Abx that inhibit cell wall synthesis

• B-lactams (penicillins and cephalosporins)
• Vancomycin
• Bacitracin

Abx that inhibit/disrupt cell membrane fxn

• Polymyxins
• Ionophores

Abx that inhibit nucleic acid synthesis

• Sulfonamides
• Diaminopyrimidines
• Nitrofurans
• Metronidazole
• Fluoroquinolones
• Rifamycins

Abx that inhibit protein synthesis:

• Macrolides
• Chloramphenicol
• Lincosamides
• Aminoglycosides
• Spectinomycin
• Tetracyclines

Example of synergism

• B-lactam with aminoglycoside: penicillin inhibits cell wall synthesis, resulting in enhanced uptake of gentamicin so it can inhibit protein synthesis inside the cell

Examples of antagonism:

• bactericidal with bacteriostatic (B-lactam with tetracycline). tetracycline slows growth of org due to its inhibition of protein synthesis, but penicillin can't do its job because it can only act on growing cells
• Combo of dugs with common targets: macrolides with chloramphenicolor lincosamide (all of which inhibit protein synthesis by binding to 50s ribosomal subunit).

Plasmid-mediated resistance is rare amongst _____ bacteria, except _______spp. and is common amongst ________ bacteria

• gram positive
• Staphylococcus
• gram negative

Gram-positive aerobes

Cable 'R S MN

• corynebacterium
• acniobaculum, actinomyces, arcanobacterium
• bacillus
• listeria*
• enterococcus, erysipelothrix*
• rhodococcus*
• staph/strep
• Mycobacterium*
• Nocardia*

Gram negative aerobes

C Phlem Fab Y

• Campylobacter
• Pasteurella, pseudomonas
• Haemophilus*, Histophilus*
• Leptospira
• Enteroacteriacea (E. coli, klebsiella, proteus, salmonella)
• Mannheimia, moraxella
• Francisella*
• Actinobacillus
• Bordetella, borrelia*, brucella*, Burkholderia
• Yersinia*
  

Gram positive anaerobe

Clostridium

Gram negative anaerobes

born to fuck suck dick

• Bacteroides
• Dichelobacter
• Fusobacterium necrophorum
• Serpulina hyodysenteriae
• Treponema

Intracellular Bacteria

MARCH BEN (to) FL

• Mycobacterium
• Anaplasmataceae
• Rhodococcus, rickettsia
• Chlamydia, coxiella
• Haemophilus, histophilus
• Brucella, bartonellaceae, Borrelia
• Erhlichiaea, Eperythrozoon
• Nocardia
• Francisella
• Lawsonia intracellularis, Listeria

Abx that affect Gram-positive cell wall

• Penicillins (inhibit peptidoglycan synthesis)
• Cephalosporins (inhibit peptidoglycan synthesis)
• Vancomycin (inhibit peptidoglycan synthesis)
• Bacitracin (inhibit peptidoglycan synthesis)
• Ionophore (Destroy cell wall integrity - good for non-replicating organisms)

***ALL BACTERICIDAL***

***Not for Mycoplasma or Intracellular Orgs***

Abx that affect Gram-Negative Cell Wall

Cephalosporins

***Bactericidal***

***Not for mycoplasma or Intracellular Orgs***

Abx that disrupt the outer membrane of Gram negatives

Polymyxins

***Bactericidal***

***Does not do mycoplasma or intracellular orgs***

Penicillins are effective against

• Gram+ aerobe (minus Staph)
• Penicillinase-Resistant Penicillins can do Staph
• Gram- aerobe (Only the following:)
• Aminopenicillin (minus Pseudomonas)
• Extended-Spectrum Penicillins
• Gram+ anaerobe
• Gram - anaerobe

Penicillins and Cephalosporins

are Bacteri______

Bactericidal

Penicillins and Cephalosporins

are primarily used for:

• Systemic (oral/parenteral): septicemia
• Soft Tissue (oral/parenteral): pneumonia, peritonitis, endometritis, vaginitis
• GI(oral/parenteral)
  
• External (topical): wound, eye, skin infections
  
• UTI (oral)

***NOT for CNS or Joint Infections***

Distribution of Penicillins and Cephalosporins

• Water soluble, becomes well-distributed
• Do not penetrate tissues well
• Excreted unchanged in urine

Penicillins and Cephalosporins

are often used in combination with:

• B-lactamase inhibitors (irreversible inhibitor):
• Calvulanic acid
• Sulbactam
• Tazobactam

