AntibioticsAntibioticsUpdate Update

2005 2005

Jeffrey Buyten, MDJeffrey Buyten, MDDavid Teller, MDDavid Teller, MD

Francis B. Quinn, Jr., MDFrancis B. Quinn, Jr., MDUniversity of Texas Medical BranchUniversity of Texas Medical Branch

December 2004December 2004

► Overview of Antibiotics.Overview of Antibiotics. Cell wall inhibitors.Cell wall inhibitors. Protein synthesis inhibitors.Protein synthesis inhibitors. Folate antagonists.Folate antagonists. Miscellaneous.Miscellaneous.

► Treatment of Methicillin resistant Treatment of Methicillin resistant Staphlyococcus aureusStaphlyococcus aureus (MRSA). (MRSA).

► Fluoroquinolones in children.Fluoroquinolones in children.

Cell Wall Synthesis InhibitorsCell Wall Synthesis InhibitorsBeta LactamsBeta Lactams

Penicillins (PCN)Penicillins (PCN)CephalosporinsCephalosporinsCarbapenemsCarbapenemsMonobactamsMonobactams

VancomycinVancomycinBacitracinBacitracinPolymyxinPolymyxin

Beta LactamsBeta Lactams► B-lactams inhibit B-lactams inhibit

transpeptidase.transpeptidase.► Only effective against Only effective against

rapidly growing rapidly growing organisms that organisms that synthesize peptidoglycan. synthesize peptidoglycan. (Ineffective against (Ineffective against mycobacteria.)mycobacteria.)

► The size, charge and The size, charge and hydrophobicity of the hydrophobicity of the molecule determines the molecule determines the extent of its antibacterial extent of its antibacterial activity.activity.

PenicillinsPenicillins► Derived from Derived from Penicillium Penicillium

chrysogenumchrysogenum..► PCN G and PCN V are PCN G and PCN V are

unaltered products of unaltered products of PenicilliumPenicillium fermentation. fermentation.

► Semi-synthetic penicillins Semi-synthetic penicillins are formed by addition of are formed by addition of R groups to the main 6-R groups to the main 6-aminopenicillanic acid aminopenicillanic acid ring.ring.

Adverse ReactionsAdverse Reactions► 5% of patients will 5% of patients will

develop a develop a hypersensitivity hypersensitivity reaction (penicilloic reaction (penicilloic acid).acid).

► Rashes - most common Rashes - most common reaction. 50% do not reaction. 50% do not have a recurrent rash.have a recurrent rash.

► Ampicillin - rash in 50-Ampicillin - rash in 50-100% of patients with 100% of patients with mononucleosis.mononucleosis.

Adverse reactionsAdverse reactions► Anaphylaxis – 1/10000 Anaphylaxis – 1/10000

patientspatients Hives, angioedema, Hives, angioedema,

rhinitis, asthma, and rhinitis, asthma, and anaphylaxis.anaphylaxis.

10% mortality rate.10% mortality rate. Anaphylaxis possible after Anaphylaxis possible after

negative skin testing.negative skin testing. Desensitization is an Desensitization is an

option if penicillin must be option if penicillin must be given.given.

Avoid all other B-lactams.Avoid all other B-lactams.

Natural PenicillinsNatural Penicillins► PCN G (IV/IM; PCN G (IV/IM; $12/day$12/day))► PCN V (Oral; PCN V (Oral; $0.52/day$0.52/day))► Active against Active against StrepStrep., .,

peptostreptococcus,peptostreptococcus, B B anthracisanthracis, , AActinomycosisctinomycosis, , CorynebacteriumCorynebacterium, , ListeriaListeria, , NeisseriaNeisseria & & TreponemaTreponema..

► Used for common oral Used for common oral infections.infections.

Anti-Staphylococcal Anti-Staphylococcal PenicillinsPenicillins

► Methicillin, nafcillin, oxacillin, Methicillin, nafcillin, oxacillin, cloxacillin and dicloxacillin.cloxacillin and dicloxacillin.

► Resist degradation by penicillinase.Resist degradation by penicillinase.► Useful for treating Useful for treating S. aureus.S. aureus.

No added benefit in treating No added benefit in treating StrepStrep. species.. species.► Methicillin is rarely used due to Methicillin is rarely used due to

toxicity.toxicity.► Dicloxacillin ($0.87/day) - highest Dicloxacillin ($0.87/day) - highest

serum levels orally.serum levels orally.► Nafcillin ($15/day) - preferred Nafcillin ($15/day) - preferred

parenteral drug.parenteral drug.

AminopenicillinsAminopenicillins► Ampicillin (IV; Ampicillin (IV; $1.95/day$1.95/day))► Ampicillin/sulbactam (Unasyn; IV; Ampicillin/sulbactam (Unasyn; IV; $30.76/day$30.76/day))► Amoxicillin (Oral; Amoxicillin (Oral; $0.32/day$0.32/day).).► Amoxicillin/clavulanate (Augmentin; Amoxicillin/clavulanate (Augmentin;

$6.63/day$6.63/day))► Sulbactam and clavulanic acid increase Sulbactam and clavulanic acid increase

activity against B-lactamase producing activity against B-lactamase producing organisms.organisms.

► Extended antimicrobial spectrum.Extended antimicrobial spectrum. Gram negatives: Gram negatives: E. coliE. coli, , ProteusProteus, , SalmonellaSalmonella, ,

Haemophilus, M. catarrhalis, Klebsiella, Neisseria, Haemophilus, M. catarrhalis, Klebsiella, Neisseria, Enterobacter, BactoroidesEnterobacter, Bactoroides..

► Used as first line therapy for acute otitis Used as first line therapy for acute otitis media and sinusitis.media and sinusitis.

