Strep

Staph

Enterics: bacteria that occupy the intestines.

E. coli, P. aeruginosa

Cover G+ and G- cocci only

Blocks Dihydropteroate Synthase to inhibit folic acid synthesis.

Rx: IV or Oral to tx G+/G- (does not cover anaerobes)

Blocks Dihydrofolate Reductase to inhibti folic acid synthesis.

Rx: IV or Oral to tx G+/G- (does not cover anaerobes)

Beta lactam antibiotics inhibit cell wall synthesis.

Are Bactericidal

In a growing bacterial cell wall autolysins (cell wall-hydrolyzing enzymes) must cleave bonds in the old cell wall to enable the insertion of new peptidoglycan units.

If peptidoglycan syntheisis is inhibited, autolysins continue their activity which leads to damage of the peptidoglycan cell wall causing lysis of the cell in hypotonic media.

Beta lactam narrow spectrum antibiotic

Binds to and inactivates PBPs (Penicillin-binding proteins) to block peptidoglycan cell wall synthesis.

Highest activity against G+ bacteria and G- cocci (not G- enterics).

Sensitive to Penicillinase (beta-lactamase) which breaks the beta lactam ring.

Given IV

Shortcomings: lability in stomach acid, sensitivity to penicillinase, allergic repsonses, ineffectiveness against G- enterics.

*Note that with the exception of allergic responses, all of these have been improved in semisynthetic penicillins.

Binds to and inactivates PBPs to block peptidoglycan cell wall synthesis.

Highest activity against G+ bacterai and G- cocci (not enterics).

Sensitive to Penicillinase

More acid-stable than Penicillin G which allows it to be given orally!

Binds to and inactivates PBPs to block peptidoglycan cell wall synthesis.

Effective against G+ and G- Enteric bacilli (E.coli, P.aerugosa etc...)

Sensitive to Penicillinase.

IV or Oral administration.

Binds to and inactivates PBPs to block peptidoglycan cell wall synthesis.

Higher serum levels than Ampicillin.

Effective against G+ and G- enteric baccilli

Sensitive to Penicillinase.

Oral administration.

Binds to and inactivates PBPs to block peptidoglycan cell wall synthesis.

Was the first beta lactam effective against P. aeruginosa.

Still sensitive to Penicillinase.

IV administration.

Binds to and inactivates PBPs to block peptidoglycan cell wall synthesis.

Effective against G+ and G- enteric + P. aeruginosa

2x as active as Carbenicillin

IV administration

Binds to and inactivates PBPs to block peptidoglycan cell wall synthesis.

The most active penicillin against G- enterics, P. aeruginosa and G- anaerobes (*is less active against G+ cocci)

Sensitive to Penicillinase.

IV adminstration.

Binds to and inactivates PBPs to block peptidoglycan cell wall synthesis.

Anti-Staphylococcal (narrow spectrum)

Not E. coli, lower activity than Penicillin G BUT

Is Resistant to Penicillinase*

IV administration.

No longer used due to adverse effects and the availibility of alternate agents*

Methicillin-resistant Staph aureus (MRSA) is a huge problem in healthcare settings.

Binds to and inactivates PBPs to block peptidoglycan cell wall synthesis.

Anti-Staphylococcal (not E.coli)

Resistant to Penicillinases

IV or Oral dministration

Binds to and inactivates PBPs to block peptidoglycan cell wall synthesis.

Anti-Staphylococcal (not E.coli)

Resistant to Penicillinases

IV or Oral administration

Binds to and inactivates PBPs to block peptidoglycan cell wall synthesis.

Anti-Staphylococcal (not E.coli)

Resistant to Penicillinases

Oral adminstration

Binds to and inactivates PBPs to block peptidoglycan cell wall synthesis.

Anti-Staphylococcal (not E.coli)

Resistant to Penicillinases

Oral administration.

1st generation Cephalosporin

Effective against G+ + G- enterics (though not P. aerugosa)

Sensitive to Cephalosporinase

IV or Oral administration

1st generation Cephalosporin

Effective against G+ + G- enterics (though not P. aerugosa)

Sensitive to Cephalosporinase

IV or Oral administration

Second Generation Cephalosporin

Improved anaerobic activity

More resistant to cephalosporinases but sensitive to ESBLs (Extended-spectrum beta lactamases).

IV or Oral administration

Second Generation Cephalosporin

Improved anaerobic activity

More resistant to cephalosporinases but sensitive to ESBLs (Extended-spectrum beta lactamases).

