• gm+ has thicker peptidoglycan
• gm- has outer membrane surround thin peptidoglycan. gm- outer membrane has porin, that allow  drug to enter.
• Enzymes (e.g., β-lactamases) that inactivate certain antibacterial agents locate in the periplasmic space existing between the outer membrane and the cell membrane of gram-negative bacteria.

Different between bacterial cell and human cell that allow antimicrobial agents seletive toxicity?

• Bacterial cell: cell wall, 70s ribosome= 50s and 30s, structural different in topoisomerase, DNA polymerase, pteroate synthase, dihydrofolate reductase.
• Host cell:no cell wall, 80s ribosome=60s + 40s

IC50= EC50 measure potency

Emax= maximal effect (Vmax)

• Bacteriostatic:ab that inhibit growth and reproduction of bacteria but DO NOT kill it. The body immunity clear the bacteria.
• Bactericidal: ab that killed >99.9% of the infective organism and hence eradicate it. Use when host immunity is impaired. meningitis, endocarditis, osteomeylitis
  
  

Elaborate on antibiotic pectra of activity.

what's narrow spectrum?

what's extended-spectrum?

what's board-spectrum?

• Narrow-spectrum: drugs that are effective against a limited group of microorganisms.
• Extended-spectrum: drugs that are effective against gm+ and a significant amount of gm-
• Board-sepctrum: wide variety or organism.
  

• susceptibility testing: determine possible antimicrobial that would eradicate an organism.
• Minimal inhibitory concentration (MIC): the lowest concentration of antibacterial agent that inhibit visible growth.
• Minimal bactericidal concentration (MBC): the lowest concentration of antibacterial that either totally prevent growth of result in >99.9% decrease in intitial inoculum.
  

• same rate and same extent of killing at therapeutic concentration. Increase concentration will not increase killing

Cmax/MIC ratio: increase killing and extents with higher peak concentration

AUC/MIC: total drug exposure determine killing rate.

• prophylactic therapy: use on immunosuppressed patient, surgical procedure (prevent wound infection-colon resectioning, cardio/neuro surgery), Endocarditis-dental procedures.
• empiric therapy: used when delayed in initiating ab therapy could be fatal. use >1 agents with board spectrum. sp. meningitis when lumbar puncture is delayed.
  
• definitive therapy:when the organism is identified. should use more specific and narrow-spectrum agent. if no pathogen documented, Ab should be discontinued.
• combination therapy: boarden spectrum or for synergy.
  

Mechanism of bacterial resistance:

• decrease drug penetration
• efflux pump altered target site
• inactivation of drug with enzyme (beta-lactamase)

nafcillin cannot penetrate outer membrane of gm- bacteria.

normal microbs developed into a virulent and resistance strain through selection pressure.

Vertical transfer: transfer of this trait to daughter

horizon transfer: transfer this trait to other bacterial cells via conjugation of plasmid or phage.

• Drugs do not reach target: alter porin reduce entry. enhance efflux pump pump drug out.
  
• Drug inactivation:inactivate drugs
• Target alteration: modify drug's target
  
• Alternative pathway: microb develops way to bypass route blocked by drug.

Beta-Lactams:

Penicillin (PenG/PenV, Nafcillin/Methicillin/Oxacillin, ampicillin/amoxicillin, Ticarcillin/carbenicillin/piperacillin)

Cephalosporin (cefazolin/cephalexin/cefadroxil-PEcK, cefoxitin/cefaclor/cefuroximine-HEN PEcK,Ceftriaxone/cefotaxime/ceftazidim- meningitis/pseudomonas, Cefapime-pseudomonas and gm+)

Carbapenem (imipenem/cilastatin-gm+ cocci, gm-rods, enterobacter. Meropenem/ertapenem.)

Aztreonam (monobactam resistant to beta-lactamase. gm-aerobic cocci and bacillus-enterobacteriae/P. aeruginosa)

OTHER:

Vancomycin (D-ala-D-ala. gm+ only. pseudonomiae, MRSA

Daptomycin (create pore, MRSA, MRSE, VISA, VRSA, VRE)

1. Block transpeptide x-linking
2. Block cell wall synthesis
3. Initiate bacterial autolysis
4. osmotic rupture
5. other means of collapsing bacterial cell wall

B-Lactams are bactericidal only when bacteria are growing and peptidoglycan are being produced.

