mechanism is protein synthesis
inhibition by prevention of
peptidyltransferase from adding
the peptidyl attached to tRNA
– Bind reversibly to the P site on the
subunit 50S of the bacterial
ribosome
– Action is mainly bacteriostatic, but
can also be bactericidal in high
concentrations
Macrolides, Ketolides
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Commonly used in outpt settings for
upper respiratory and simple skin
infections
Used to treat infections caused by G+
bacteria, S pneumoniae, and H
influenzae
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Spectrum is slightly wider than
penicillin
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Does not cover coag (-) staph or MRSA
Are a common substitute for patients
with a penicillin allergy
Also effective against mycoplasma,
mycobacteria, some rickettsia, and
chlamydia
Clarithryomycin esp useful for H pylori
Ketolides have increase activity
against resistant organisms
Erythromtycin is effectively replaced by
the newer generations because of its
numerous side-effects, only advantage
is cost
Non-antibiotic Macrolides
• Tacrolimus, pimecrolimus and sirolimus
– Are used as immunosuppressants or
immunomodulators
– Have similar activity to cyclosporin
Side-effects
• A combination of macrolides and statins can
lead to debilitating myopathy.
– Macrolides are potent inhibitors of the cytochrome
P450 system, particularly of CYP3A4
• Class effect of QT prolongation
– Can cause torsade de pointes.
• Macrolides exhibit enterohepatic recycling
– Can lead to a build-up of the drugs
Lincosamides
• Clindamycin only agent that
remains in the class
• Mechanism: binds the 50S
ribosome unit
• Has good G+ and
antianaerobic coverage (B
fragilis resistance is
increasing), but poor Gcoverage
• Used for surgical prophylaxis
in PCN allergic pts
• Has an association with C Diff
colitis
Streptogramins
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Seperate class from the other MLS
drugs
Most contain a macrolide in a binary
formulation
Of the three, Quinupristin/dalfopristin is
the most widely used
– While each is only bacteriostatic, the
combination is bactericidal activity
– Dalfopristin binds to the 23S portion of
the 50S ribosomal subunit, and
enhances the binding of quinupristin by
a factor of about 100
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Also inhibits peptidyl transfer
Quinupristin binds nearby on the 50S
subunit, preventing elongation
polypeptides and causing incomplete
chains to be released
Used to treat staphylococci and by
vancomycin-resistant Enterococcus
faecium (VRE)
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Pristinamycin
– Oral
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Quinupristin/dalfopristin (Synercid)
– IV
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Virginiamycin
– Used for herbivores and to
prevent bacterial contamination of
fuel
Resistance Mechanisms
• PCNs
– Destruction of antibiotic by β-lactamase
• most common mechanism of resistance (G+)
• β-Lactamases covalently react with the β-lactam ring, rapidly
hydrolyze it, and destroy its activity
– Failure of antibiotic to penetrate the outer membrane of Gbacteria to reach PBP targets
– Efflux of drug across the outer membrane
• Most common in G- and P aeruginosa in particular
– Reduced or low-affinity binding of antibiotic to target PBPs
• Result of mutations in PBP genes that lower binding affinity
(penicillin-resistant pneumococci or Neisseria spp)
• Or presence of an extra, low-affinity PBP
– PBP 5 produced by Enterococcus faecium
– PBP 2a produced by methicillin-resistant staphylococci
Resistance Mechanisms
• Macrolides
– The primary means is by a posttranscriptional methylation of the 23S
bacterial ribosomal RNA
• Can be either plasmid-mediated or chromosomal
– Two other types of acquired resistance
• Drug-inactivating enzymes (esterases or kinases)
• Active ATP-dependent efflux proteins
References
• Long: Principles and Practice of
Pediatric Infectious Diseases, 3rd ed.,
2008.
• Asensio: Current Therapy of Trauma
and Surgical Critical Care, 2008.
• Drug Eruptions
(http://emedicine.medscape.com/article
/1049474-overview)