Antipseudomonal PenicillinsAntipseudomonal Penicillins► Ticarcillin, Piperacillin (Ticarcillin, Piperacillin ($49.36/day$49.36/day), ),

Mezlocillin.Mezlocillin.► Piperacillin/tazobactam (Zosyn; IV; Piperacillin/tazobactam (Zosyn; IV;

$53.24/day$53.24/day)) Tazobactam (B-lactamase inhibitor)Tazobactam (B-lactamase inhibitor)

► Ticarcillin/clavulanate (Timentin; IV; Ticarcillin/clavulanate (Timentin; IV; $38.80/day$38.80/day))

► Active against Active against PseudomonasPseudomonas, , E. coli, E. coli, klebsiella, enterobacter, serratia and B. klebsiella, enterobacter, serratia and B. fragilisfragilis..

► Lower activity against gram positivesLower activity against gram positives► Often used with aminoglycosides when Often used with aminoglycosides when

treating pseudomonal infections.treating pseudomonal infections.

Resistance MechanismsResistance Mechanisms► B-lactamase – hydrolyze B-lactamase – hydrolyze

the B-lactam ring.the B-lactam ring. H. flu (7-24%)H. flu (7-24%) M. cat (93-100%)M. cat (93-100%)

► Penicillinase – Penicillinase – StaphStaph► Alteration of penicillin-Alteration of penicillin-

binding protein (PBP) binding protein (PBP) affinity. (affinity. (Strep. Pneumo., Strep. Pneumo., MRSA)MRSA)

Alteration of PBP affinity.Alteration of PBP affinity. 6 PBP’s are found by PCN in 6 PBP’s are found by PCN in

susceptible pneumococci.susceptible pneumococci.► Isolates with reduced susceptibility Isolates with reduced susceptibility

show decreased PCN affinity for one or show decreased PCN affinity for one or more of the 6 PBP’s.more of the 6 PBP’s. PBP-2b alteration is responsible for most PBP-2b alteration is responsible for most

PCN resistant strains.PCN resistant strains.► Increased concentration of PCN Increased concentration of PCN

overcomes low binding affinity.overcomes low binding affinity.

Strep. pneumo Strep. pneumo resistance.resistance.► PCN resistance is increasing in the US.PCN resistance is increasing in the US.

Current national statistics:Current national statistics:► Susceptibility 60%Susceptibility 60%► Intermediate resistance 20%Intermediate resistance 20%► Resistant 20%Resistant 20%

Current UTMB statistics:Current UTMB statistics:► Susceptibility 46 % (outpatient), 53% (inpatient)Susceptibility 46 % (outpatient), 53% (inpatient)► Intermediate resistance 41% (outpatient), 40% Intermediate resistance 41% (outpatient), 40%

(inpatient)(inpatient)► Resistant 13% (outpatient), 7% (inpatient)Resistant 13% (outpatient), 7% (inpatient)

► Amoxicillin resistance < 5%.Amoxicillin resistance < 5%.

CephalosporinsCephalosporins► Semisynthetic B-lactams Semisynthetic B-lactams

derived from chemical side derived from chemical side chains added to 7-chains added to 7-aminocephalosporanic acid.aminocephalosporanic acid.

► Generally more resistant to Generally more resistant to B-lactamases.B-lactamases.

CephalosporinsCephalosporins► Adverse reactions.Adverse reactions.

5-10% cross-sensitivity 5-10% cross-sensitivity with pcn allergic pts.with pcn allergic pts.

1-2% hypersensitivity 1-2% hypersensitivity reactions in non-pcn reactions in non-pcn allergic pts.allergic pts.

Broader spectrum leads Broader spectrum leads to opportunistic to opportunistic infections (candidiasis, infections (candidiasis, C. difficile colitis).C. difficile colitis).

First GenerationFirst Generation► Cefazolin (Ancef; IV; Cefazolin (Ancef; IV; $9.60/day$9.60/day), Cephalexin ), Cephalexin

(Keflex; Oral; (Keflex; Oral; $0.78/day$0.78/day))► Spectrum: Most gram positive cocci (Spectrum: Most gram positive cocci (StrepStrep, ,

S. aureusS. aureus)), E. coli, Proteus, Klebsiella, E. coli, Proteus, Klebsiella. . ► Use: Use: S. aureusS. aureus infection, surgical infection, surgical

prophylaxis.prophylaxis.

Second GenerationSecond Generation► Cefuroxime (Ceftin; Cefuroxime (Ceftin; IV IV $7.84/day$7.84/day; Oral ; Oral $14.04/day$14.04/day))► Increased activity against Increased activity against H. flu, H. flu,

enterobacter, Neisseria, proteus, E. coli, enterobacter, Neisseria, proteus, E. coli, klebsiella, M. catarrhalis, anaerobes klebsiella, M. catarrhalis, anaerobes andand B. B. fragilisfragilis..

► Not as effective against S. aureus as the 1Not as effective against S. aureus as the 1stst generation.generation.

► Cefpodoxime and Cefuroxime active against Cefpodoxime and Cefuroxime active against intermediate level resistant strep pneumo.intermediate level resistant strep pneumo.

Third GenerationThird Generation► Spectrum: gram negative > Spectrum: gram negative >

gram positive.gram positive.► Ceftriaxone (Rocephin; IM/IV; Ceftriaxone (Rocephin; IM/IV;

$25.79/day), Cefotaxime $25.79/day), Cefotaxime ($11.55/day).($11.55/day). Useful for meningitis.Useful for meningitis. Ceftriaxone used for highly Ceftriaxone used for highly

resistant and multi drug resistant and multi drug resistant strep pneumo along resistant strep pneumo along with vancomycin.with vancomycin.