IV or Oral administration

Third generation Cephalosporin

Improved G- activity

More resistant to cephalosporinases than first genration but still sensitive to ESBLs.

IV or Oral administration.

Fourth generation Cephlosporin

Anti-Psudomonal and preserved activity for Streptococci

Resistant to both cephalosporinase and ESBLs*

IV or Oral administration.

A Monobactam

Like Cephalosporins, are more acid-stable, penicillinase reisstant and atigenically dissimilar to penicillins.

G- activity is equal to 3rd generation cephalosporins but has no anaerobic or G+ activity*

Can be used in Penicillin-allergic Pt.

IV administration

A Carbapenem

Like Cephalosporins and Monobactams, is more acid stable, penicillinase resistant, and antigenically different than penicillins.

Very Broad Spectrum

G+/-, anti pseudomonal, anaerobes, and strep pneumo.

Sensitive to Carbanpenemases.

Bacteria can also alter porin channels decreasign permiability.

IV administration

Cilastatin inhibits renal dehydropeptidase which prevents impipenem metabolism.

A Carbapenem

Like Cephalosporins and Monobactams, is more acid stable, penicillinase resistant, and antigenically different than penicillins.

Very Broad Spectrum

G+/-, anti pseudomonal, anaerobes, and strep pneumo.

Sensitive to Carbanpenemases.

Bacteria can also alter porin channels decreasign permiability.

IV administration

A Carbapenem

Like Cephalosporins and Monobactams, is more acid stable, penicillinase resistant, and antigenically different than penicillins.

Very Broad Spectrum

G+/-, anti pseudomonal, anaerobes, and strep pneumo.

(*Has lower pseudomonas and acietobacter activity than other family members)

Sensitive to Carbanpenemases.

Bacteria can also alter porin channels decreasing permiability.

IV administration

Has a long half life*

Binds to peptidoglycan precursors to inhibit the transfer of precursors to growing cell walls.

Activity is restricted to G+

*Drug of chice to tx MRSA

REsistance already occurs in Enterococcus species (source of resistance for the first VRSA (Vanc-resistant Staph aureus).

IV or Oral administration.

Blocks phosphatase to inhibit carrier lipid in peptidoglycan synthesis.

Used as topical therapy for G+ infections.

Polymoxins

(Polymoxins B and E + Colistin)

Cationic detergent which damages the cell membrane.

Rx: Topical therapy for G- Rods.

Bactericidal

Irreversibly binds the cell membrane and depolarizes it causing cell death.

Effective against G+

(*Note that binding to pulmonary surfactant causes inactivation(?))

Disrupts proper pentapeptide formation in peptidoglycan precursors.

Rx: to tx Tuberculosis

A family of Abx that are bactericidal.

Act by inibiting protein synthesis.

*Aminoglycosides can cause damage to the kidneys and to CN VIII (leading to renal failure, hearing loss, or vestiblar damage).

An aminoglycoside

Specivically binds to a 30S ribosomal protein dostroting the proteins acceptor site and causing a misreading. This missreading causes 'bad' proteins to be made causing membrane leaks and increased uptake.

High concentrations of strepotomycin causes the formation of defective initiation complexes that irreversibly block translation.

Broad Spectrum

Though not anaerobes or intracellular bacteria*

IV administration

An aminoglycoside

Specivically binds to a 30S ribosomal protein dostroting the proteins acceptor site and causing a misreading. This missreading causes 'bad' proteins to be made causing membrane leaks and increased uptake.

High concentrations causes the formation of defective initiation complexes that irreversibly block translation.

Broad Spectrum

Though not anaerobes or intracellular bacteria*

IV administration

An aminoglycoside

Specivically binds to a 30S ribosomal protein dostroting the proteins acceptor site and causing a misreading. This missreading causes 'bad' proteins to be made causing membrane leaks and increased uptake.

High concentrations cause the formation of defective initiation complexes that irreversibly block translation.

Broad Spectrum

Though not anaerobes or intracellular bacteria*

Too toxic for parenteral use, Topical only.

An aminoglycoside

Specivically binds to a 30S ribosomal protein dostroting the proteins acceptor site and causing a misreading. This missreading causes 'bad' proteins to be made causing membrane leaks and increased uptake.

High concentrations cause the formation of defective initiation complexes that irreversibly block translation.

Extended Spectrum*

Including activity against Psudomonas.

