MEDCH 561PBeta-lactam antibiotics: Penicillins II

http://botit.botany.wisc.edu/toms_fungi/nov2003.html

April 11, 2012Kelly Lee, Ph.D.

H-172Jkklee@u.washington.edu

Penicillium chrysogenum + Staph. Aureus

Narrow vs broad spectrum antimicrobial

๏Generally would like to use as narrow spectrum of antibiotic as possible so as to reduce impact on non-pathogenic flora and so as to maintain balance, prevent overgrowth

๏ Broader spectrum increases risk of antibiotic-associated diarrhea (AAD)

๏ Potentially provides opportunity for Clostridium difficile or Candida yeast overgrowth

๏ But often we do not know the bacterial target, or may have a super-infection involving multiple species

๏ Empiric therapy with broad spectrum

๏ Identify pathogen

๏ Switch to narrower spectrum

Clostridium difficile (C. diff.)

๏ Gram+, anaerobe; spore (infective state) forming

๏ While some normally carry the bacteria, most are exposed to it in health care settings; ingested from contaminated surfaces, contact

๏ Spores are resistant to antimicrobial therapy, can lead to relapse

๏ Gains a foothold when other gut flora are wiped out or imbalanced.

๏ Produces enterotoxin (toxin A) and cytotoxin (toxin B) that damage host cells

๏ ~14,000 deaths/year in US

๏ AAD, fever, abdominal pain

๏ Pseudomembranous colitis: a severe infection of the colon

Clostridium difficile (C. diff.)

๏ Treatment:

๏ Vancomycin

๏ Metronidazole

๏ Rifamixin: targets RNA polymerase

๏ Fidamoxicin: targets C. diff RNA polymerase (FDA approved 2011)

๏ Probiotics: Saccharomyces boulardii (yeast), lactobacillus

๏ Stool transplant

Pseudomembranous colitis

Why use Pen G over a broader spectrum drug?

around the world during the past three decades(4-10). This resistance has been temporallyrelated to increased or excessive use of macrolideantibiotics. Because of this relation, it isimportant to determine the geographic

prevalence of resistant S. pyogenes to facilitateclinical care and to address public healthconcerns.

Our study shows that penicillin is active for S.pyogenes in low MIC values. This finding is

17ERG N FT , LKER DO RU, HALUK G R Z, AHMET DERYAAYSEV, ERDAL NCE

TTaabbllee 11:: Resistance to eleven antibiotics, MIC90 values, and MIC ranges of 263 S. pyogenes strains.

AAnnttiibbiioottiicc RReessiissttaanntt ssttrraaiinnss MMIICC9900 MMIICC rraannggeess((nn//%%)) ((µµgg//mmll)) ((µµgg//mmll))

Penicillin G 0/0 0.0075 0.0004-0.03Ampicillin 0/0 ! 0.125 ! 0.125-0.25Cefazolin 0/0 ! 0.125 ! 0.125-1.00Cefuroxime 0/0 ! 0.125 ! 0.125-0.50Ceftriaxone 0/0 ! 0.125 ! 0.125-! 0.25Ofloxacin 0/0 1.0 ! 0.50-1.0Vancomycin 0/0 ! 0.25 ! 0.25-0.50Clindamycin 8/3.0 0.25 ! 0.25->2.0Erythromycin 10/3.8 ! 0.125 ! 0.125-2.0Clarithromycin 11/4.2 0.25 ! 0.125-2.0Azithromycin 11/4.2 0.25 ! 0.125->2.0

TTaabbllee 22:: Penicillin G MBC/MIC ratios of S. pyogenes strains.

MMBBCC//MMIICC NNuummbbeerr ooff ssttrraaiinnss

1 2462 154 28 0

16 032 0

Total 263

FFiigguurree 11:: Penicillin G MIC and MBC values of S. pyogenes strains.