► Ceftazidime active against Ceftazidime active against pseudomonas.pseudomonas.

Fourth GenerationFourth Generation► Cefepime (IV; Cefepime (IV; $22.28/day$22.28/day))► Active against Active against Strep, StaphStrep, Staph (mssa), aerobic (mssa), aerobic

gram negatives (gram negatives (enterobacter, e. coli, enterobacter, e. coli, klebsiella, proteusklebsiella, proteus and and pseudomonaspseudomonas).).

CarbapenemsCarbapenems► Imipenem-Cilastin ( Primaxin; IV;Imipenem-Cilastin ( Primaxin; IV;

$84.76/day; Requires ID approval @ UTMB).$84.76/day; Requires ID approval @ UTMB).► Cilastin - dehydropeptidase inhibitor Cilastin - dehydropeptidase inhibitor

that inhibits degradation into a that inhibits degradation into a nephrotoxic metabolite.nephrotoxic metabolite.

► Broadest spectrum B-lactam.Broadest spectrum B-lactam. StaphStaph (not MRSA), (not MRSA), Strep Strep (highly resistant)(highly resistant), ,

Neisseria, Haemophilus, Proteus, Pseudomonas, Neisseria, Haemophilus, Proteus, Pseudomonas, Klebsiella, BacteroidesKlebsiella, Bacteroides, anaerobes (excluding , anaerobes (excluding C. C. difdif))

Double coverage of Double coverage of PseudomonasPseudomonas is is recommended when using imipenemrecommended when using imipenem..

► Toxicities: Toxicities: PCN allergy cross reactivity.PCN allergy cross reactivity. Seizures noted in Imipenem studiesSeizures noted in Imipenem studies..

MonobactamsMonobactams► Aztreonam (Azactam; IM/IV; Aztreonam (Azactam; IM/IV;

$52.62/day$52.62/day))► B-lactamase resistant.B-lactamase resistant.► Narrow antibacterial Narrow antibacterial

spectrum.spectrum. Aerobic gram negative rods (Aerobic gram negative rods (H. H.

flu, N. gonorrheaflu, N. gonorrhea (penicillinase (penicillinase producers), producers), E. coli, Klebsiella, E. coli, Klebsiella, Proteus, PseudomonasProteus, Pseudomonas).).

Ineffective against gram positive Ineffective against gram positive and anaerobic organisms.and anaerobic organisms.

Antipseudomonal activity is Antipseudomonal activity is greater than Timentin and Zosyn greater than Timentin and Zosyn but less than the carbapenems.but less than the carbapenems.

AztreonamAztreonam►Very little cross-allergenicity due to its Very little cross-allergenicity due to its

low immunogenic potential. May be a low immunogenic potential. May be a safe alternative for pcn allergic safe alternative for pcn allergic patients.patients.

►Adverse reactions;Adverse reactions; Gram positive superinfection (20-30%)Gram positive superinfection (20-30%)

VancomycinVancomycin► Tricyclic glucopeptide - Tricyclic glucopeptide - Streptomyces Streptomyces

orientalis.orientalis.► Inhibits synthesis of cell wall phospholipids Inhibits synthesis of cell wall phospholipids

and prevents cross-linking of peptidoglycans and prevents cross-linking of peptidoglycans at an earlier step than B-lactams.at an earlier step than B-lactams.

► Active against gram positive bacteria, highly Active against gram positive bacteria, highly resistant resistant Strep. pneumo, Clostridia, Strep. pneumo, Clostridia, Enterococcus, Staph. epiEnterococcus, Staph. epi and MRSA. and MRSA.

► Synergy with aminoglycosides.Synergy with aminoglycosides.► Used in treatment of MRSA and highly Used in treatment of MRSA and highly

resistant resistant Strep.Strep. species. species.

VancomycinVancomycin► Resistance: changes in permeability and Resistance: changes in permeability and

decreased binding affinity.decreased binding affinity.► Adverse effects.Adverse effects.

Fever, chills, phlebitis and red man syndrome.Fever, chills, phlebitis and red man syndrome.► Slow injection and prophylactic antihistamines.Slow injection and prophylactic antihistamines.

Ototoxic – may potentiate known ototoxic Ototoxic – may potentiate known ototoxic agents.agents.

► Renal excretion (90-100% glomerular Renal excretion (90-100% glomerular filtration).filtration). Normal half-life 6-10 hours.Normal half-life 6-10 hours. Half life is over 200 hours in pts with ESRD.Half life is over 200 hours in pts with ESRD.

► Cost - Cost - $8.39/day$8.39/day and and $29.39/day$29.39/day with serum with serum levels.levels.

BacitracinBacitracin► Polypeptide produced by Polypeptide produced by Bacillus Bacillus

subtillissubtillis..► Inhibits regeneration of Inhibits regeneration of

phospholipids receptors involved phospholipids receptors involved in peptidoglycan synthesis.in peptidoglycan synthesis.

► Originally isolated from debris in Originally isolated from debris in a pt’s wound.a pt’s wound.

► Active against gram positives Active against gram positives and negatives.and negatives.

► Topical use only (nephrotoxicity).Topical use only (nephrotoxicity).

BacitracinBacitracin► Adverse effects.Adverse effects.

Contact dermatitis – top 10 allergen.Contact dermatitis – top 10 allergen. Reports of anaphylaxis.Reports of anaphylaxis.

► Dermatology study showed no increase in wound infection when clean surgical Dermatology study showed no increase in wound infection when clean surgical wounds were dressed with white petrolatum vs. bacitracin.wounds were dressed with white petrolatum vs. bacitracin.