IV administration

An aminoglycoside

Specivically binds to a 30S ribosomal protein dostroting the proteins acceptor site and causing a misreading. This missreading causes 'bad' proteins to be made causing membrane leaks and increased uptake.

High concentrations cause the formation of defective initiation complexes that irreversibly block translation.

Extended Spectrum

Including some activity against Pseudomonas

IV administration

An aminoglycoside

Specivically binds to a 30S ribosomal protein dostroting the proteins acceptor site and causing a misreading. This missreading causes 'bad' proteins to be made causing membrane leaks and increased uptake.

High concentrations cause the formation of defective initiation complexes that irreversibly block translation.

Extended Spectrum

Including some activity against Pseudomonas

IV administration

Aminoglycoside-like activity (bacteriocidal)
Binds 30S ribosomal subunit to inhibit protein synthesis.

Effective against Nisseria gonorrhoea

IM administration*

A class of Bacteriostatic drugs

Act by blocking an acceptor site on the 30S ribosomeal subunit to inhbit the binding of aminoacyl-tRNAs.

Act by blocking an acceptor site on the 30S ribosomeal subunit to inhbit the binding of aminoacyl-tRNAs.

Broad Spectrum

Incl Mycoplasma, Rickettsia and Chlamydia

IV or Oral administration

A Tetracycline

Act by blocking an acceptor site on the 30S ribosomeal subunit to inhbit the binding of aminoacyl-tRNAs.

Broad Spectrum

Incl Mycoplasma, Rickettsia and Chlamydia

IV or Oral administration.

A Tetracycline

Act by blocking an acceptor site on the 30S ribosomeal subunit to inhbit the binding of aminoacyl-tRNAs.

Broad Spectrum

Incl Mycoplasma, Rickettsia and Chlamydia

IV or Oral administration.

Glycylcyclines

A class of bacteriostatic drugs

Act like tetracyclines in blocking the acceptor site on the 30S ribosomal subunit inhibiting aminoacyl-tRNA binding.

Broad Specturm

Effective against Tetracycline-resistant strains.

IV or oral administration.

A class of bacteriostatic drugs

Act by binding the 50S ribosomal subunit to cause disscoiation of tRNA and termination of peptide linking/protien synthesis.

Macrolide (Bacteriostatic)

Act by binding the 50S ribosomal subunit to cause disscoiation of tRNA and termination of peptide linking/protien synthesis.

Similar to Penicillin G but includes ability to handle Mycoplasma and Chlamydia.

Stomacy acid hydrolyzes the drug and its metabolites are often very irritating to the stomach.

IV or Oral administration.

Macrolide (Bacteriostatic)

Act by binding the 50S ribosomal subunit to cause disscoiation of tRNA and termination of peptide linking/protien synthesis.

Similar to Penicillin G but includes ability to handle Mycoplasma and Chlamydia.

*more active than erythromycin

IV or Oral administration.

Macrolide (Bacteriostatic)

Act by binding the 50S ribosomal subunit to cause disscoiation of tRNA and termination of peptide linking/protien synthesis.

Similar to Penicillin G but includes ability to handle Mycoplasma and Chlamydia.

*More active than erythromycin

IV or Oral administration.

 ketolide (macrolide-related) bacteriostatic drug

Act by binding the 50S ribosomal subunit to cause disscoiation of tRNA and termination of peptide linking/protien synthesis.

Respiratory tract pathodens (common and atypical) Strep pneumo, effective against beta lactam and macrolide-resistant strains.

*Unable to induce MLSB resistance*

IV or Oral administration.

Lincosamide (bacteriostatic agents)

Binds to the 50 S ribosomal subunit to inhibit peptidyl transfer.

Similar effectiveness to erythromycin + is highly effective against most anaerobes

IV or Oral administration.

Serious Side Effect: Pseudomembranous colitis cuased by an overgorwth of C. Difficile in the enteric flora.

A lincosamide bacteriostatic agent

Binds to the 50S ribosomal subunit to inhibit peptidyl transfer.

Also effects human mitochondria.

Broad Spectrum

IV or Oral administration

Side Effect: Bone Marrow depression (due to effects on human mitochondria).

Straptogamin bactericidal agent

Blocks the channel in the ribosome where nascent peptides exit.

Effective against G+, VRSA, VR enterocci, and MRSA

Straptogamin bactericidal agent

Blocks the channel in the ribosome where nascent peptides exit.

Effective against G+, VRSA, VR enterocci, and MRSA

A combination of Quinupristin and Dalfopristin

Straptogamin bactericidal agent

Blocks the channel in the ribosome where nascent peptides exit.