E. Ciftci et al., J. Ank. Med School (2003) 25:15-20

Notable UW formulary penicillins: Pen GPenicillin G Spectrum:

๏ Gram+ cocci๏ S. pyogenes: minimal resistance observed, does not produce beta-lactamases๏ S. pneumoniae: modified PBP in 30-40% gave rise to PRSP (penicillin resistant S. pneumo),

not due to beta-lactamase๏ most common cause of CAP (community-aquired pneumonia) 50-80%๏ very common cause of otitis media ~35%

๏ S. viridans: usually still sensitive๏ Endocarditis (heart valve infection)

๏ Enterococcus faecalis: Pen G, amoxicillin generally effective๏ But note, E. faecium: highly resistant to Pen G (92%) and vancomycin

๏ Gram+ rods๏ Clostridium tetani (tetanus), C. perfringens (gangrene, food poisoning) sensitive,

but C. difficile resistant

๏ Gram- cocci๏ Neisseria meningitidis: PenG can penetrate meninges due to inflammation, sensitive๏ But, N. gonorrhoeae no longer sensitive due to beta-lactamases

๏ Gram- rods: mostly resistant๏ E.g. Enterobacteriaceae, Pseudomonas, H. influenzae

๏ Helical and spirochetes:๏ Treponema pallidum (syphilis): sensitive to Pen G still๏ Helicobacter pylori (stomach ulcers): not Pen G; amox + clarithromycin (macrolide) + PPI

Notable UW formulary penicillins: Pen G

Bicillin® L-A

Bicillin® C-R(penicillin G benzathine andpenicillin G procaine injectable suspension)Disposable Syringefor deep IM injection only

WARNING: NOT FOR INTRAVENOUS USE. DO NOT INJECT IN TRAVENOUSLY OR ADMIX WITH OTHER INTRAVENOUS SOLUTIONS. THERE HAVE BEEN REPORTS OF INADVERTENT INTRAVENOUS ADMIN-ISTRATION OF PENICILLIN G BENZATHINE WHICH HAS BEEN ASSOCIATED WITH CARDIORESPIRA-TORY ARREST AND DEATH. Prior to administration of this drug, carefully read the WARNINGS, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION sections of the labeling.

Rx OnlyTo reduce the development of drug-resistant bacteria and maintain the effectiveness of Bicillin C-R and other anti-bacterial drugs, Bicillin C-R should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.DESCRIPTIONBicillin C-R (penicillin G benzathine and penicillin G pro-caine injectable suspension) contains equal amounts of the benzathine and procaine salts of penicillin G. It is available for deep intramuscular injection.Penicillin G benzathine is prepared by the reaction of diben-zylethylene diamine with two molecules of penicillin G. It is chemically designated as (2S,5R,6R)-3,3-Dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid compound with N,N’-dibenzyleth-ylenediamine (2:1), tetrahydrate. It occurs as a white, crystalline powder and is very slightly soluble in water and sparingly solu-ble in alcohol. Its chemical structure is as follows:

Molecular Formula Molecular Wt. (C16H18N2O4S)2 16H20N2 2O 981.19

Penicillin G procaine, (2S,5R,6R)-3,3-Dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid compound with 2-(diethylamino)ethyl p-aminobenzoate (1:1) monohydrate, is an equimolar salt of procaine and penicillin G. It occurs as white crystals or a white, microcrystalline powder and is slightly soluble in water. Its chemical structure is as follows:

Molecular Formula Molecular Wt. C16H18N2O4 13H20N2O2 2O 588.72

Each disposable syringe (2 mL size) contains the equivalent

of 1,200,000 units of penicillin G comprising: the equivalent of 600,000 units of penicillin G as the benzathine salt and the equivalent of 600,000 units of penicillin G as the pro-caine salt in a stabilized aqueous suspension with sodium citrate buffer; and as w/v, approximately 0.5% lecithin, 0.55% carboxymethylcellulose, 0.55% povidone, 0.1% methylparaben, and 0.01% propylparaben.Bicillin C-R injectable suspension in the disposable-syringe formulation is viscous and opaque. Read CONTRAINDICA-TIONS, WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION sections prior to use.CLINICAL PHARMACOLOGYGeneralPenicillin G benzathine and penicillin G procaine have a low solubility and, thus, the drugs are slowly released from intramuscular injection sites. The drugs are hydrolyzed to penicillin G. This combination of hydrolysis and slow absorption results in blood serum levels much lower but more prolonged than other parenteral penicillins.Intramuscular administration of 600,000 units of Bicillin C-R in adults usually produces peak blood levels of 1.0 to 1.3 units per mL within 3 hours; this level falls to an average concentration of 0.32 units per mL at 12 hours, 0.19 units per mL at 24 hours, and 0.03 units per mL at seven days.Intramuscular administration of 1,200,000 units of Bicillin C-R in adults usually produces peak blood levels of 2.1 to 2.6 units per mL within 3 hours; this level falls to an average concentration of 0.75 units per mL at 12 hours, 0.28 units per mL at 24 hours, and 0.04 units per mL at seven days.Approximately 60% of penicillin G is bound to serum pro-tein. The drug is distributed throughout the body tissues in widely varying amounts. Highest levels are found in the kid-neys with lesser amounts in the liver, skin, and intestines. Penicillin G penetrates into all other tissues and the spinal fluid to a lesser degree. With normal kidney function, the drug is excreted rapidly by tubular excretion. In neonates and young infants and in individuals with impaired kidney function, excretion is considerably delayed.MicrobiologyPenicillin G exerts a bactericidal action against penicillin-susceptible microorganisms during the stage of active multiplication. It acts through the inhibition of biosynthesis of cell-wall mucopeptide. It is not active against the peni-cillinase-producing bacteria, which include many strains of staphylococci. The following in vitro data are available, but their clinical sig-nificance is unknown. Penicillin G exerts high in vitro activity against staphylococci (except penicillinase-producing strains), streptococci (Groups A, C, G, H, L, and M), and pneumococci. Other organisms susceptible to penicillin G are Neisseria gonorrhoeae, Corynebacterium diphtheriae, Bacillus anthracis, Clostridia species, Actinomyces bovis, Streptobacillus moniliformis, Listeria monocytogenes, and Leptospira species. Treponema pallidum is extremely sus-ceptible to the bactericidal action of penicillin G.Susceptibility Test: If the Kirby-Bauer method of disc sus-ceptibility is used, a 10-unit penicillin disc should give a zone greater than 28 mm when tested against a penicillin-susceptible bacterial strain.

Bicillin® C-R(penicillin G benzathine andpenicillin G procaine injectable suspension)Disposable Syringefor deep IM injection only

WARNING: NOT FOR INTRAVENOUS USE. DO NOT INJECT IN TRAVENOUSLY OR ADMIX WITH OTHER INTRAVENOUS SOLUTIONS. THERE HAVE BEEN REPORTS OF INADVERTENT INTRAVENOUS ADMIN-ISTRATION OF PENICILLIN G BENZATHINE WHICH HAS BEEN ASSOCIATED WITH CARDIORESPIRA-TORY ARREST AND DEATH. Prior to administration of this drug, carefully read the WARNINGS, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION sections of the labeling.

Rx OnlyTo reduce the development of drug-resistant bacteria and maintain the effectiveness of Bicillin C-R and other anti-bacterial drugs, Bicillin C-R should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.DESCRIPTIONBicillin C-R (penicillin G benzathine and penicillin G pro-caine injectable suspension) contains equal amounts of the benzathine and procaine salts of penicillin G. It is available for deep intramuscular injection.Penicillin G benzathine is prepared by the reaction of diben-zylethylene diamine with two molecules of penicillin G. It is chemically designated as (2S,5R,6R)-3,3-Dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid compound with N,N’-dibenzyleth-ylenediamine (2:1), tetrahydrate. It occurs as a white, crystalline powder and is very slightly soluble in water and sparingly solu-ble in alcohol. Its chemical structure is as follows:

Molecular Formula Molecular Wt. (C16H18N2O4S)2 16H20N2 2O 981.19

Penicillin G procaine, (2S,5R,6R)-3,3-Dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid compound with 2-(diethylamino)ethyl p-aminobenzoate (1:1) monohydrate, is an equimolar salt of procaine and penicillin G. It occurs as white crystals or a white, microcrystalline powder and is slightly soluble in water. Its chemical structure is as follows:

Molecular Formula Molecular Wt. C16H18N2O4 13H20N2O2 2O 588.72

Each disposable syringe (2 mL size) contains the equivalent

of 1,200,000 units of penicillin G comprising: the equivalent of 600,000 units of penicillin G as the benzathine salt and the equivalent of 600,000 units of penicillin G as the pro-caine salt in a stabilized aqueous suspension with sodium citrate buffer; and as w/v, approximately 0.5% lecithin, 0.55% carboxymethylcellulose, 0.55% povidone, 0.1% methylparaben, and 0.01% propylparaben.Bicillin C-R injectable suspension in the disposable-syringe formulation is viscous and opaque. Read CONTRAINDICA-TIONS, WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION sections prior to use.CLINICAL PHARMACOLOGYGeneralPenicillin G benzathine and penicillin G procaine have a low solubility and, thus, the drugs are slowly released from intramuscular injection sites. The drugs are hydrolyzed to penicillin G. This combination of hydrolysis and slow absorption results in blood serum levels much lower but more prolonged than other parenteral penicillins.Intramuscular administration of 600,000 units of Bicillin C-R in adults usually produces peak blood levels of 1.0 to 1.3 units per mL within 3 hours; this level falls to an average concentration of 0.32 units per mL at 12 hours, 0.19 units per mL at 24 hours, and 0.03 units per mL at seven days.Intramuscular administration of 1,200,000 units of Bicillin C-R in adults usually produces peak blood levels of 2.1 to 2.6 units per mL within 3 hours; this level falls to an average concentration of 0.75 units per mL at 12 hours, 0.28 units per mL at 24 hours, and 0.04 units per mL at seven days.Approximately 60% of penicillin G is bound to serum pro-tein. The drug is distributed throughout the body tissues in widely varying amounts. Highest levels are found in the kid-neys with lesser amounts in the liver, skin, and intestines. Penicillin G penetrates into all other tissues and the spinal fluid to a lesser degree. With normal kidney function, the drug is excreted rapidly by tubular excretion. In neonates and young infants and in individuals with impaired kidney function, excretion is considerably delayed.MicrobiologyPenicillin G exerts a bactericidal action against penicillin-susceptible microorganisms during the stage of active multiplication. It acts through the inhibition of biosynthesis of cell-wall mucopeptide. It is not active against the peni-cillinase-producing bacteria, which include many strains of staphylococci. The following in vitro data are available, but their clinical sig-nificance is unknown. Penicillin G exerts high in vitro activity against staphylococci (except penicillinase-producing strains), streptococci (Groups A, C, G, H, L, and M), and pneumococci. Other organisms susceptible to penicillin G are Neisseria gonorrhoeae, Corynebacterium diphtheriae, Bacillus anthracis, Clostridia species, Actinomyces bovis, Streptobacillus moniliformis, Listeria monocytogenes, and Leptospira species. Treponema pallidum is extremely sus-ceptible to the bactericidal action of penicillin G.Susceptibility Test: If the Kirby-Bauer method of disc sus-ceptibility is used, a 10-unit penicillin disc should give a zone greater than 28 mm when tested against a penicillin-susceptible bacterial strain.

Bicillin® C-R+

Penicillin GIM formulations:๏ Procaine/Pen G (local anaesthesia + benzylpenicillin)๏ IM shot (including the local anesthetic procaine)

๏ Benzathine/Pen G (Bicillin® L-A and Bicillin® C-R): slowly absorbed to circulation๏ IM shot (not IV: cardiac arrest, black bo x warnin)๏ Low levels of PenG (but close to MIC) persist for 14-20 days๏ Bicillin L-A has all Pen G bound with benzathine: gradually Pen G is freed๏ Bicillin C-R has half of Pen G bound with benzathine and half with procaine๏ E.g. @ day 14, 0.02 µg/ml PenG, MIC for S. pneumo ~0.03µg/ml๏ Syphilis (only Bicillin L-A; FDA warning on confusion with C-R, C-R not for syphilis)

black box warning

Notable UW formulary penicillins: Pen VKPenicillin VK Spectrum:

๏ Similar spectrum to Pen G, but oral (PO); acid stable but food interferes w/ absorption

๏ Difficult to achieve as high concentrations as for Pen G (not PO), so primarily for more moderate infections

๏ Common prescription for Strep.