► CombinationsCombinations Neosporin – neomycin, polymyxin B, bacitracinNeosporin – neomycin, polymyxin B, bacitracin Polysporin – polymyxin B, bacitracinPolysporin – polymyxin B, bacitracin

PolymyxinPolymyxin► Bacillus polymyxaBacillus polymyxa► Decapeptide that disrupts the Decapeptide that disrupts the

phospholipid layer in cell membranes.phospholipid layer in cell membranes.► Limited spectrum.Limited spectrum.

Decreased gram positive coverage.Decreased gram positive coverage. Active against Active against Pseudomonas, Proteus, Pseudomonas, Proteus,

Serratia, E. coli, Klebsiella Serratia, E. coli, Klebsiella andand EnterobacterEnterobacter..

► Cross reaction with bacitracin.Cross reaction with bacitracin.

Protein Synthesis InhibitorsProtein Synthesis Inhibitors► Target the bacterial ribosome.Target the bacterial ribosome.

► Bacterial – 70S (50S/30S)Bacterial – 70S (50S/30S)► Mammalian – 80S (60S/40S)Mammalian – 80S (60S/40S)

High levels may interact with High levels may interact with mammalian ribosomes.mammalian ribosomes.

► 50S binders - Macrolides, 50S binders - Macrolides, Clindamycin, Chloramphenicol, Clindamycin, Chloramphenicol, Streptogramins.Streptogramins.

► 30S binders - Aminoglycosides, 30S binders - Aminoglycosides, TetracyclinesTetracyclines

► MupirocinMupirocin

MacrolidesMacrolides► Erythromycin (IV Erythromycin (IV $13.64/day$13.64/day; Oral ; Oral

$0.59/day$0.59/day),),► Clarithromycin (Biaxin; IV Clarithromycin (Biaxin; IV

$101.50/day$101.50/day; Oral ; Oral $101.15/day$101.15/day))► Azithromycin (Zithromax, Z-PAK; Azithromycin (Zithromax, Z-PAK;

Oral Oral $48.80/day, $20.30/day$48.80/day, $20.30/day))► Macrocyclic lactone structures - Macrocyclic lactone structures -

Streptomyces erythreusStreptomyces erythreus..► Irreversibly bind the 50S subunit.Irreversibly bind the 50S subunit.

Binding site is in close proximity to Binding site is in close proximity to the binding sites of lincomycin, the binding sites of lincomycin, clindamycin and chloramphenicol.clindamycin and chloramphenicol.

MacrolidesMacrolides► Antibacterial spectrum: Antibacterial spectrum:

Erythromycin: Erythromycin: ► Gram positives: Gram positives: StaphStaph.(MRSA is resistant), .(MRSA is resistant),

Strep., Bordetella, Treponema, CorynebacteriaStrep., Bordetella, Treponema, Corynebacteria..► Atypicals: Atypicals: Mycoplasma, Ureaplasma, ChlamydiaMycoplasma, Ureaplasma, Chlamydia

Clarithromycin: Clarithromycin: ► Similar to erythromycin.Similar to erythromycin.► Increased activity against gram negatives (Increased activity against gram negatives (H. H.

flu, Moraxellaflu, Moraxella) and atypicals) and atypicals Azithromycin:Azithromycin:

► Decreased activity against gram positive cocci.Decreased activity against gram positive cocci.► Increased activity against Increased activity against H. fluH. flu and and M. catM. cat..

MacrolidesMacrolides► Adverse effects.Adverse effects.

10-15% of pts do not finish the prescribed course 10-15% of pts do not finish the prescribed course of erythromycin because of GI distress.of erythromycin because of GI distress.

JaundiceJaundice Ototoxic (high doses)Ototoxic (high doses)

► Drug interactionsDrug interactions Oxidized by cytochrome p-450.Oxidized by cytochrome p-450. Inhibits other substrates and increases their Inhibits other substrates and increases their

serum concentrations.serum concentrations.► Theophylline, warfarin, astemizole, carbemazepine, Theophylline, warfarin, astemizole, carbemazepine,

cyclosporine, digoxin, terfenadine.cyclosporine, digoxin, terfenadine.

Macrolides ResistanceMacrolides Resistance► Efflux mechanism (msrA).Efflux mechanism (msrA).► Ribosomal alteration Ribosomal alteration

(ermA/ermC)(ermA/ermC) MLSMLSBB (macrolide- (macrolide-

lincosamide-streptogramin lincosamide-streptogramin B) resistance.B) resistance.

MLSMLSBB inducible strains are inducible strains are

resistant to erythromycin resistant to erythromycin and susceptible to and susceptible to clindamycin. Further clindamycin. Further exposure to clindamycin exposure to clindamycin induces MLSinduces MLSBB resistance. resistance.

ClindamycinClindamycin► Clindamycin (Cleocin; IV Clindamycin (Cleocin; IV

$24.45/day$24.45/day; Oral ; Oral $13.71/day$13.71/day))► LincosamideLincosamide► Irreversibly binds the 50S Irreversibly binds the 50S

subunit.subunit.► Antibiotic spectrum:Antibiotic spectrum:

Strep Strep speciesspecies, Staph, Staph (some MRSA), (some MRSA), B. fragilisB. fragilis, anaerobes, anaerobes

Does not cover Does not cover Clostridium difficileClostridium difficile..

ClindamycinClindamycin► Used for deep neck space Used for deep neck space

infections, chronic tonsillo-infections, chronic tonsillo-pharyngitis, odontogenic pharyngitis, odontogenic abscesses, and surgical abscesses, and surgical prophylaxis in contaminated prophylaxis in contaminated wounds.wounds.

► Concomitant use of macrolides Concomitant use of macrolides or Chloramphenicol adds no or Chloramphenicol adds no benefit.benefit.

► Resistance: MLSResistance: MLSBB – ribosomal – ribosomal alteration.alteration.