Effective against G+, VRSA, VR enterocci, and MRSA

Oxazolidone bacteriostatic agent.

Blocks the interaction of the 50S ribosomal subunit with fMet tRNA.

Effective against G+, VSRA, VRE and Strep pneumo.

IV or Oral administration (is better tolorated than synercid)

A bactericidal agent.

Given as a prodrug and activated by the recipient.

Binds to DNA and causes strand breakage.

Broad spectrum

Effective against anaerobes and protazoa as well.

Bacteriostatic agents.

Given as a prodrug.

Binds covalently to cellular proteins.

Effective against G+, G-, protazoa, fungi

Especially useful in tx Urinary tract infections.

Binds to bacterial leucyl-tRNA synthetase

A topical agent used to tx Staph aureus and Impetigo in kids.

A class of bacteriostatic agents that inhbit nucleic acid synthesis.

Includes Ciprofloxacin and Norfloxacin

Quinolone (Bacteriostatic)

Inhbits DNA gyrase and topoisomerases

Broad Spectrum + Strep Pneumo

IV or Oral administration

Quinolone (Bacteriostatic)

Inhbits DNA gyrase and topoisomerases

Broad Spectrum + Strep Pneumo

IV or Oral administration

Must muse multiple agents!

Includes Isonazid, Pyrazinamide, Ethionamide, Ethambutol, Cycloserine, Streptomycin, Rifampin

Anti-Mycobacterial agent

Inhbits Fas2 which weakens the cell envelope

IV or Oral administration

Anti-Mycobacterial agent

Inhbits Fas1 decreasing building blocks for Fas2

Oral administration

Anti-Mycobacterial agent

Inhbits Fas2 weakening the cell envelope

Oral administration

Anti-Mycobacterial agent

Inhbits the synthesis of arabinofuranose (links mycolic acid to backbone)

Oral administration

Anti-Mycobacterial agent

Inhbits alanine incorporation into the peptidoglycan.

A second line Anti-TB med*

Anti-Mycobacterial agent

Binds to the 30S ribosomal subunit.

Selective for TB

IV administration

Bactericidal Anti-Mycobacterial agent

Binds the the beta subunit of bacterial RNA plymerase to inhibit initiation of transcription.

Broad spectrum, 1st line anti-TB

Oral administration

A class of anti-fungal agents

Act by blocking Cytochrome P450-dependent metabolis of a pregursor of ergosterol which increases opsinization.

Are not very specific and have several side effects.

Include Ketoconazole, Miconazole, and Otrimazole.

Imidazole anti-fungal agaent

Blocks cytochrome P450-dependant metabolism of a precursor of ergosterol increasing opsinization

Less specific than other anti-fungals, many side effects.

Imidazole anti-fungal agaent

Blocks cytochrome P450-dependant metabolism of a precursor of ergosterol increasing opsinization

Less specific than other anti-fungals, many side effects.

Imidazole anti-fungal agaent

Blocks cytochrome P450-dependant metabolism of a precursor of ergosterol increasing opsinization

Less specific than other anti-fungals, many side effects.

A class of anti-fungal agents

Block cytochrome P450-dependant metabolism of a precursor of ergosterol increasing opsinization

Important in pt with recurrent fungal infections.

Broader spectrum and fewer side effects than Imidazoles.

Include Fluconazole and Itraconazole.

Triazole anti-fungal agent

Block cytochrome P450-dependant metabolism of a precursor of ergosterol increasing opsinization

Important in pt with recurrent fungal infections.

Broader spectrum and fewer side effects than Imidazoles.

Triazole anti-fungal agent

Block cytochrome P450-dependant metabolism of a precursor of ergosterol increasing opsinization

Important in pt with recurrent fungal infections.

Broader spectrum and fewer side effects than Imidazoles.

Anti-fungal agent

Block cytochrome P450-dependant metabolism of a precursor of ergosterol increasing opsinization

Newest.

Increased activity for aspergillus

Inhbits synthesis if 1,3-beta-D-glucan whcih is essential to form the fungal cell wall.

Effective against Candida and aspergillus fungi

Anti-fungal agent

Inhbits microtubule formation to block mitosis and cell wall synthesis

Effective against Dermatophytes

Not effective topically. Is given in an oral preparation bound to keratin.

Bind to sterols in cell membranes damaging it.