๏ Since PO, as w/ all self-dosed antibiotics, counsel to complete the full course

๏ Caution about allergies, diarrhea

Notable UW formulary penicillins: AmpicillinAmpicillin Spectrum: note, w/o beta-lactamase inhibitor, similar to Pen G๏ Used in combination w/ aminoglycoside for E. faecalis

๏ Even though amp can penetrate the outer Gram- bacterial membrane, many Gram- bugs produce beta-lactamases that can degrade ampicillin. For example:

๏ E. coli (80-90% of UTIs), 50% resistant to ampicillin due to beta-lactamase production

๏ Proteus mirabilis (UTIs), 30% resistant

๏ N. meningitidis generally sensitive, but some produce penicillinase

๏ N. gonorrhoeae significant penicillinase production now

๏ H. influenzae ~30% produce beta-lactamases

๏ Most nosocomial pathogens are resistant either due to innate impermeability or several resistance mechanisms including beta-lactamase production

๏ Note, significant enterohepatic recycling (as w/ bile acids):

๏ Portal vein from GI tract carries absorbed nutrients

๏ Liver secretes drug back into GI tract in bile

๏ Unmodified Amp re-secreted into bile many cycles, leading to high intestinal levels of the drug. Potentially useful for Shigella, Salmonella, enteric infections.

๏ Greater risk of adverse effects such as antibiotic-associated diarrhea and C. difficile overgrowth.

Notable UW formulary penicillins: AmpicillinAmpicillin + Sulbactam spectrum (IV, IM):๏ Inclusion of beta-lactamase inhibitor (sulbactam) increases coverage of Gram- to also include:

๏ M. catarrhalis (otitis media, pneumo, sinusitis)

๏ H. influenzae (otitis media, pneumo, sinusitis)

๏ S. pneumoniae (otitis media, pneumo, sinusitis)

๏ Non-MRSA S. aureus, MSSA.

๏ Klebsiella

๏ Enterobacter

๏ E. coli

๏ N. gonorrhoeae

๏ Good activity against anaerobes

Notable UW formulary penicillins: AmoxicillinAmoxicillin Spectrum: similar spectrum to ampicillin (PO)

๏ Since oral absorption is better, less Amox makes into enterohepatic recycling, less perturbation of gut flora, but also less effective w/ enteric infections than amp

๏ Ear, nose, throat infections, otitis media

๏ S. pneumoniae, S. pyogenes, H. influenzae

๏ Resistance to amox alone can be problematic; combination w/ inhibitor can be effective

๏ Still widely prescribed for otitis media

Amoxicillin + Clavulante spectrum (PO):๏ Similar spectrum to Amp + Sulbactam

Penicillinase resistant and Extended Spectrum

Penicillinase resistant penicillins:

๏ Nafcillin (IV, IM)

๏ Dicloxacillin (PO)

๏ Mainly used for sensitive S. aureus (not MRSA)

Extended spectrum penicillins (anti-Pseudomonas): only used in combination w/ inhibitors

๏ Primarily used against Pseudomonas infections, for complex infections, or for empiric therapy where the pathogen is not known. Also generally good Gram- coverage.

๏ Piperacillin + Tazobactam (Zosyn ®)

๏ More potent against Gram- than Ticarcillin, e.g. Klebsiella

๏ Pseudomonas aeruginosa more sensitive, less resistance (15%) than for Timentin (30%)

๏ Ticarcillin + Clavulanate (Timentin ®) http://us.gsk.com/products/assets/us_timentin_iv.pdf

Beta-lactam antibioticsAmoxicillin (penicillin) Cephalexin (cephalosporin)

Imipenem (carbapenem) Aztreonam (monobactam)

Cephalosporins

๏ First isolated by Brotzu from Cephalosporium acremonium (a mold) from a sewage outfall (and popular swimming spot) in Sardinia. He noticed the C. acremonium cultures inhibited the growth of Salmonella enterica (typhi), a Gram- bug that produces a penicillinase

๏ M.O.A. same as penicillins, to inhibit synthesis and maintenance of bacterial peptidoglycan

Cephalosporin C

Semi-synthetic cephalosporins

๏ Cephalosporin C had poor bioavailability, rapidly cleared

๏ All cephalosporins in use are of the semi-synthetic variety, no equivalents to Pen G and V in use.

๏ Cleave off natural sidechain to yield 7-aminocephalosporanic acid (7-ACA) core, which then could be synthetically substituted with other sidechains (R1, R2).