Clindamycin Adverse EffectsClindamycin Adverse Effects► Pseudomembranous colitis Pseudomembranous colitis

– clindamycin > – clindamycin > cephalosporins (Ceftin) > cephalosporins (Ceftin) > aminopenicillins.aminopenicillins. Abdominal pain, fever, Abdominal pain, fever,

leukocytosis, bloody stool…leukocytosis, bloody stool… Diarrhea commonly develops Diarrhea commonly develops

on days 4-9 of treatment.on days 4-9 of treatment. Typically resolves14 days Typically resolves14 days

after stopping the antibiotic.after stopping the antibiotic. Treat with Flagyl (PO or IV).Treat with Flagyl (PO or IV). Life threatening cases can Life threatening cases can

be treated with oral be treated with oral Vancomycin.Vancomycin.

AminoglycosidesAminoglycosides► Neomycin Neomycin ($12.05/day),($12.05/day), Gentamicin Gentamicin

($4.28/day),($4.28/day), Tobramycin Tobramycin ($6.77/day),($6.77/day), Amikacin Amikacin ($7.81/day).($7.81/day). (Additional (Additional $21.00/day with serum levels)$21.00/day with serum levels)

► Binds the 30S subunit.Binds the 30S subunit.► Only active against anaerobes Only active against anaerobes

because an oxygen dependent because an oxygen dependent system is required to transport system is required to transport the molecules into the cell.the molecules into the cell.

► Synergism with cell wall inhibitors Synergism with cell wall inhibitors is seen because they increase the is seen because they increase the permeability of the cell.permeability of the cell.

AminoglycosidesAminoglycosides►Antibacterial spectrum:Antibacterial spectrum:

Gram negatives: Gram negatives: Pseudomonas, Proteus, Pseudomonas, Proteus, Serratia, E. coli, KlebsiellaSerratia, E. coli, Klebsiella

NeomycinNeomycin►S. aureusS. aureus and and ProteusProteus►PseudomonasPseudomonas and and StrepStrep are resistant are resistant

►Resistance – decreased uptake, Resistance – decreased uptake, decreased binding affinity, enzymes decreased binding affinity, enzymes (plasmids).(plasmids).

AminoglycosidesAminoglycosides► Adverse effects:Adverse effects:

Ototoxic – associated with high Ototoxic – associated with high peak levels and prolonged peak levels and prolonged therapy. Pts on loop diuretics, therapy. Pts on loop diuretics, vancomycin and cisplatin are at vancomycin and cisplatin are at higher risk.higher risk.

► Cochlear and vestibular.Cochlear and vestibular.► Concentrates in endolymph and Concentrates in endolymph and

perilymph.perilymph. Nephrotoxic.Nephrotoxic.

► Proximal tubule damage.Proximal tubule damage.

MupirocinMupirocin► Bactroban (Bactroban ($76.70$76.70))► Pseudomonas fluoroscensPseudomonas fluoroscens..

(E)-(2S, 3R, 4R, 5S)-5-[(2S, 3S, 4S, 5S)]-(E)-(2S, 3R, 4R, 5S)-5-[(2S, 3S, 4S, 5S)]-2,3-Epoxy-5-hydroxy-4-2,3-Epoxy-5-hydroxy-4-methly[hexyl]tetrahydro-3, 4-dihydroxy-methly[hexyl]tetrahydro-3, 4-dihydroxy-B-methly-2H-pyran-2-crotonic acid, ester B-methly-2H-pyran-2-crotonic acid, ester with 9-hydroxynonanioc acid.with 9-hydroxynonanioc acid.

► Binds isoleucyl transfer-RNA synthetase.Binds isoleucyl transfer-RNA synthetase.► Active against Active against Staph aureusStaph aureus (MRSA), (MRSA),

Staph epi, Strep pyogenesStaph epi, Strep pyogenes..► Used for Impetigo and elimination of Used for Impetigo and elimination of

StaphStaph infections, including MRSA infections, including MRSA carriers.carriers. Intranasal application qid can reduce Intranasal application qid can reduce

carriage for up to one year.carriage for up to one year.

Folate AntagonistsFolate Antagonists► Bacteria must synthesize folate in order to Bacteria must synthesize folate in order to

form cofactors for purine, pyrimidine and form cofactors for purine, pyrimidine and amino acid synthesis.amino acid synthesis.

► p-aminobenzoic acid (PABA) agonists.p-aminobenzoic acid (PABA) agonists. Substrates for dihydropteroate synthetase.Substrates for dihydropteroate synthetase. SulfonamidesSulfonamides

► Sulfamethoxazole (SMP)Sulfamethoxazole (SMP)► SulfasoxazoleSulfasoxazole

► Dihydrofolate Reductase Inhibitors.Dihydrofolate Reductase Inhibitors. Inhibits activation of folate to its active form, Inhibits activation of folate to its active form,

tetrahydrofolate.tetrahydrofolate. Trimethoprim (TMP)Trimethoprim (TMP)

Clinical applications.Clinical applications.► Antibacterial spectrum.Antibacterial spectrum.

H. fluH. flu, , Strep. pneumoStrep. pneumo, , NeisseriaNeisseria species, species, S. aureusS. aureus, , and and Pneumocystis cariniiPneumocystis carinii

► Pediazole (erythromycin + sulfasoxazole)Pediazole (erythromycin + sulfasoxazole) Alternative to amoxicillin for first line treatment of Alternative to amoxicillin for first line treatment of

acute otitis media.acute otitis media.► Co-trimoxazole (trimethoprim + Co-trimoxazole (trimethoprim +

sulfamethoxazole; IV sulfamethoxazole; IV $8.71/day$8.71/day; Oral ; Oral $0.15/day)$0.15/day) MRSA, UTI’s, PCP prophylaxis.MRSA, UTI’s, PCP prophylaxis. 97% of UTMB outpt 97% of UTMB outpt Staph. aureus Staph. aureus isolates are isolates are

susceptible to Bactrim.susceptible to Bactrim.