Rx: Thrush (oral candidiasis)

Includes Amphotericin B and Nystatin

Polyene antibiotic

Bind to sterols in cell membranes damaging it.

Rx: Thrush (oral candidiasis)

Polyene antibiotic

Bind to sterols in cell membranes damaging it.

Rx: Thrush (oral candidiasis)

Clavulanic acid + Amoxicillin

Addition of a beta-lactamase inhbitor gives improved activity of the abx against S. aureus, H. influenza, E. coli, B. fragilis, K. pneumonae, and M. catarrhalis.

Clavulanic acid + Ticarcillin

Addition of a beta-lactamase inhbitor gives improved activity of the abx against S. aureus, H. influenza, E. coli, B. fragilis, K. pneumonae, and M. catarrhalis.

Sulbactam + Ampicillin

Addition of a beta-lactamase inhbitor gives improved activity of the abx against S. aureus, H. influenza, E. coli, B. fragilis, K. pneumonae, and M. catarrhalis.

Tazobactam + Piperacillin

Addition of a beta-lactamase inhbitor gives improved activity of the abx against S. aureus, H. influenza, E. coli, B. fragilis, K. pneumonae, and M. catarrhalis.

Block enyzmes in the pathway that forms Tetrahydrofolic acid (ness for Pur and Pyr biosynthesis) → no bases = no DNA synthesis

Sulfonamides (block dihydropteroate synthetase)

Trimethoprim (inhbits reduction of DHF → THF, very bacterial-selective effects)

Trimethoprin-Sulfamethoxalone (TMP-SMX, is a 1:5 ratio combination of TMP and SMX causing a sequential enzyme blockade)

Quinolones inhibit DNA synthesis by targeting Topoisomerase IV and/or DNA gyrases.

Incl Norofloxacin (low aff for both targets), Levofloxacin, Ciprofloxicin, Galifloxacin (high affinity for gyrase, low for topoisomerase), Moxifloxacin, Gemifloxacin (high aff for both targets, prefered Abx).

Fluroquinolones same MoA with ↑ spectrum/clinical uses. Incl drugs with the suffix "-xacin" Ex: Ciprofloxacin (2nd gen).

Those that inhbit peptidoglycan formation

Beta-lactams use a beta lactam ring that mimics the peptidoglycan pentapeptide, binds and inactivates PBPs.

Incl Penicillins (Natural, Anti-staphylococcal, Extended spectrum and Anti-psudomonal types)

Cephalosporins which have the same MoA as PCNs but are all penicillinase resistant, more acid stable and antigenically dissimlar to PCNs. 4 generations.

Carbapenems have a carbon instead of a Sulfur in their beta lactam rings and are highly resistant to beta-lactamases. Ex incl Imipenem+cilastin and Ertapenem

Monobactams which have only G- activity because they have no thiazolide ring and half a beta lactam ring. Useful for PCN-allergic pts. Ex: Aztreonam.

Vancomycin which has G+ activity only. Drug of choice for MRSA.

Telavancin which is rapidly bactericidal; has MRSA, VISA, VRSA, and VRE activity and acts by inhbiting PG chain formation and by direct action on the cell membrane.

Less important agents that act this way: Teicoplanin (vancomycin-like, IM admin), Dalbavancin (long half life)

Are active against G+ cocci and bacilli, some G-cocci and spirochetes.

Not effective against G- enterics.

Penicillinase sensitive.

Incl PCN-G (parenteral, acid labile) and PCN-V (oral, more acid stable)

Are penicillinase resistant and effective therefore against the many Staph strains that produce beta lactamases.

Methicillin (Parentaral, acid labile, no longer used due to SE, lead to the development of MRSA)

Nafcillin (pranteral/oral)

Oxacillin, Cloxacillin, Dicloxacillin (oral)

Have the actions of PCN-G (G+ cocci/bacilli, some G- cocci + spirochetes) + activity against G+ and G- Enterics*

Are Penicillinase sensitive (not as good against Staph/Strep)*

Ampicillin (pranteral/oral)

Amoxicillin, Cyclacillin (oral, tx influenza and E. coli),

Effective agianst enteric G- rods and bacilli

Carbenicillin, Ticarcillin, Mezlocillin, Piperacillin (Parenteral, tx psudomonas aeruginosa and Influenzae. For serious infections combined with an aminoglycoside, Piper is the most active).

All cephalosporins are Penicillinase resisitant, acid stable and antigenically dissimilar from PCNs.

