Med Agents Test 4

• What is it?: chemical structure and class. Natural or synthetic product?
• How does it work?: target site and MOA
• When is it used?: spectrum of activity and important clinical uses
• What are the problems?: Toxicity and microbial resistance.
• Where does it go?: ADME
• How do we get it there?: Route of administration and product formulation
• How much does it cost?: Cost effectiveness

• Empiric therapy: based on treatment of most likely organisms for a specific infection
• Definitive therapy: after organism is identified. May or may not have information on susceptibility and resistance.

• Prokaryotes: 70S (50S and 30S subunits)
• Eukaryotes: 80S (60S and 40S subunits)

• Prokaryotes: complex structure containing lipids, proteins (receptors), and peptidoglycan
• Eukaryotes: Absent or composed of cellulose (plants) or chitin (insects, fungi)

• inhibition of cell wall synthesis
• inhibition of protein synthesis
• inhibition of nucleic acid synthesis
• effects on cell membrane sterols (antifungal agents)
• inhibition of unique metabolic steps (antimetabolites like MTX and 5FU)

• Humans: Contain cholesterol.
• Fungi: Contain ergosterol.

• aminoglycosides
• tetracyclines

• macrolides
• clindamycin
• linezolid
• CAP (cholroamphenicol?)

• Chromosomal mediated: spontaneous mutation
• Plasmid mediated: -

• cojugation: "swapping plasmids"
• bacteriophage-mediated transduction: virus transfers resisance genes
• transformation: uptake of resistance transposon by a sensitive bacterium after lysis of resistant bacteria (only clinically significant with Gm+ bacteria

• inactivation of drug by enzymes - usually plasmid mediated
• alteration of membrane permeability
• efflux pumps - active transport pump to remove antimicrobial agents
• alteration of intracellular target site
• alteration of intracellular target enzyme
• overproduction of target enzyme
• auxotrophs that bypass blocked step
• absence of autolytic enzymes

• change in porins
• change in transport proteins

• non-specific host defense mechanisms
• non-specific immunity
• acquired or adaptive immunity (antibody-mediated)

• skin: defensins, PGLYRP-3 & 4
• mucous membranes: IgA production, lysozyme
• saliva: PGLYRP-4
• lungs: cilia, bronchial seretions - lysozyme
• liver: PGLYRP-2 (peptidoglycan amidase)
• GI tract: stomach acid, intestinal microflora, IgA, PGLYRP-3
• bladder: flushing, Tamm-Horsfall protein
• vagina: normal flora
• eye: tears, lysozyme, PGLYRP - 3 & 4

peptidoglycan recognition proteins: proteins found in some tissues that recognized peptidoglycan in the cell walls of gram positive bacteria

• alternative complement pathway
• toll receptor recognition system

An innate component of the immune system's natural defense against infections, which can operate without antibody participation.

Toll-like Receptors (TLRs) on the surface of T cells are recognition sensors for Pathogen-Associated Molecular Patterns (PAMPs) that are unique to different types of pathogens or damaged host tissues. When TLRs are activated, there is a release of cytokines.

• Antigen recognition and antibody production
• classical complement pathway

• IgG: opsonic activity
• IgM: antibacterial lysis
• IgA: antiviral lysis
• IgD: ?
• IgE: anaphylaxis

• Groups with primary genetic immune deficiencies like X-linked agammaglobulinemia (bruton's disease)
• Groups with secondary immunodeficiencies like AIDS
• Other disease states or conditions associated with depressed immune function like diabetes

• Dipeptide analogs of D-ala-D-ala
• Bind to penicillin binding proteins (PBPs)
• Inhibition of PBPs 1-3 is bacterialcidal
• PBP inhibition is a reult of acylation of the enzyme by attack of a serine residue on the B-lactam ring
• Only active against rapidly growing bacteria (requires cell wall biosynthesis)

• Penicillin G: IV, PO
• Penicilin G procaine: IM
• Penicillin G benzathine: IM, longer DOA, used for syphilus and others
• Penicillin V: PO