๏ Alter the spectrum, stability, bioavailability, resistance to beta-lactamases

๏ More modifications possible than w/ penicillins

Cephalosporin C

7-ACAR

side chain(s)affects activity, spectrum, etc.

Cephalosporin C

R

1

2

Cephamycin general features

๏ Cephamycin beta-lactams + cephalosporins = cephems (but we will use “cephalosporin” to refer to both).

๏ Originally isolated from Streptomyces; now semi-synthetic derivatives

๏ Cephamycins have an O-methylated beta-lactam ring ( )

๏ Good anaerobic activity

Cefotetan

Cephalosporins general features๏ Generally broader spectrum coverage than penicillins

๏ Whereas original penicillins had primarily Gram+ coverage, most cephalosporins also cover some Gram-

๏ Better resistance to beta-lactamases, but susceptible to AmpC, ESBL (if bug makes ESBL or AmpC, typically go to carbapenems instead).

๏ Cleared renally with ~5-30% metabolic breakdown, much active drug excreted in urine

๏ Low toxicity:

๏ Lower allergenicity than penicillins though still some due to beta-lactam ring opening (10% cross-reactivity with penicillin G)

Cephalosporins general features๏ Uses: UTI (esp penicillin allergic), otitis media, MSSA, URTI, LRTI, meningitis,

sepsis, surgical prophylaxis

๏ Cephalosporin “generations”: generally get more broader, more Gm- coverage with later generations

๏ Generation 1: Generally had better Gram+ than Gram- activity; susceptible to many Gram- beta-lactamases

๏ Examples: Cephalexin, Cefazolin, Cefadroxil

๏ Generation 2: Better resilience to Gram- beta-lactamases, Gram- coverage

๏ Examples: Cefuroxime, Cefaclor, Cefprozil, Cefoxitin, Cefotetan, Cefuroxime

๏ Generation 3: More potent, better Gram- beta-lactamase stability, better penetration; pick up some anti-Pseudomonal activity, give up some Gram+ coverage

๏ Examples: Cefpodoxime, Cefdinir, Cefixime, Cefotaxime, Ceftriaxone, Ceftazidime, Ceftizoxime, Ceftibutin, Cefditoren

๏ Generation 4: Like generation 3, but more so

๏ Example: Cefepimeunderlined are on UW formulary

Cephalosporins general features๏ Toxicity

๏ Lower allergenicity than penicillins though still some due to beta-lactam ring opening (10% cross-reactivity with penicillin G)

๏ Cefotetan has an N-methylthiotetrazole (N-MTT) moiety that is released as a metabolic byproduct. This can cause hypoprothrombinemia, which manifests as bleeding due to combination of effects: 1) altered gut flora changes vitamin K production, 2) direct interaction of N-MTT with prothrombin, 3) platelet dysfunction. First noted with moxalactam (2-3% fatalities; off market).

๏ N-MTT also can inhibit aldehyde degydrogenase, giving rise to a disulfram-like reaction following alcohol consumption. Intense hang-over feeling, hyper-sensitivity to alcohol.

Cefotetan

N-MTT

Oral cephalosporins

30

b) Gram-negative (2nd, 3rd, 4th generations are better)

i. E. coli - usually sens.

ii. Proteus; 2nd and 3rd generation also active against Morganella, Providencia,

and Serratia.

iii. Salmonella

iv. Shigella – usually sen.

v. Neisseria meningititis – useful if ceph. will enter CSF

vi. Neisseria gonorrhoeae – OK, particularly ceftriaxone, cefixime, and cefpodoxime

which are agents of choice

vii. H. influenza – 2nd, 3rd and 4th generations are better

viii. Klebsiella – K. pneumonia – usually sen., and is important use of Cephs.

ix. Enterobacter and Pseudomonas – only 3rd and 4th generations; sensitivity varies

x. Anaerobes – Cefoxitin, cefotetan and some 3rd generation only

xi. ESBL producing pathogens are resistant

6. Use

a) respiratory infections – gram-positive and gram-negative, Klebsiella

b) sepsis – especially mixed infections using 3rd or 4th generations

c) surgical prophylaxis – first or 2nd generations

d) meningitis – some will penetrate CSF and cover E. coli, Klebsiella pneumoneae,

Serratia, and Neisseria meningitidis

e) UTI – very high renal conc.

f) alternate drug for penicillin allergic patient, for penicillinase resistant penicillins, for

staph infections

Table - Oral Cephalosporins

structure genera-

tion

name brand name

R1 R2 R3 X

dose

1 cephalexin generic

QID

1 cephradine generic

BID

1 cefadroxil generic

BID

2 cefaclor generic

TID

2 cefuroxime

axetil

generic

BID

2 cefprozil generic

BID

Courtesy Prof. Gary Elmer

Oral cephalosporins (cont.)