Penicillins and Cephalosporins are effective vs. both gram+ and gram- anaerobes because

they can gain entry via diffusion due to lack of energy-dependent transport mechanisms

All cell wall and membrane targeting Abx only work on replicating cells except for:

Polymyxins and Ionophores

Resistance to Penicillin

• B-lactamases on plasmids for Staph and Gram-neg aerobes, as well as natural resistance due to exclusion due to outer membrane of Gram neg aerobes.
• Penicillin usually not effective for Staphylococcus with B-lactamase, except for penicillinase-resistant penicillins
• Many Penicillins not effective vs. Gram-neg aerobe due to outer membrane AND B-lactamases. Aminopenicillins work on Gram-neg aerobe except for Pseudomonas. Extended spectrum penicillins will do Gram-neg aerobes including Pseudomonas

Differences in resistance to Cephalosporins

from that of Penicillins

• Most cephalosporins are not excluded from gram-negative aerobic bacteria
• Cephalosporins are resistant to B-lactamases produced by S. aureus and many of htose produced by gram-neg bacteria

Spectrum of activity for Cephalosporin

• Pretty much all Gram-pos aerobes, and both Gram pos and Gram neg anaerobes
• First, second, and third gen cephalosporins differ in their effectiveness vs. Gram-neg aerobes.

Adverse Effects of Penicillins and Cephalosporins

• Bind bacterial proteins and has little to no direct toxic effect on host.
• Hypersensitivity rxns due to formation of IgE Abx against degradation products from prior admin (cross-allergenicity between penicillins and cephalosporins too)
• Cardiac arrythmia following IV bolus of formulations with K+
• Mod of normal flora: diarrhea due to death of normal flora. Thrush and/or vaginitis due to overgrowth of Candida. Abx-associated colitis in hind-gut fermenters with some cephalosporin preps.
  

Other caveats with Penicillins and Cephalosporins

• Secreted in milk
• Most preps are not shelf-stable

Examples and Uses of Natural Penicillins

• Penicillin G and Penicillin V
• Used for treatment of anaerobic infections and certain gram-neg aerobic infections
• Pasteurella multocida
• Mannheimia hemolytica
• Haemophilus sp
• Histophilus somni

Examples and use of Aminopenicillins

• Ampicillin and amoxicillin
• Often combined with B-lactamase inhibitor
• Used for all types of gram +/- and aerobic/anaerobic critters

Examples and types of Extended-spectrum penicillins

• Carbenicillin, Ticarcillin, Piperacillin, Azlocillin, Mezlocyllin
• Reserved for treatment of pseudomonal infections because of their resistace to Pseudomonas sp B-lactamases

Example and use of Penicillinase-resistance penicillins

• Oxacillin, Cloxacillin, Dicloxacillin, Nafcillin, Methicillin
• Reserved for staph infections because of their resistance vs. Staph aureus B-lactamases

Examples of first gen cephalosporins

Cephalothin, cefazolin, cephapirin, cephadrine, cephalexin, cefadroxil

Examples of Second Gen Cephalosporins

cefaclor, cefamandole, cefonicid, ceforanide, and cefuroxime

Third gen Cephalosporins

Cefotaxime, moxalactam, cefoperazone, ceftizoxime, ceftazidine, ceftriaxone, ceftiofur, and cefixime

Use of Vancomycin

• Reserved for Clostricium difficile and RESISTANT staph, strep, enterococcus
• IV for systemic infections (septicemia or soft-tissue infections of resistant orgs)
• Orally for antibiotic-associated colitis caused by Clostridium difficile.

***Extralebel use banned in food animals***

Spectrum of activity for Vancomycin

• Essentially all gram positive organisms (cannot penetrate outer membrane of gram neg)

Distribution of vancomycin

• Poor tissue distribution/penetration, so must administer directly to site of infection
• Not for joint or CNS
• Nor for UTI (need to administer IV to achieve adequate urine levels)

Metabolism/excretion of vancomycin

Oral admin: Excreted unchanged in feces

IV admin: Excreted unchanged in urine

Side Effects of Vancomycin

• With oral admin, poorly absorbed from GI tract, and very few adverse effects
• With IV admin, widely distributed in tissues and serious side effects can occur
• Red-neck syndrome (shock-like state, paresthesis around mouth, chills, fever) following rapid IV admin
• Nephrotoxicity and Ototoxicity

Mechanism of Vancomycin Activity

• Blocks peptidoglycan formatiln in gram pos orgs by binding D-alanyl-D-alanine during cell wall synthesis