Adverse ReactionsAdverse Reactions► Dermatologic: Rashes are Dermatologic: Rashes are

common, ranging from common, ranging from photodermatitis to Stevens-photodermatitis to Stevens-Johnsons syndrome.Johnsons syndrome.

► Hematologic: Hemolytic Hematologic: Hemolytic anemia (G6PDH deficient anemia (G6PDH deficient pts.), neutropenia and pts.), neutropenia and thrombocytopenia (up to thrombocytopenia (up to 80% of HIV pts)80% of HIV pts)

► Drug interactions: Warfarin, Drug interactions: Warfarin, phenytoin, methotrexate.phenytoin, methotrexate.

MiscellaneousMiscellaneous► FluoroquinolonesFluoroquinolones► RifampinRifampin► MetronidazoleMetronidazole

FluoroquinolonesFluoroquinolones► Ciprofloxacin (Cipro; IV Ciprofloxacin (Cipro; IV $103.75/day; $103.75/day;

PO/Topical; PO/Topical; Restricted use @ UTMBRestricted use @ UTMB), Ofloxacin ), Ofloxacin (Floxin; Topical (Floxin; Topical $60.90$60.90), Levofloxacin ), Levofloxacin (Levaquin; IV (Levaquin; IV 15.62/day15.62/day; Oral ; Oral $6.72/day$6.72/day).).

► Synthetic derivatives of nalidixic acid.Synthetic derivatives of nalidixic acid.► Inhibits DNA gyrase, causing permanent DNA Inhibits DNA gyrase, causing permanent DNA

cleavage. cleavage. ► Resistance:Resistance:

DNA Gyrase mutations DNA Gyrase mutations Cellular membrane efflux mechanisms.Cellular membrane efflux mechanisms. Decreased number of porins in target cells.Decreased number of porins in target cells.

► Wide distribution - CSF, saliva, bone, cartilageWide distribution - CSF, saliva, bone, cartilage

Antibiotic SpectrumAntibiotic Spectrum► Effective vs. gram +, gram -, atypicals, and Effective vs. gram +, gram -, atypicals, and

PseudomonasPseudomonas..► Decreased activity against anaerobes.Decreased activity against anaerobes.► Respiratory quinolones (levofloxacin).Respiratory quinolones (levofloxacin).

Active against Active against StrepStrep (including penicillin-resistant (including penicillin-resistant forms), forms), S. aureusS. aureus (including MRSA), (including MRSA), H. fluH. flu, , M. catM. cat (including penicillin-resistant strains), and atypicals.(including penicillin-resistant strains), and atypicals.

Used in AOM, sinustiis, pharyngitis…Used in AOM, sinustiis, pharyngitis…► Antipseudomonas quinolones Antipseudomonas quinolones

(ciprofloxacin/ofloxacin)(ciprofloxacin/ofloxacin) Active against Active against Pseudomonas, H. flu, M. cat.Pseudomonas, H. flu, M. cat. Strep pyogenes,Strep pyogenes, Strep pneumoniae, Strep pneumoniae, and MRSA are and MRSA are

resistant.resistant. Used in children with Cystic Fibrosis.Used in children with Cystic Fibrosis. Topicals used for otitis media.Topicals used for otitis media.

► Levofloxacin and Moxifloxacin have increased Levofloxacin and Moxifloxacin have increased StaphStaph activity even against cipro-resistant strains. activity even against cipro-resistant strains.

FluoroquinolonesFluoroquinolones►Adverse effects.Adverse effects.

Headache, dizziness, nausea, lightheadednessHeadache, dizziness, nausea, lightheadedness Limit use in pregnancy, nursing mothers, and Limit use in pregnancy, nursing mothers, and

children < 18.children < 18. Drug interactions: may increase levels of Drug interactions: may increase levels of

theophylline, warfarin, caffeine and theophylline, warfarin, caffeine and cyclosporine. cyclosporine.

Absorption decreased when taken with Absorption decreased when taken with cations.cations.

Arthralgias - 1%.Arthralgias - 1%.

Fluoroquinolones in children.Fluoroquinolones in children.► Only one approved Only one approved

indication in children.indication in children.► Animal studies show Animal studies show

joint/cartilage damage in joint/cartilage damage in wt bearing joints of wt bearing joints of young animals.young animals. Dose and animal Dose and animal

dependent.dependent.► All fluoroquinolones All fluoroquinolones

have demonstrated this have demonstrated this toxicity.toxicity.

► Mechanism unclear.Mechanism unclear.

Fluoroquinolones in children.Fluoroquinolones in children.► Fluoroquinolones still given to children.Fluoroquinolones still given to children.► Compassionate care cases have shed light on Compassionate care cases have shed light on

potential toxicity rates in children.potential toxicity rates in children. No significant differences have been found in children No significant differences have been found in children

treated with long term Cipro and age matched treated with long term Cipro and age matched controls.controls.

CF pts - 1.3% incidence of arthralgia (self-limited).CF pts - 1.3% incidence of arthralgia (self-limited). Short term use – no acute arthritis or serious adverse Short term use – no acute arthritis or serious adverse

effects (>1700 pts in general database review).effects (>1700 pts in general database review). Bayer studies - 1% incidence of arthralgia (90% had Bayer studies - 1% incidence of arthralgia (90% had

CF). Control groups had similar side effect profile as CF). Control groups had similar side effect profile as study group.study group.

No radiographic evidence of joint changes in any No radiographic evidence of joint changes in any study.study.