1st Gen: Have a similar spectrum to Ampicillin (ext spec PCN, G+/- cocci, rods, bacilli, enterics).

Most important are their actions against G+ cocci (Staph and Strep) and several G- bacilli

Cephalexin (oral),

Cefazolin (IV)

Improved anaerobic activity.

Less active for G+ and more active for G- (a trend as you get into later generations of cephalosporins)

Cefoxitin and Cefotetan

Improved G- activity.

G- enterics*

Reserved for serious infections as they cross the BBB*

Ceftriaxone

Preserved activity for Streptococci + Antipsudomonal activity.

↑ activity for G+, beta-lactamase producing organisms.

Broad spectrum; active against Klebsiella in immunocomp pt.

Cefepime

Have a beta lactam ring that has a carbon instead of a sulfur group in the ring and ahydroxyethy side chain that allows it to move through the outer membrane of G-.

Are highly resistant to (act as a potent suicide inhbitor of) beta-lactamases*

Imipenem(+Cilastin)

Meropenem,

Doripenem (improved psudomonas activity),

Ertapenem (long half life, low psudomonas/acinetobacter activity)

Monobactams have only G- activity.

Due to their lack of a thiazolidine ring and having half a beta lactam ring (as opposed to the typical 2 fused rings).

Can be used in PCN allergic Pt.

Aztreonam (G- activity ~ that of a 3rd gen Ceph),

Those that act on the 30s or 50s ribosomal subunits.

Aminoglycosides diffuse through a porin channel and irreversibly bind to the 30s subunit causing an irreversible block of translation, 'cidal effects are conc and O2-dependant, large doses can damage kidneys and CN VIII). Ex incl Streptomycin, Neomycin, Kanamycin, Gentamicin, Amikacin, and Tobramycin.

Tetracyclines block the ribosomal acceptor site, 'static, broad spectrum, CI during pregnancy and in kids under 8 due to tooth damage, many side chains can create many variants but resistance to 1=resistance to all*

Macrolides bind irreversibly causing tRNA dissociation and termination of peptide linking. Incl Erythromyci, Azithromycin, Clarithromycin.

Lincosamides inhibit peptidyl transfer, 'static, highly effective against anaerobes. Incl Clindamycin, Chloramphenicol.

Streptogramin inhibits protein synthesis by inhibiting tRNA synthetase and aa addition to the chain. Incl Synercid.

Oxazolidinoes which are novel synthetic highly active against resistant G+ organisms

Ketolides which are derivatives of macrolides, Incl Telithromycin.

Glycyclines have a very broad spectrum of activity, incl Tigecycline.

Rifampin binds the beta subunit of RNA pol to inhbit RNA synthesis, 'cidal (G+ cocci, incl MRSA, and mycobacteria incl TB).

Always used in combo with other drugs because resistance develops rapidly*

Peptide Abx

Daptomycin side chin inserts into the bacterial cell membrane depolarizing the cell, active against G+ incl MRSA, VRE and pyogenes and is potent against G+ organisms resistant to methicillin, vancomycin and linezolids.

Is bound by pum surfactant so is not active in the lugs.

Resistance is rare.

Rapid-acting, used in sepsis.

Polymyxin also has a tail that disrupts membrane integrity by interacting with phospholipids.

Toxic for G- (selective for the LPS of G- bacteria).

Used against resistant strains of psudomonas and enterobacter).

Use is cautious bc it is neurotoxic and nephrotoxic*

Polymyxin B is found in Neosporin*

Antifungal agents target the cytoplasmic membrane of fungi (which is similar to human cytoplasmic membranes but has a cell wall which can be targeted to ↓ toxicity).

Polyene Afx are the "Gold Standard" Afx agents.

Amphipathic and target the PM forming pores in the fungal cell membrane through which K+ and Mg2+ can leak.

Amphotercin B (parenteral, toxic so only used in serious infections, prefered agent in pregnancy as Azoles are teratogenic*)

Nystatin (topical only)

5-Flucytosine (prodrug, used in combo with amphotercin or fluconazole tx meningitis)

Afx agents that inhbit the synthesis of ergosterol which is necess for fungal cell membranes. Cause defective assembly of the cell membrane.

All are CYP450 inhbitors* (alcohol consumption is CI)

Broad spectrum Afx

Ketoconazole (oral, tx systemic fungal infections, inhbits hyphae formation allowing fungi to be phagocytosed more readily),

Triazoles (Fluconazole & Itraconazole) have fewer SE and broader spectrum than Ketoconazole, tx recurrent fungal infections)

Afx agent that inhbits the synthesis of 1-3 beta D-glucan in cell walls.