• Methicillin: IV, IM
• Oxacillin: IV, IM, PO
• Nafcillin:IV, IM, PO
• Cloxacillin: PO
• Dicloxacillin:PO

• Ampicillin: IV, IM, PO
• Amoxicillin: PO
• Bacampicillin: PO, prodrug to ampicillin but costly and not used much

• Carboxypenicillins: Cabenicillin indanyl (PO) and Ticarcillin (IV)
• Ureidopenicillins: Piperacillin (IV, with taobactam makes Zosyn) and Mezlocillin (IV)

• Amoxillin-clavulanic acid: PO
• Ampicillin-sulbactam: IV
• Ticarcillin-clavulanic acid: IV
• Piperacillin-tazobactam (Zosyn): IV

• inactivation by enzymes (B-lactamases)
• altered penicillin binding proteins (PBPs)
• altered permeability to penicillins

• -Strep. pneumoniae, Strep. viridans, Strep pyogenes: (penicillin-resistant strains of -Strep. pneumoniae are emerging)
• -Enterococcus faecalis, NOT E. faecium: (in combination with AGs)
• -N. menigitidis: (non penicillinases producing strains)
• -Treponema pallidum: (syphilis)
• -Listeria monocytogenes: (in newborn or elderly)
• -Corynebacterium diphtheriae: x
• -Anaerobes: clostridum perfringens and C. tetani (not C. difficile), BACTEROIDES FRAGILIS (non-penicillinase producing strains), fusobacterium, peptostreptococcus

• Gram positive cocci (5)
• -strep throat and scarlet fever - Strep. pyogenes is generally sensitive
• -pneumonia and meningitis due to Strep. pneumoniae
• -streptococcal skin and soft tissue infections caused by Strep. viridans, Group B Strep., Strep. pyogenes
• -Anaerobic streptococcal infections
• -Endocarditis due to Strep. Viridans and Enterococcus sp. (in combo with AG)

• Gram positive rods (2)
• -tetanus
• -gas gangrene

• Gram negative cocco-bacilli - Neisseria (2)
• -menigitis due to N. meningitidis
• -gonorrhea (no longer drug of choice, now third gen cephalosporins is first line)

• Syphilis

• Gm+ only, like Pen G, but spectrum includes Staph aureus and Staph epidermidis.
• Not active vs MRSA and MRSE

• Have similar Gram + pectrum to Penicillin V and K: x
• E. coli, Proteus mirabilis: (exp. for UTIs)
• Haemophilus influenzae: (resistance is common)
• Listeria: x
• Borrelia burgdoferi: alternative to doxycycline; DOC in childre under 8 and pregnancy

Note: Amoxicillin is the number one antibiotic sold in US

• Meningitis: ampicillin alternative choice to second generation cephalosporins.
• Bronchitis/Pneumonia: widely used, but resistance is a problem
• Prophylaxis for bacterial endocarditis: 2 gm amox PO 1 h prior to dental procedures, DOC
• Lymes Disease: alternate to doxycyline ( 1 g amox and 05 g probenicid q 8 h) or 20 mg/kg in children
• Susceptible strains of N. gonorrheae: this is an alternate
• Diarrhea: due to Salmonella, Shigella, and E. coli

Amoxicillin 90 mg/kg/day divided every 12 hours

• Strep. pneumoniae
• Haemophilus sp.
• Moraxella catarrhalis (not a good pathogen)

No.

Haemophilus sp. that cause otitis media are not encapsulated, so vaccine is not effective

• Srep. pneumoniae
• N. meningitidis
• group B Strep.
• Listeria monocytogenes
• H. influenzae
• E. coli

• pseudomonas aeruginosa infections
• mixed infections
• complicated urinary tract infections
• prostatitis dues to susceptible strains of various organisms
• surgical prophylaxis in intra-abdominal and gynecologic surgeries only

suicide inhibitors that lock the enzyme in the acyl-enzyme intermediate because the deacylation step is very slow.

See page 49 of course packet for structure of the intermediate.

No!

Nothing to the left of the beta-lactam ring.