Resistance to vancomycin

• Plasmid mediated alteration of vancomycin binding site on transposon (replaces D-alanyl-D-alanine with D-alanyl-D-lactate)
• Genes VanR and Van S stimulate transcription of other Van genes in presence of vancomycin --> change to D-alanyl-D-lactate bridges

Use of Bacitracin

• Topical use for treatment of wound, skin, and eye infections with all gram positive bacteria
• Never administered systemically (orally or parenterally) due to severe nephrotoxicity.
• Not absorbed when administered via skin/mucous membranes

Spectrum of Bacitracin

• Gram positive aerobes and anaerobes only
• cannot penetrate outer membranes of gram neg cell wall

Bacitracins are often combined with:

• polymyxin +/- neomycin to formulate mixture that expands spectrum of activity to gram-neg aerobes and anaerobes

Bacitracin mechanism of action

• Inhibits cell wall synthesis in growing cells by blocking formation of peptidoglycan via inhibition of lipid pyrophosphatase dephosphorylation which is a carrier necessary for transfer of peptidoglycan subnit

Side Effects of Bacitracin

• Nephrotoxic if given systemically (orally/parenterally)
• No adverse effects topically (skin/mucous membranes) due to poor absorption.

Resistance to Bacitracins

Rare

 Use of Polymyxins

• External and GI infections caused by any extracellular gram-negative bacteria.
• Usually used topically for treatment of wound, skin, or eye infections (Moraxella, E.coli)
• Orally for treatment of GI infections (Salmonella, E.coli)
• Rarely, IV sytemtically for endotoxemia - Extremely nephrotoxic and enurotoxic.

Polymyxins are usually used in combo with

Bacitratins +/- neomycin to increase spectrum of activity to Gram + infections

Mechanism of Action of Polymyxins

• Inhibit cell membrane function in gram neg bacteria.
• Are cationic polypeptides with fatty acid moiety. Cationic portion binds LPS (anionic) within outer membrane. Fatty acid tail then penetrates membrane and disrupts outter membrane --> loss of ion transport mechanisms and maintenance of physiologic osmolarity within cell.
• Can also bind to LPS during endotoxemia
  
• GOOD FOR BOTH REPLICATING AND NON-REPLICATING CELLS

Resistance to Polymyxins

Rare

Adverse Effects from Polymyxins

• Topically and orally: not absorbed from GIT/skin/mucous membranes, so no toxicity
• Parenterally (IV): polymyxins cross-react with host cell membranes, so can induce severe nephrotoxicity and neurotoxicity. Only use for possible life threatening endotoxemia in horses.

Examples of Ionophores

Monensin, lasolacid, narasin, salinomycin, gramicidin

Ionophore mech. of action

• Long hydrophilic molecules that intercalate into the PG layer of gram positive cell wall AND carbohydrate layer of coccidia cell wall
• Results in formation of channels, whose presence facilitates loss of K+ ions, entry of Na+ ions, and subsequent reversal of the Na-H transporter
• Net influx of  hydrogen ions results in decreased intracellular pH which ultimately kills cells

*** WORKS ON BOTH REPLICATING AND NON-REPLICATING ORGS***

Use of ionophores

• Primarily as food additiives in feedlot animals for growth promotant and anti-coccidial activity
• In rumen, ionophores kill off gram-pos aerobes, thereby shifting rumen microflora composition to more gram-neg bacteria (which produces proprionate rather than acetate which results in more calories --> better feed converswion)
• Also indirectly promotes growth due to coccidiostat activity
• Gramicidin combined with neomycin +/-nystatin for use as topical ointment with activity vs. gram pos AND neg aerobes, intracellular bacteria, and Mycoplasma
  

Spectrum of activity for Ionophores

Gram positive aerobes - PG wall

Protozoa (esp coccidia) - Carb wall

***don't do anaerobes because active transport needed***

Adverse Effects of ionophores

• Cross-react with host cells and cause enhanced Na+ uptake and K+ efflux, which results in increased intracellular Ca++ --> severe cell damage esp in cardiac/skeletal muscle (CARDIOTOXICITY)
• Toxicity Horse>>ruminants>swine>dogs>>poultry
• Symptoms: anorexia, ataxia, depression, mild diarrhea, dyspnea, weakness, recumbency, sudden death upon recent feed change

Sulfonamides are structurally similar to

PABA (first building block of folic acid)

Sulfonamides are usually used in combo with ______ because:

Diamonopyrimidines (dihydrofolic acid analogue - 2nd step in folic acid synthesis), because together gives bactericidal activity when alone only has bacteriostatic activity

Both sulfonamides and diaminopyrimidines are

_______ inhibitors

Competitive

Folic acid are used as building blocks for:

1. Thymidine - DNA
2. Purines (Adenosine, Guanine) - DNA/RNA
3. Methionine - tRNA, protein

Resistance to sulfonamide and diaminopyrimidine

• Very common
• Chromosomal upregulation of PABA (so much that competitive inhibition no longer works)
• Plasmid encoded for enzyme's decrease in affinity for sulfonamide and diaminopyrimidines
• Natural resistance by anaerobes, since they are able to scavange folic acid and end-products of folic acid metabolism

Diaminopyrimidines are structurally similar to:

Dihydrofolic acid (DHFA)

Sulfonamides inhibit which enzyme?

Pteridine synthetase

Diaminopyrimidines inhibit which enzyme?

Dihydrofolate reductase

Use of Sulfonamides and Diaminopyrimidines

• For systemic, GI, UT, and external due to intracellular/extracellular gram pos AND neg AEROBES, mycoplasma, and protozoa
• Orally/parenterally (IM, IV, SQ) for systemic and GI infections
• Soft tissue: pneumonia, peritonitis, endometritis, vaginitis
• Joint and CNS infections (penetrates tissues WELL)
• Orally for UTI - excretes unchanged in urine, but resistance common so not first choice drug usually
  
• Topically for wound, eye, and skin infections.
  
• Abscesses due to Actinomyces bovis, Arcanobacterium pyogenes, Corynebacterium pseudotuberculosis
  
• Sulfasalazine orally for canine/feline inflammatory bowel dz (ulcerative colitis, chronic enterocolitis, llymphocytic-plasmacytic enteritis)
• Pyrimethamine for protozoal infections (Eimeria, toxo, Sarcocystis, and neospora)
• Great hose membrane penetration, so commonly used for Chlamydia and Nocardia
  

Resistance to Sulfonamides & diaminopyrimidines

• Natural: Anaerobes because infection associated with lots of pus --> can scavange folic acid and derivatives
• Chromosomal: Increased expression of PABA
• Plasmid: Decreased affinity by Pteridine synthetase and dihydrofolate reductase

***Acquired resistance very common. Combo use helps***

Spectrum of activity for Sulfonamides + diaminopyrimidines

• Gram pos AND neg aerobes (they don't scavange folic acid)
• Mycoplasma sp
• Select intracellular bacteria (Chlamydia, nocardia asteroides)
• Protozoa (Eimeria, toxoplasma, sarcocystis, neospora)

Adverse Effects of sulfonamides and diaminopyrimidines

• Hypersensitivity rxns:
• Rashes, hepatitis, fever, arthalgia, or naphylaxis
• Keratoconjunctivitis sicca in dogs
• Polyarthritis and fever in Dobermans
• Hemolytic anemia
• Modification of normal flora:
• Diarrhea due to destruction of normal GI flora
• Thrush and/or vaginitis due to overgrowth of Candida
  

Common Sulfonamide + Diaminopyrimidines

• Sulfadimethoxine (albon)
• Sulfamethzine (Sustain, SMZ)
• Sulfamethoxazole
• Sulfasalazine (Azulfidine)
• Trimethoprim + Sulfamethoxazole (SMZ-TMP)

First choice drug for mycoplasma infection

sulfonamides + diaminopyrimidines

First choice drug for Chlamydia spp

sulfonamides and diaminopyrimidines

First choice drug for Nocardia asteroides

Sulfonamides and diaminopyrimidines

Mechanism of Metronidazole activity

• Taken up by gram-pos AND neg ANAEROBIC bacteria via passive diffusion. Undergoes reduction by ferrodoxin --> metabolites bind DNA and induce breakage of DNA strands (DNA replication and transcription inhibited)

Spectrum of Metronidazole Activity

• Gram pos AND neg ANAEROBES (have ferrodoxin)
• Protozoa: Trichomonas sp, Giardia sp, Entamoeba histolytica, Balantidium coli

***NOT FOR AEROBES (NO ferrodoxin)***

First choice drug for Giardia

Metronidazole

Metroniazole is combined with:

Penicillin, cephalosporin, flouroquinolone, or aminoglycoside to expand coverage to include gram pos AND neg aerobes

Resistance to Metronidazole

• Natural: aerobes lack ferrodoxin to create toxic metabolites
• Acquired resistance RARE

Pharmacokinetics of Metronidazole

• Available for oral and IV admin --> well absorbed and becomes widely distributed throughout the entire body and penetrates virtually all tissues

Adverse effects of metronidazole

• Carcinogenicity/teratogenicity demonstrated in lab animals
• Do not use in pregnant animals
• Banned in food animals
• If very high doses + chronic use (e.g. for giardia), can develop CNS signs.