B-lactams has Time-dependent killing effect (increase Concentration pass effective dose will not increase killing rate)

• PBPs lack affinity for B-Lactams
• Organism lack peptidoglycan cell wall (mycoplasma)
• Intracellular organism/ B-lactams cannot enter cell (L. Pneumophila, Chlamydia)
• Porin that do not allow passage of drug (many gm- have this eg. P. Aeruginosa)
• Efflux pumps (P. aeruginosa, N. gonorrhea, E.coli)
• B-Lactamase (gm+ secrete, gm- has B-lactamase in periplasmic space)
  

express by many E.Coli, K. pneumoniae, enterobacteriacea spp.

• Class A TEM-1 (E.Coli) and SHV-1 (K. pneumoniae): B-lactamase activity. resist ampicillin and amoxicillin.
• Class A ESBL (extended-spectrum beta-lactamases): resist all PNCs, and CEPHs. B-lactamase activity. can horizontal transfer.
• Class A KPC (Klesiella Pneumoniae): resist carbapenem, PCNs and extended-spec CEPHs
  
• Class B (Zn2+ dependent metalloprotease): resist all B-lactams, board spect carbepenem and cephamycin
• Class C AmpC (P. aeruginosa, Citrobacter, enterobacter, Serratia): plasmid mediated, hydrolyse extended spect cephalosporin.
• Class D  (gm- rod): penicillinase.
  

• decrease growth rates
• greater number of organism capable of resisting.

• B-lactam drug
• IV, IM, Oral but  not  intrathecal (into spinal cord)
• poorly penetrate CNF
• Eliminate: renal
• Side effect: hypersensitivity rxn: x-rxn with other B-lactams, anaphylaxis (HTN), angioedema, serum sickness, hemolytic anemia, steven-johnson, fever, nephritis.
• No contraindication in pregnancy, can be use in kid > 3months old.

• Natural PNC: Gm+ aerobic/anaerobic, Neisseria meningitis, H. influenzae

1. PenG (IV, IM)
2. PenV(oral)

• Penicillinase-resistance Penicillin: tx MSSA

1. Nafcillin (IM, IV)
2. Methicillin (IM, IV)
3. Oxacillin (IM, IV)

• Aminopenicillin: Pen G activity + extended spec on enteric bacteria (H.E.L.P.S  kill enterococci - H. Influenzae, E.Coli, Listeria Monocytogenes, Proteus mirabilis, Salmonella, Enterococci)
  

1. Ampicillin (oral, IV, IM)
2. Amoxicillin (oral only)

• Anti-pseudomonals: activity of ampicillin + activity against pseudomonas. TCP: Take Care of Pseudomonas.

1. Ticarcillin (IM, IV)
2. Carbenicillin (Oral only)
3. Piperacillin (IM, IV)

• Streptococcus pneumoniae: modify PBP
• Straphylococcus aureus: Penicillinase, low PBP affinity.
• Enterococcus faecium: point mutation in PBP, decrease affinity
• Gm- Bacilli (intrinsic resistance): PenG and PenV cannot penetrate porin. have B-lactamase activity.

respiratory tract

meningitis

skin-skin structure

bacteremea

endocarditis

syphilis

• Hypersensitivity rxn
• seizure
• electrolyte disturbance
• Jarish-Herxheimer rxn: complication of syphilis tx. consquence of rxn with dying Treponema pallidum

What's the main MOA of penicillinase-resistance penicillin

• Nafcillin (IM, IV), Oxcillin (IV, IM), Dicloxacillin (oral), Cloxacillin (ora, IM, IV)
• Bulk side chain prevent binding of staphyloccocus B-lactamase to the drug
• Hepatic metabolism
• against MSSA, MSSE
• SHOULD NOT be used to treat infection susceptible to Pen G
• Adverse effect: Hepatitis, Nephritis

• Ampicillin (ora, IM, IV), Amoxicillin (oral-acid stable)
• amino group on side chain increase hydrophilicity, allowing them to pass through porins in the outer membrane of enterobactericeae
• Tx: gm+ (like pen G), gm- extended spect
• side effect: rash (nonallergic), nonallergic rash can also be observed with use of Allopurinol. Hypersensitivity--> contraindicate future use of PNC

• Polar-side chain-> able to pass through porins in the outer membrane of Pseudomonas aeruginosa, and enterobactericiae.
• Ureidopenicillin: Piperacillin, Piperacillin-tazobactam (has the boardest spect of all PCN)
  