• Upper respiratory tract infections (URIs) such as otitis media and sinusitis
• LRIs
• skin infections
• intra-abdominal infections
• gynecologic infections

Zosyn

• appendicitis/peritonitis
• skin and skin structure infections
• pelvic inflammatory disease and post partum endometritis
• community acquired and nosocomial acquired pneumonia

Short

• Hypersensitivity reactions: rashes and anaphylaxis
• cross reaction with cephlosporin is small: can use cephlasporin cautiously
• idiopathic reaction associated with mononucleosis and allopurinol: ampicillin and amoxicillin contraindicated

No

the acyl side chain

Like penicillins, they also bind to penicillin binding proteins and inhibit cell wall biosynthesis in both Gm + and Gm - bacteria.

penicillin

• 
• Cephalosporin

• cefazolin (IV)
• cephalaxin (oral)

• cefuroxime (IV)
• cefuroxime axetil (PO)
• cefoxitin (IV)

• cefotaxime (IV)
• ceftriaxone (IV)
• ceftibuten (oral)

ceftazidime

• production of beta-lactamases (in general they are more resistant to beta-lactamases)
• altered PBPs
• altered uptake (since they are bigger than the penicillins)

Staph aureus: excellent against b-lactamase producing strains, not effective against MSRA and MSRE

Streptococci: not effective against penicillin-resistant Strep. pneumoniae

Other Gm + bacteria: except Enterococcus sp.

Gm - bacteria: moderate activity (see Q57 for specific organisms)

• E. coli
• Proteus mirabilis
• Indole + Proteus sp (many strains resistant)
• Haemophilus influenzae (some strains resistant)
• Neisseria sp. (some gonococci resistant)

• Skin infections due to MSSA and MSSE
• Lower respiratory tract infections
• Surgical prophylaxis for orthopedic and cardio operations (not gut operations)
• Staphylococcal infections (need sensitivity data!)

• Expanded activity against gram negative.
• Anaerobic infections (cefoxitin has OCH3 group above the beta-lactam ring which provide res to beta-lactamase)

• Neisseria sp
• H. influenzae
• Moraxella ctarrhalis
• E. coli
• Proteus mirabilis

• community acquired pneumonia
• skin and soft tissue infection (MSSA and MSSE)
• UTIs ( require 7 days of treatment)
• Pelvic inflammatory disease (with doxycycline)
• upper respiratory tract infections
• mixed aerobic and anaerobic infections
• surgical prophylaxis

bleeding problems due to methylthiotetrazole ring.

• unpleasant taste
• reasonable well absorbed (F=35-45%)

Ceftidoren pivoxil (spectracef) because pivalic acid (released from prodrug) reduces carnitine levels.

Extended spectrum beta lactamase.

further expansion of Gm negative spectrum to include hard to treat organisms usch as Morganela, Serratia, and Pseudomonas.

Almost always sensitive: E. coli (non-ESBL producing), klibsiella pneumoniae and oxytoca (non-ESBL), Proteus mirabilis and proteus vulgaris.

• Generally sensitive: morganella morganii, providencia retgerri, citrobacter freundii, serratia marcescens, Pseudomonas aeruginosa (ceftazidime only).
• Sometimes sensitive: enterobacter, citrobacter, acinetobacter (50% untreatable)

• Gram negative septicemeia and other serious Gm - infections
• Pseudomonas aeruginosa infections (eq to zosyn)
• Meningitis (empiric treatment) - IV ceftriaxone or cefoaxime.
• Gonnorrhea - single shot ceftriaxone
• Complicated UTI
• Osteomyelitis
• Lyme disease (chronic)

cefotaxime over ceftriaxone

it has a shorter half life but it is less highly protein bound.

• surgical prophylaxis (use 1st or 2nd generation)
• otitis media, URIs - cefixime and ceftibuten have poor Gm + activity
• Uncomplicated UTIs (unless resistant to TMP-SMX)

Cefpodoxime proxetil

Cefdinir

Biliary sludge.

Cefepime

A 5th Generation Cephalosporin just approved that is active against MSRA.

The positive charge