Fungicidal for Candida, active against Aspergillis.

Very safe for human use because it specifically targets cell wall (which we don't have).

Mupirocin (inhibits bacterial RNA and proteins synthesis, tx impetigo and MRSA nasal carriage).

Retapamulin (binds 50s subunit and inhbits peptidyl transferase activity)

Horozontal Gene Transfer

(aquisition of DNA from other bacteria through transduction, transformation, or, most efficently, conjugation).

Beta-lactams are inactivated by beta-lactamases.

Aminoglycosides are inhbitied by acetylation, deadenylation and phosphorylation.

Beta-lactams: altered porins in G- bacteria limit access of drug to targets.

Tetracyclines: Active efflux out of target cells.

Beta-lactams: When PBPs are altered/new PBPs are generated.

Streptomycin: mutation in the target ribosomal protein.

A plasmid-determined beta-lactamase confirs resistance of most Staph strains to PCN G (>Tx w/ methicillin).

Methacillin resistance (generation of MRSA) emerged with a methicillin-resistant PBP encoded by a mobile genetic element. Now strains are PCN and Methicillin-resistant (>Tx w/ Vancomycin).

Recently, VISA and VRSA has appeared.

New PBPs have arisen due to mobile genetic elements containing the gene for new PBPs. These mobile elements can spread within and btw staph specieis and is the origin of community-acquired MRSA.

Vancomycin-intermediate Staph aureus

Has a thickened peptidoglycan layer.

PG is normal there are just abnormal amts of it.

Vancomycin gets stuck in it and can't get to targets!

VRSA

VRE

Vancomycin-resistant Staph aureus

Binding of vancomycin is blocked by altering peptidoglycan

Vancomycin-resistant Enterococcus replaces and Alaninie with a Lac at the 5th position on the peptidoglycan preventing Vancomycin binding.

Intermediate resistance appeared due to low affinity type PBPs (this resistance could be overcome with high doces of PCN).

In the 1980s and 90s highly and multi-drug resistant strains emerged.

Most strains are sensitive to newer synthetic fluroquinolones.

Note that Strep pneumo strains do not have PCN resistance due to beta-lactamases.

Have many new PBPs that are mosaics of original PBPs and probably were aquired via transformation.

Periplasmic cephalosporinases: Virtually all G- bacteria have a chromosomal gene that encodes a beta-lactamase (which is usually a cephalosporinase) that is present at at least low levels in the periplasmic space.

Outer Membrane permiability: G- outer membrane and lateration of this emmbrane's porins allows less abx to be taken up and provides resistance to G-'s.

Plasma-derived Beta-lactamases: also occur and provide additional resistance.

*Ubiquitous periplasmic beta lactamases and poor uptake of PCN-G through the porins of the outermembrane explain the lackf of activity of PCN-G vs G- enterics.

Because these factors were present before the Abx tx, this is considered Intrinsic Resistance.

Genetic elements that contain specific components that recgonize and capture mobile Abx resistance gene cassettes.

Are present in many resistant strains of G- bacteria.

Can be present on the bacterial chromosome or on a plasmid.

There are multiple types that can confer resistance to several classes of Abx simultaneously.

-Beta-lactamases are the most common elements (includes ESBLs, extended spectrum and Carbapenemases)

-Aminoglycosides and many others.

The use of a single Abx may activate an entire resistance gene cassette.

If the selection pressure provided by the Abx is removed the entire integron may be lost.

A Beta-lactamase inhbitor

Works as a 'distractor' that occupies the otherwise resisitant organism while the Abx it is coupled with works.

Staph and TEM penicillinases are sensitive to clavulanic acid.

Ubiquitious G- periplasmic cephalosporinases are resistant to clavulanic acid.

Methicillin-Resistant Staph Aureus

Has a normal peptidoglycan layer but produces Beta-Lactamase that inhbits beta-lactam Abx from binding PBPs.

**Resistance to one aminoglycoside does not provide resistance to all** (Unlike tetracycline resistance)

-Enzymatic modification (acetylation, phosphorylation, adenlation)

-Target mutation (methylation of the 16s rRNA)

-Reduced drug accumulation/failure to penentrate the cytoplasmic membrane (this is energy and O2 dependant and therefore not present in anaerobic microbes).