Use of Metronidazole

• Giardia
• Abx associated colitis
• Fusobacterium necrophorum abscesses
• Peritonitis

Drugs within Nitrofurans used clinically

Nitrofuantoin (PO for UTI)

Nitrofurazone (topical)

Furazolidone (topical)

Mechanism of Nitrofuran action

• Taken up by gram pos AND neg AEROBES via active transport. Degraded by nitroreductase into active metabolites --> metabolites cause DNA strand breakage --> inhibits DNA replication and transcription

Spectrum of activity for Nitrofurans

• Only gram pos AND neg AEROBES (have nitroreductase and active uptake mechanisms)

Uses of Nitrofurans

• Nitrofurazone and furazolidone used topically for treatment of wound, eye and skin infections
• Nitrofurantoin used orally in human med for UTI. Readily absorbed from GIT and excreted in urine

Adverse effects of Nitrofurans

• Carcinogenic potential (banned in food animals)
• Topical use common, esp OTC - can cause rash due to hypersensitivity reaction (WEAR GLOVES)
• Systemic (PO) use:
• Neurotoxicity - nausea, vomiting, dizziness, headaches
• Hematologic abnormalities
• Allergic hypersensitivity reactions - rashes, hepatitis

Resistance

• Acquired is rare
• Natural: anaerobes lack nitroreductase and active uptake mechanisms.

First choice drugs for UTI

Fluoroquinolones

Drug names of Fluoroquinolones

Enrofloxacin (Baytril)

Orbifloxacin (Orbax)

Difrloxacin (Dicural)

Morbafloxacin (Zeniquin)

Mechanism of Fluoroquinolone Action

• Enter Gram-pos aerobes via diffusion, and Gram-neg aerobes via porin channels. Also diffuses through host cell membranes to intracellular aerobic bacteria
• Binds either:
• DNA gyrase and inhibits ability of gyrase to faciliate nicking/resealing--> supercoiling of bacterial DNA. DNA gets destroyed by exonucleases. Bacteria dies
• Topoisomerase IV and inhibits relaxation of supercoiled DNA --> DNA can't be replicated
• Inhibits plasmid replication (may limit plasmid-med resistance)
  

Spectrum of Activity Fluoroquinolones

• Gram pos AND neg aerobes
• Intracellular bacteria: Chlamydia, mycobacteria, rickettsia, mycoplasma

NOT FOR ANAEROBES (gyrase/topoisomerase

lacking or different...?)

Use for Fluoroquinolones

• Orally, parenterally (IM, IV, SQ) for systemic and GI infections
• Septicemia
• Soft tissue infections (pneumonia, peritonitis, endometritis, vaginitis, etc...)
• Joint infections, CNS infections
• PO for UTI

**GI absorption impaired by presence of divalent cations (antacids, mineral supplements)**

Resistance to Fluoroquinolones

• Natural for anaerobic bacteria: gyrase/topoisomerase not the same?
• Emerging plasmid mediated:
• Alteration of DNA gyrase/Topoisomerase IV so that fluoroquinolone can't bind
• Decreased cell permeability (MDR)
• Increased drug efflux (MDR)

Adverse Effects of Fluoroquinolones

• Rare because sp to bacterial enzymes, but can:
• Modify normal flora (diarrhea due to destruction of normal flora, thrush and vaginitis due to Candida overgrowth, Abx assoc colitis in hind-gut fermentators
• Cartilage erosion due to apoptosis of cartilage cells esp in dogs (within hrs after admin). DO NOT give to small/med dogs <8 mos and large breed dogs <18 mos. DO NOT give to young, growing, or athletic animals
• Neurotoxic: Nausea, headaches, dizziness, tremors, seizures (DO NOT give to animals with history of seizures
• Retinopathy in cats: due to ocular penetration and tissue degradation --> blindness if used at high levels for long time
• Tendon rupture in humans.
  

Drug used for human Mycobacterium tuberculosis

Rifamycins

Drug used for Rhodococcus equi pneumonia in foals.