31

3 cefpodoxime

proxetil

generic

BID

3 ceftibutin Cedax!

qd

3 cefdinir generic

BID

3 cefditoren

pivoxil

generic

BID

3 cefixime Suprax! ---- ---- ---- ---- qd

Table - Parenteral Cephalosporins and Cephamycins Cephalosporin *Cephamycin

structure generation name brand name

R1 R2

dose

1 cefazolin generic

TID

2 cefoxitin* generic

QID

2 cefotetan* generic

BID

2 cefuroxime generic

TID

3 cefotaxime generic

TID

3 ceftizoxime Cefizox!

TID

3 ceftriaxone generic

qd

Courtesy Prof. Gary Elmer

Parenteral cephalosporins/cephamycins

31

3 cefpodoxime

proxetil

generic

BID

3 ceftibutin Cedax!

qd

3 cefdinir generic

BID

3 cefditoren

pivoxil

generic

BID

3 cefixime Suprax! ---- ---- ---- ---- qd

Table - Parenteral Cephalosporins and Cephamycins Cephalosporin *Cephamycin

structure generation name brand name

R1 R2

dose

1 cefazolin generic

TID

2 cefoxitin* generic

QID

2 cefotetan* generic

BID

2 cefuroxime generic

TID

3 cefotaxime generic

TID

3 ceftizoxime Cefizox!

TID

3 ceftriaxone generic

qd

Courtesy Prof. Gary Elmer

32

3 ceftazidime generic

TID

4 cefepime generic

BID

7. Formulary Oral Cephalosporins

a) General comments: used for follow-up and ambulatory patient therapy, UTI (pen.

Allergic), otitis media, staph. URI, LRI

b) First Generation

Cephalexin Keflex ! Dista and generics

Indications:

1) respiratory tract – Strep. pneumoniae and Strep. pyogenes

2) otitis media – Strep. pneumonia, H. flu, M. cat. (the H. flu and M. cat may be

resistant)

3) skin – Staph., Strep.

4) bone – Staph., Proteus mirabilis

5) GU – E. coli, Klebsiella, Proteus mirabilis

c) Second Generation – not on formulary in 2009

Cefuroxime Axetil Ceftin® Glaxo Wellcome and generic

Broad spectrum oral cephalosporin that gets into CNS

Indications:

1) pharyngitis and tonsillitis – Strep. pyogenes

2) otitis media – Strep. pneumoniae, M. cat., H. flu, including "-lactamase producing

3) sinusitis – Strep. pheumoniae, H. flu

4) exacerbation of chronic bronchitis – Strep. pneumoniae, H. flu, H. parainfluenzae

5) UTI – E. coli, Klebsiella, Proteus

6) skin – Staph., Strep.

7) GU – E. coli, Klebsiella, Proteus

8) impetigo – Staph., Strep.

d) Third Generation

Cefpodoxime proxetil Vantin! Pharmacia and now generic

Broad spectrum, beta lactamse resistant cephalosporin with an unusual structure

Indications:

1) acute CAP Strep. pneumo, H. flu, M. cat

2) chronic bronchitis Strep. pneumo., H. flu, M. cat

3) otitis media

4) pharyngitis

5) STD - N. gonorrheae, 200mg stat single dose

6) uncomplicated skin infections Staph., Strep. pyogenes

7) UTI

Parenteral cephalosporins/cephamycins (cont.)

Courtesy Prof. Gary Elmer

Some oral cephalosporins are prodrugs๏ Examples: Cefpodoxime, Cefuroxime, Ceftizoxime, Cefditoren,, Cefetamet, Cefditoren

๏ Better absorption

๏ Metabolized to active drug by intestinal mucosal tissue

cefpodoxime proxetil cefpodoxime