-Efflux pumps

**Resistance to one tetracycline=resistance to all**

(Remember different tetracyclines differ only slightly in their side chains)

-Efflux pumps

-Protection of the target ribosomal target site by a specialized protein.

-Altered ribosomal target (ie by methylation)

-Efflux pumps

-Enzymatic inactivation

-Altered DNA gyrase target site

-Efflux pumps

-Protection of the target site encoded by the Qnr-integron

--encodes a duel activity (acetylation of aminoglycosides and inactivation of ciprofloxacin)

Multi-activity and multi-class resistance

Resistance to Beta-lactam Abx: Class A (TEM, ESBL), Class B (Metallo-beta-lactamase), Class C (chromosomal ampC), Class D (OXA ESBL)

Changes to outer membrane proteins and to PBPs

Efflux pumps (AdeABC efflux pump: effective against aminoglycosides, TCN, TMP, Fluroquninolone, cefotaxime, and erythromycin).

Resistance to aminoglycosides (enzymes that modify the Abx and reduce effectiveness)

Resistance to fluroquinolone (gyrA/parC genes, efflux)

Resistance to TCN (ribosomal protection protein, Tigecycline pumped out by AdeABC efflux pump)

Resistance to Polymiyxins (heteroresistance, alteration of LPS)

As you can see, Acinetobacter is a "Resistance Machine" which contains a region called the AbaR1 resistance island, a cluster of 45 resistance genes and can be found in many types of G- bacteria.

Based on ther activity against G- bacteria and penicillinase resistance.

Narrow Spectrum I: Pen sensitive, ineffective vs G- enterics.

Narrow Spectrum II: low affinity but Pen resistant.

Broader Spectrum (2nd gen) are active against G+ and G- enterics + psudomonas (Carbenicillin), Pen Sensitive.

Extended Spectrum: active vs wide variety of G- bacilli incl Pseudomonas but less active against G+.

Pipercillin is the most active against G- enterics, G- anaerobes, and psudomonas.

How are Cephalosporins classified?

Mostly on activity against G- enteric bacilli.

Progression from 1st to 4th gen marked by ↑ G- bacterial effectiveness, ↓ activity against G+, ↑ resistance to beta lactamases and ↑ ability to enter CSF.

*Activity against G-enterics and ability to cross BBB comes with 3rd gen.

1st gen are resitant to S. aureus penicillinases but sensitive to cephalosporinases.

2nd and 3rd gen are much more resistant to cephalosporinases "Extended Spectrum" drugs.

4th generatin is resistant to the ESBLs responsible for resistance to 2nd and 3rd gen abx.

Subsequent generations have ↑ G- activity, gain G+ and anaerobe activity.

1st Gen: Only used for uncomplicated UTI, resistance emerged rapidly.

2nd Gen: ↑ G- activity.

3rd Gen: Broad spectrum G- activity and extended G+ activity+activity against anaerobes.

4th gen: Pulled from the marked due to toxicity!

(S.aureus)

A beta-lactamase

Encoded on a plasmid

Exoenzyme (workes extracellularly)

Clavulanate Sensitive

(G-)

Beta-lactamase

Located on a plasmid.

Periplasmic

Clavulanate Sensitive

G-

Beta-lactamase

Chromosomal*

Periplasmic

Clavulanate Resistant*

Extended-Spectrum Beta Lactamases

G-

Encoded on a Plasmid

Periplasmic

Clavulanate Sensitive

Minimum Inhbitory Concentration

The dilution at which a bacteria-containing broth is no longer turbid following overnight culture with abx.

The lowest concentration of Abx that will inhbit bacterial growth*

Represents the Abx dosage needed to arrest bacterial growth.

Minimum Bacteriocidal Concentration

The diltuion at which no growth is seen on a subculture plate.

The lowest [Abx] required to kill the microbe.

*There is usually a 4x difference between MIC and MBC*

A larger difference may indicate tolorance or resistance.

-When the infection is in an immunoprivileged site (on a heart valve[bacterial endocarditis], in the CSF [Meningitis]).

-Infections in immunocomprimisd hosts (AIDS, neutropenia, transplant pt)

-Infections in which waiting for the immune system response to eliminate the pathogen will cause damage to the host.

-Synergistic Abx action expected

-Susceptibility of the most probable pathogens req mult agents

-Pathogen is unknown

-Cocktail effect to reduce the likelihood of resistance

-When combination therapy allows the dosage of a toxic drug to be reduced.

Better Abx result of two Abx agents together than with either alone.

Indication for combined Abx therapy.