Rifamycins

Mechanism of Rifamycin action

• Enters via passive diffusion (also diffuses through host cells)
• Binds to RNAP and prevents initiation of transcription. Does not effect once transcription has started
• ONLY WORKS IN METABOLICALLY ACTIVE BACTERIA
• Mostly bacteriostatic, though sometimes bactericidal

Spectrum of Rifamycin Action

• Gram-pos aerobes
• Gram-pos AND neg anaerobes
• Intracellular aerobes (Coxiella, Mycobacteria, Rickettsiales, Chlamydia, Rhodococcus)

**NOT for Gram NEG aerobe b/c too big to fit thru pore**

**Reserved for Rhodococcus in foals, and human TB**

Resistance to Rifamycins

• Natural: gram neg aerobe (porin too small) + mycoplasma
• Chromosomal point mutation within rpoB (gene encoding portion of RNAP where rifampin binds)
• RARE BUT rifampin has unique mech of action and must be protected
• Only used for Rhodococcus foal pneumonia
• Used in combo with macroliede (erythromycin, azithromycin)

Side Effects of Rifampin

• Orange-red blody fluids due to excretion/secretion of rifampin (reddish in color within urine, tears, and saliva). No harmful consequences
• Following PO admin (only PO formulations available), well-absorbed from GIT and becomes distributed EVERYWHERE. Metabolized in liver and excreted in bile. Dose must be adjusted in patients with hepatic insufficiency.

Bacterial ribosomal subunits

• 30S - Binds mRNA during initation and holds peptide during elongation
• A - Aminoacyl-tRNA site (Acceptor Site)
• P - Peptidyl-tRNA site (Donor site)
• 50S - Accepts and translocated charged tRNA

**30S + 50S subunits = 70s ribosome**

Abx that bind 30S Ribosomal Subunit

Aminoglycosides
Spectinomycin
Tetracyclines

Mechanism of Aminoglycoside action

• Entry via active transport (does not penetrate host cell membrane)
• Bind irreversibly to 30S ribosomal subunit (both before or after initiation complex formation)
• Inhibition of initiation complex formation
• Inhibition of peptide extension by misreading
• Inhibition of translocation along mRNA
• BACTERICIDAL
• REPLICATING ORGANISMS ONLY
  

Mechanism of Spectinomycin Activity

• Entry via active transport (Can't penetrate host cell)
• Reversibly binds 30S subunit of bacterial ribosomes
• Inhibits initiation complex formation
• Cannot bind 30s subunit once attached to 50s. --> Does not cause misreading or inhibit translocation along mRNA
• BACTERIOSTATIC
• REPLICATING ORGANISMS ONLY

Spectrum of activity of Aminoglycosides & Spectinomycin

• Gram pos AND neg AEROBES (but typically reserved for Gram Neg infections)
• Protozoa - Cryptosporidium sp (Paromomycin only)
  
• Not effective vs. intracellular (does not penetrate tissues)
• Not effective vs. Anaerobes (need active transport)
• Not effective vs. Mycoplasma
  

Examples of Aminoglycosides

Gentamycin

Neomycin

Tobramycin

Amikacin

Streptomycin

Use of Aminoglycosides and Spectinomycin

• Poor distribution, must admin directly to site of infection
• PO for GI infections (E. coli, Salmonella, etc...)
• IV for septicemia
• Intrathecally for CNS infectiosn
• Paromomycin PO for Cryptosporidium infection
• If PO, excreted in feces
• If IV or intrathecal, excreted unchanged in urine (but minor, so not enough for UTI)

Aminoglycosides & Spectinomycin are often used in combo with ______ because _________

B-lactams (e.g. penicillin)

For synergistic activity

Resistance vs. Aminoglycosides/spectinomycin

• Natural: Anaerobes (no active transport)
• Acquired: all plasmid mediated
• Alteration of aminoglycoside/spectinomycin structure such that binding to 30s ribosomal subunit is inhibited
• Decreased entry/increased efflux (MDR)
• Alteration of binding site within 30s ribosomal subunit such that drugs can't bind target site