• Carboxypenicillin: Ticarcillin-clavulnate (with attached B lactamase inhibitor.
• Adverse side effecT: congestive heart failure, thrombocytopenia, leukopenia, rash

These drugs needed to be combined with a PNC for full action

• Clavulanic acid (oral, parenteral), hepato metabolize, renal secrete
  
• Sulbactam (parenteral), renal secretion
• Tazobactam (parenteral), hepato metabolize, renal secrete

• FX: inhibit bacterial B lactamase, no sign antibacterial properties
• activity against plasmid encoded: B lactamase of staph, Class A B lactamase
• Ineffective against: AmpC B lactamase

These organisms are L.A.M.E.

Listeria monocytogene

Atypical (mycoplasma-no cell wall, chlamydia (intracell)

MRSA

Enterococci

• first gen: Cefazolin (Parenteral) for surgical propylaxis, Cephalexin (oral)/ cefadroxil (oral) for infection
• second gen:Cefuroxim (parenteral), Cefaclor/loracarbef (oral). This generation offer no advantages over other B-lactam ab
• The cephamycine: cefoxitin, cefotetan- activity against B. fragilis, gm- enteric bacilli and mixed aerobes and anaerobs bacteria
• Third gen: ceftriaxone, cefotaxime-tx serious infection like meningitis, ceftaxidim- tx psedomonas, serattia, enterobacteriacea
• Forth gen: cefepime-tx gm+ not MRSA, gm-
• anti-MRSA CEPHs: Ceftaroline, Ceftobiprole

• bone marrow suppression
• renal tubule  necrosis
• Cefttriaxone (3rd gen): cholestatic hepatitis/gallbladder dz, Hyperbilirubinemia
• cefotetan (cephamycin): hypoprothrombinemia

• penetrate CNS
• renal secreted
• Imipenem-Cilastatin: cilastatin inhibits dehydropeptidase I, which is responsible for convert imipenem to inactive form
• activity against: gm-, gm+ pathogen, ESBL class and AmpC class
• Resisted by MRSA, Class B zn, Class A serine protease
  

• Should not be used alone for empiric therapy.
• Used for infection by suseptible gm-bacilli
• Inhale Aztreonam for pseudomonas aeruginosa.
• Adverse effecT:low immunogenic potential: limited x-reaction with other B-lactamase drug
  

• Bulky vancomycin molecule binds to D-ala-D-ala on precursor ® prevents formation of bridges between peptidoglycan chains
• Work on gm+ pathogens only, MRSA, C. Diff infection
  
• Bactericidal against penicillin-resistance S. pneudomoniae
• resistance to vancomycin: Intrinsic (all gm- bacilli) vacomycin cannot enter porin.
• Acquired resistanct:

1. Enterococci: inducible VanA gene

D-Ala-D-Ala--->D-Ala-D-Lactate or D-serine

this transformation decrease Vancomycin's affinity for target.

1. S. Aureus Intermediate resistance:

Alter cell wall metabolism-->abnormal thick cell wall--->false target sequesterd drug

• hypersensitivity rxn
• Red man syndrome
• Phlebitis
• Ototoxicity
• Nephrotoxicity

• cyclic lipopeptide
• IV use only
• Not for meningitis
• Concentration-dependent killing
• inactivate by pulmonary surfactant

• Step 1: Daptomycin binds to the cytoplasmic membrane;
• Step 2,3: Forms complexes in a calcium-dependent insertion of its lipid tail®causes a rapid loss of cellular K+ ®membrane depolarization and loss of membrane potential ---> arrest of DNA, RNA, and protein synthesis ® cell death (without lysis)

• Effective against MRSA, MRSE, VISA, VRSA, and possibly VRE
• Daptomycin is used in the treatment of:
  •Complicated skin and soft tissue infections
  •Complicated bacteremia
  •VRE right-sided endocarditis
• Daptomycin is INEFFECTIVE in:
  •Infections by gram-negative bacteria – inherently resistant
  •Left-sided endocarditis
  •Pneumonia:
  ▫likely due to drug inactivation by pulmonary surfactants

• myopathy
• eosinophilic pnemonia
• peripheral neuropathy
• HMG CoA-reductase inhibitors (statins):
  ▫Potential for additive muscle toxicity; consider temporarily the HMG CoA-reductase inhibitor during daptomycin therapy