RifampinRifampin► Interacts with the bacterial DNA-dependent Interacts with the bacterial DNA-dependent

RNA polymerase, inhibiting RNA synthesis.RNA polymerase, inhibiting RNA synthesis.► Antibacterial spectrumAntibacterial spectrum

Mycobacteria, Mycobacteria, gram positives, gram negatives.gram positives, gram negatives. Used to treat carriers of meningococci or Used to treat carriers of meningococci or H. H.

fluflu..► Resistance.Resistance.

Develops rapidly during therapy. Should use Develops rapidly during therapy. Should use in combination with other drugs to decrease in combination with other drugs to decrease resistance rates.resistance rates.

Decreased affinity of the polymerase.Decreased affinity of the polymerase.► Metabolized in liver and may induce the Metabolized in liver and may induce the

cytochrome p-450 system.cytochrome p-450 system.► Cost: IVCost: IV $106.90/day$106.90/day; PO; PO $8.00/day$8.00/day

MetronidazoleMetronidazole► Flagyl; IV Flagyl; IV $17.00/day$17.00/day; PO ; PO $8.00/day$8.00/day► Forms cytotoxic compounds by accepting Forms cytotoxic compounds by accepting

electrons on its nitro group.electrons on its nitro group.► Distribution: nearly all tissues, including CSF, Distribution: nearly all tissues, including CSF,

saliva, bone, abscesses.saliva, bone, abscesses.► Antibacterial spectrum: anaerobes and Antibacterial spectrum: anaerobes and

parasites.parasites.► Used for Used for C. difficile C. difficile and other anaerobic and other anaerobic

infections (abscesses).infections (abscesses).► Toxicity: disulfram reaction.Toxicity: disulfram reaction.

Treatment of MRSATreatment of MRSA► PrevalencePrevalence► Mechanisms of Mechanisms of

resistance.resistance.► Healthcare Associated Healthcare Associated

vs. Community vs. Community Acquired.Acquired.

► Vancomycin Vancomycin intermediate intermediate susceptible strains susceptible strains (VISA).(VISA).

► Vancomycin resistant Vancomycin resistant strains (VRSA).strains (VRSA).

► Treatment approaches Treatment approaches and new drugs.and new drugs.

MRSA - PrevalenceMRSA - Prevalence► First isolates of MRSA First isolates of MRSA

were reported in the were reported in the early 1960’s after early 1960’s after methicillin was methicillin was introduced in 1959.introduced in 1959.

► 3 pandemic MRSA clones 3 pandemic MRSA clones were traced back to the were traced back to the 1960’s isolates from 1960’s isolates from Denmark and England.Denmark and England.

► 5 major MRSA clones 5 major MRSA clones were identified by 2002.were identified by 2002.

MRSA PrevalenceMRSA Prevalence► Data through 2002 indicate that Data through 2002 indicate that S. aureusS. aureus isolates isolates

from ICU pts. were 51% MRSA and 41% from non-from ICU pts. were 51% MRSA and 41% from non-ICU pts.ICU pts.

► A prospective study showed that MRSA prevalence A prospective study showed that MRSA prevalence rose sharply from 22% to 57% between 1995-2001.rose sharply from 22% to 57% between 1995-2001.

► Community acquired MRSA prevalence has been Community acquired MRSA prevalence has been reported to be 21-29% in adults and 35-50% in reported to be 21-29% in adults and 35-50% in children.children.

► Current UTMB statistics.Current UTMB statistics. Modified from Antimicrobial Susceptibility Profile July 2003-June 2004Modified from Antimicrobial Susceptibility Profile July 2003-June 2004InpatieInpatie

ntntOutpatieOutpatientnt

TDCTDC PICUPICU Adult Adult ICUICU

MRSA MRSA PrevalencePrevalence

64%64% 59%59% 6262%%

47%47% 71%71%

MRSA – Resistance MRSA – Resistance MechanismsMechanisms

► Definition; Oxacillin MIC Definition; Oxacillin MIC >> 4ug/ml… 4ug/ml… resistant to all B-lactams.resistant to all B-lactams.

► mec gene – staphylococcal chromosomal mec gene – staphylococcal chromosomal cassette (SCCmec)cassette (SCCmec) Present in all MRSA isolates.Present in all MRSA isolates. Five SCCmec types (I-V).Five SCCmec types (I-V).

► Types I-III – prevalent in healthcare Types I-III – prevalent in healthcare associated isolatesassociated isolates

► Type IV – prevalent in community acquired Type IV – prevalent in community acquired isolatesisolates

mecA – encodes PBP2a (low affinity PBP)mecA – encodes PBP2a (low affinity PBP)► PBP2a is able to substitute for the activity of PBP2a is able to substitute for the activity of

other inactivated PBP’s.other inactivated PBP’s.► Resulting peptidoglycan is structurally Resulting peptidoglycan is structurally

different but functional.different but functional. mecR1-mecI – negative regulator if mecA mecR1-mecI – negative regulator if mecA

transcription.transcription. B-lactamase genes – Can down regulate B-lactamase genes – Can down regulate

mecA transcription.mecA transcription.

MRSA – HA vs. CAMRSA – HA vs. CA► Community acquired (CA) MRSACommunity acquired (CA) MRSA

Younger population.Younger population. High risk groups – athletes, High risk groups – athletes,

prisoners, men who have sex with prisoners, men who have sex with men, drug users and Native men, drug users and Native Americans.Americans.

More likely to produce skin and soft More likely to produce skin and soft tissue infections.tissue infections.

Not multi-drug resistant.Not multi-drug resistant.► Healthcare associated (HA) MRSAHealthcare associated (HA) MRSA

Multi-drug resistant.Multi-drug resistant. Associated with foreign bodies.Associated with foreign bodies.