Adverse effects of aminoglycosides

• PO admin: poorly absorbed from GIT, so don't get systemic adverse effects, but can cause mod of normal flora (the usual 3)
• Following IV, distributes well but not bone, joint, CNS, or eye
• Following parenteral admin, excreted unchanged in urine --> NEPHROTOXICITY. Aminoglycosides enter proximal renal tubular cells via pinocytosis and inhibit lysosomal enzymes --> lysosomal phospholipidosis, inhibition of Na-K ATPase, destruction of tubular cells (Can see increase in BUN/creatinine, proteinuria, cells/casts in urine. Usually reversible once meds discontinued, but MUST monitor all patients on IV. Make sure adequate hydration of patient AND try not to give to patients with renal insufficiencies
• Ototoxicity (CN VIII toxicity) both vestibular and auditory due to accumulation within inner ear fluid and binding to phosphotidylinositol on hair cells. Subsequent iron activation of bound aminoglycosides results in localized free radical formation --> destruction of hair cells
• Neuromuscular blockade and peripheral neuropathy. Drug binds Ca++ within NMJ and inhibit ACh release, resulting in paralysis. Reverse with Ca++ admin

**Systemic administration can be multiple low-doses, or single high daily dose. Latter more effective because killing of bacteria relies on high aminoglycoside levels, and reduces exposure time of host cells**

**Aminoglycosides do cross placenta, so DO NOT give to pregnant animals)**

Adverse effects of Spectinomycin

• PO admin: poorly absorbed from GIT, so don't get systemic adverse effects, but can cause mod of normal flora (the usual 3)
• Following IV, distributes well but not bone, joint, CNS, or eye.
• DOES NOT show the same serious toxic effects of aminoglycosides, and are thus administered IM and SQ.
  

Example of Tetracyclines

Tetracycline

Chlortetracycline

Minocycline

Doxycycline

Mechanism of Tetracyline Action

• Enters cells via active transport (Diffuses well through tissue too)
• Reversibly bind the 30s ribosomal subunit, and blocks addition of aminoacyl-tRNA on acceptor (A) site

Spectrum of Tetracyclines Action

• Gram pos AND neg AEROBES
• Mycoplasma spp
• Intracellular bacteria (Chlamydia, Rickettsiales, Coxiella)
• Protozoa - Balantidium coli

**NOT anaerobes because lacking active transport)

Uses for Tetracyclines

• Admin PO or parenterally (IM, IV) for GI or systemic infections - penetrates tissue well
• CNS infections, joint infections, soft tissue infections, wound infections, pneumonia
• Intracellular bacterial infections: Mycoplasma, Listeria monocytogenes, Anaplasma marginale, Chlamydia, Borrelia, Erhlichia, Haemobartonella
• UTI treated wtih Doxycycline only (others excreted in feces and urine. Doxy ONLY excreted in urine)
• Protozoal infections with Balantidium coli
  

Resistance to Tetracyclines

• Natural: Anaerobes (don't have active transport)
• Acquired: Plasmid mediated MDR (increased efflux, and decreased permeability)

Adverse Effects of Tetracyclines

• Binds di- and tri-valent cations, and can result in Tooth enamel dysplasia/discoloration, and limb deformity/growth inhibition.
• DO NOT give to pregnant or young animals. 
• DO NOT give with milk, antacids, mineral suppls
• Mod of normal flora
• Neurotoxicity - photosensitivity
• Cardiotoxicity if IV in horses

The biggest use for Tetracyclines is:

Tick borne diseases and mycoplasma

You should not mix Tetracyclines wtih ________

other bacteriocidal drugs that requires replicating organisms

Examples of chloramphenicols

Chloramphenicol

Florfenicol (Nuflor)

Thiamphenicol

Mechanism of Chloramphenicol Action

• Lipid soluble and just diffuses into both bacterial and host cells
• Reversibly binds to 50S subunit and inhibits activity of peptidyl transferase --> inhibits extension

BACTERIOSTATIC IN REPLICATING CELLS ONLY

Chloramphenicols should not be used with:

• Other bactericidal drugs that function vs. replicating cells
• Lincosamides, macrolides or tiamulin, since they bind to similar sites

Spectrum of Chloramphenicol Activity

All bacteria including intracellular and mycoplasma.

***only thing it doesn't do is protozoa***

Uses of Chloramphenicol

• PO and parenterally for systemic and GI infections (joint, CNS, and soft tissue infections - pneumonia, wound infections, endometritis, vaginitis)
• UTI with thiamphenicol only
• Chloramphenicol and thiamphenicol not allowed in food animals, but florfenicol (Nuflor) sometimes okay for beef cattle and swine pneumonia.

Resistance to Chloramphenicols

• Develops easily
• Plasmid mediated: Acetylation by enzyme. Specific to chloramphenicals and no cross-resistance to other types of drugs
• MDR via efflux pumps and decreased permeability

Adverse effects of Chloramphenicals

• Chloramphenicol and florfenicol undergo hepatic glucuronization, and inactive metabolites excreted in urine (Thiamphenicol excreted unchanged in urine.) Animals which lack glucuronyl transferase mechanisms (neonatal, fetal, and feline animals) develop hepatotoxicity known as gray baby syndrome. DO NOT GIVE to babies, cats, or pregnant animals
  
• Levels secreted in milk as high as 50% serum levels. DO NOT GIVE TO DAMS
• Aplastic anemia (irreversible fatal anemia that leads to leukemia if survives) in some people --> ONLY give florfenicol in food animals. ADVISE ALL CLIENTS AND STAFF to use extreme caution
• Mod of gut flora
  

Examples of Macrolides

Erythromycin - dogs, cats, horses and cattle

Tylosin - swine

Tilmicosin (Micotil) - cattle

Azithromycin/clarithromycin - ppl, but companion animals

Mechanism of Macrolide Action

• lipid soluble and readily diffuses in host and bacteria
• Huge ring structure binds 50S ribosomal subunit
• Inhibits peptidyl transferase so no new AA can't be incorporated
• Inhibits aminoacyl-tRNA translocation

Macrolides should not be used with

• Lincosamides and chroramphenicols because they have similar binding sites
• Bactericidal drugs that functions vs. actively growing bacteria

Resistance to macrolides

• Virtually all Enterobacteriaceae produce plasmid-encoded esterase that cleaves macrolide ring
• Plasmid encoded methylation of 23s rRNA on the 50S ribosomal subunit which inhibits binding of macrolide
• Cross-resistance with lincosamide --> Any non-enterobacteriaceae that has resistance to macrolides will also be resistant to lincosamides

Spectrum of Macrolide Activity

• Gram-pos AND neg AEROBES other than Enterobacteriaceae (which cleaves the macrolide ring)
• Gram pos AND neg ANAEROBES
• Intracellular Bacteria
• Mycoplasma

Uses for Macrolides

• PO or parenteral (IM, SQ, IV) all penetrate all tissues
• Topically for skin and wound infections
• Joint, CNS, soft tissue infections (wound infections, endometritis, vaginitis, pneumonia, peritonitis)
• Erythromycin/azithromycin combo with rifampin for Rhodococcus equi pneumonia
• Tilmicosin for Pasteurella multocida or Mannheimia hemolytica pneumonia in cattle
• Erythromycin for Campylobacter jejuni enteritis in dogs
• Tylosin for Mycoplasma, Erysipelothrix, Lawsonia intracellularis, and Brachyspira hyodysenteriae in swine
• NOT for UTI treatment - excreted in feces via bile
  

Adverse Effects of Macrolides

• Mod of gut flora
• Irritation of tissue, esp IM
• Nausea, vomiting, diarrhea due to sm mm stimulation in GIT
  
• Tilmicosin: cardiotoxic (Swine, primates, horses most sensitive). Only approved for cattle use. Causes myocardial necrosis with resulting tachycardia and dereased contractility (neg inotropy). Must be administered IM because IV fatal.
• Tylosin: rectal edema/erythema and anal protrusion in swine
• Erythromycin: hyperemia in foals. Use Azythromycin instead for Rhodococcus

Examples of Lincosamides

Lincomycin

Clindamycin

Pirlimycin

Mechanism of Lincosamide Action

• Penetrates host cells/bacteria with diffusion (except for Gram-neg AEROBES because it can't penetrate outer membrane)
• Binds 50s ribosomal subunit and block activity of peptidyl transferase so new amino acids can't be added

Lincosamides should not be administered with:

• Chloramphenicols and macrolides, because share similar binding sites
• Bactericidal drugs that work only on replicating cells.

Adverse Effects of Lincosamides

• Mod of normal flora

Resistance to Lincosamides

• Natural: Gram-neg AEROBES: impermeability AND methylation of 23S rRNA of 50S ribosomal subunit
• Acquired:  Plasmid mediated methylation of the 34s rNA of 50s ribosomal subunit, which inhibits binding of lincosamide. Also results in reistance to macrolides

Spectrum of Lincosamide Action and Usage

• PO and parenteral (IM, IV) for systemic infections (Joint, CNS, soft tissue). Penetrates tissue well
• Topical for treatment of skin + wound
• NOT for UTI because hepatic metabolism and metabolites excreted in urine
• All anaerobes and Gram POS aerobes, intracellular bacteria, and Mycoplasma.
• No protozoa and no gram-neg aerobes