MRSA antibiotic MRSA antibiotic susceptibility.susceptibility.

► UTMB Antibiotic Susceptibility ProfileUTMB Antibiotic Susceptibility Profile Percent SusceptiblePercent Susceptible Modified from Antimicrobial Susceptibility Profile July 2003-June Modified from Antimicrobial Susceptibility Profile July 2003-June

20042004S. aureusS. aureus CefazoliCefazoli

nnClindamycClindamycinin

ErythromycErythromycinin

OxacilliOxacillinn

TetracycliTetracyclinene

BactriBactrimm

UTMB UTMB outpt.outpt.

41%41% 86%86% 24%24% 41%41% 88%88% 97%97%

UTMB UTMB inpt.inpt.

-------- 64%64% 24%24% 36%36% 84%84% 89%89%

PICUPICU -------- 88%88% 50%50% 53%53% 91%91% 100%100%Adult ICUAdult ICU -------- 43%43% 22%22% 29%29% 84%84% 85%85%TDCTDC -------- 59%59% 25%25% 38%38% 75%75% 73%73%

VISA and VRSAVISA and VRSA► Vancomycin intermediate susceptible Vancomycin intermediate susceptible

strains.strains. Cases reported from Japan and NYC.Cases reported from Japan and NYC. Likely due to altered peptidoglycan Likely due to altered peptidoglycan

biosynthesis which causes thicker cell walls biosynthesis which causes thicker cell walls and decreased drug exposure to the and decreased drug exposure to the cytoplasmic membrane.cytoplasmic membrane.

Pts that respond poorly to vancomycin Pts that respond poorly to vancomycin should be re-cultured and vancomycin should be re-cultured and vancomycin susceptibility tested via broth dilution susceptibility tested via broth dilution techniques.techniques.

► Vancomycin resistant strains – MIC Vancomycin resistant strains – MIC >> 32ug/ml32ug/ml Possible cross resistance with VRE.Possible cross resistance with VRE. Vancomycin is unable to bind to its target Vancomycin is unable to bind to its target

site due to an altered terminal peptide.site due to an altered terminal peptide.

Outpatient treatmentOutpatient treatment► BactrimBactrim► ClindamycinClindamycin

Must check for erythromycin resistance as a marker Must check for erythromycin resistance as a marker for MLSfor MLSBB inducible resistance. inducible resistance.

► UTMB outpatients have a 8-10% prevalence of MLSUTMB outpatients have a 8-10% prevalence of MLSBB inducible inducible resistance.resistance.

► TDC pts have a 4-6% prevalence of MLSTDC pts have a 4-6% prevalence of MLSBB inducible resistance. inducible resistance.► TetracyclineTetracycline► LevaquinLevaquin► Combination therapy with RifampinCombination therapy with Rifampin

Inpatient treatmentInpatient treatment►VancomycinVancomycin►ClindamycinClindamycin►BactrimBactrim►TetracyclineTetracycline►LevaquinLevaquin►Combination therapyCombination therapy

New antibiotics for MRSANew antibiotics for MRSA► LinezolidLinezolid► Quinupristin-Quinupristin-

dalfopristindalfopristin► DaptomycinDaptomycin► LysostaphinLysostaphin

LinezolidLinezolid► Oxazolidinone – inhibits the initiation complex of Oxazolidinone – inhibits the initiation complex of

bacterial protein synthesis.bacterial protein synthesis.► Zyvox; IV Zyvox; IV $116.85/day$116.85/day; PO ; PO $84.55/day$84.55/day..► Antibiotic spectrum – gram positivesAntibiotic spectrum – gram positives..► Oral = IVOral = IV► Similar cure rates when compared to Similar cure rates when compared to

vancomycin.vancomycin. May be superior to vancomycin for MRSA pneumonia.May be superior to vancomycin for MRSA pneumonia.

► Adverse effects.Adverse effects. Myelosuppresion, thrombocytopenia.Myelosuppresion, thrombocytopenia.

Quinupristin-dalfopristinQuinupristin-dalfopristin► Quinupristin – streptogramin AQuinupristin – streptogramin A► Dalfopristin – streptogramin BDalfopristin – streptogramin B► Binds 50S ribosome.Binds 50S ribosome.► High activity against MRSA and VISA, and High activity against MRSA and VISA, and

coag neg. staph.coag neg. staph.► Synergy with B-lactams.Synergy with B-lactams.► Additive with vancomycin.Additive with vancomycin.► Adverse effects:Adverse effects:

Arthralgias, myalgiasArthralgias, myalgias HyperbilirubinemiaHyperbilirubinemia

DaptomycinDaptomycin

► Cyclic lipopeptide Cyclic lipopeptide ► Disrupts cell membrane function.Disrupts cell membrane function.► Similar efficacy when compared to Similar efficacy when compared to

vancomycin.vancomycin.► Only approved for complicated skin and soft Only approved for complicated skin and soft

tissue infections.tissue infections.► Not used for pneumonia due to low Not used for pneumonia due to low

respiratory tract concentrationsrespiratory tract concentrations► Adverse effects – reversible myopathy.Adverse effects – reversible myopathy.

LysostaphinLysostaphin►Staphylococcus simulansStaphylococcus simulans►Cleaves pentaglycine cross-links Cleaves pentaglycine cross-links

unique to unique to S. aureusS. aureus cell wall. cell wall.►Shown to reduce vegetations in rabbit Shown to reduce vegetations in rabbit

endocarditis.endocarditis.►Synergistic effect with B-lactams.Synergistic effect with B-lactams.►Resistance – changes in the Resistance – changes in the

muropeptide crossbridge.muropeptide crossbridge.

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