The greater the drug concentration the greater the rate of killing. 

Maximize AUC/MIC

MIC: minimum inhibility concentration

ex. fluroquinolones, aminoglycosides, macrolides, ketolids, metronidazole, daptomycin

Once a drug concentration exceeds 4X the MIC the rate of killing is independent of the drug concentration and maintaining the drug concentration above MIC is the critical factor. 

Max time above the MIC is important

ex. B-lactams, vancomycin, macrolides, linezolid, tigecycline, doxycycline, and clindoamycin

MIC that determines is an organism is resistant or susceptible to an antibiotic.

FDA determines breakpoint

1. Direct (aminoglycosides are directly toxic to hair cells of the ear)

2. Allergic

3. Superinfection-secondary infection casued by the antibiotic.  Ex. Oral or vaginal candidiasis

ex. Antibiotic-induced pseudomembranous colitis: caused by toxins produced by Clostridium difficile.

Caused by the killing of the natural flora.  When you kill the natural flora you allow pathogen growth. 

Absence of the drug target or the inability of the drug to penetrate to site of action. 

ex. Outer membrane of Gm - organisms prevents entry of a number of antibiotics thereby limiting their antimicrobial spectrum to Gm + organisms.

Alteration or acquisition of genetic material

Antibiotics select  for drug resistant organisms but do not cause drug resistance

Multi-Step Random Mutation

Drug Resistance

Larger Step Random Mutations

Drug Resistance

Once critical mutation leads to total resistance. Can be very rapid (24-48hrs)

Rarely occurs

Transmission of drug resistance via a bacteriophage.

Spread of penicillinase production among S. aureus

1. Decreased intracellualr concentration of drug due to decreased entry (change in porin proteins) or increased efflux (p-glycoprotein)

2. Inactivation of drug by bacterial enzymes

ex. penicillinase

3. Decreased affinity of a receptor or enzyme for a drug

ex. nosocomial MRSA

Cause of the majority of US drug resistant hospital infections.

Enterococcus Famium

Staphylococcus Aureus

Klebsiella Pneumoniae

Acinetobacter baumanii

Pseudomonas aeruginosa

Enterobacter species

1. Indifference or additive effect

A (alone)+ B (alone) = A + B

Increase the possibility of adverse effects by exposing patient to an additional drug

2. Antagonistic

A (alone) + B (alone) > A + B

ex. Tetracycline + Penicillin

3. Synergistic:

A (alone) + B (alone) < A+B

ex. cell wall synthesis inhibitors + aminoglycosides

Trimethoprim + sulfamethoxazole

Quinupristin + Dalfopristin

Amphotericin B + Flucytosine

1. Mixed bacterial infections when a single drug is not effective

2. Delay the emergence of drug resistant organisms (Tuberculosis)

3. Enhancement of activity against specific pathogens (synergism)

4. Therapy of severe infections of unknown etiology

Act on growing bacteria by binding to and IRREVERSIBLY inactivating several penicillin binding proteins (PBP).  The most important PBP that is inactivated is transpepitdase. 

Transpepitdase is responsible for cross-linking the linear glycopeptide strands of the cell wall.

The absence of cross links in the newly formed cell wall decreases the mechanical strength of the cell wall and leads to lysis of the bacteria. 

Additionally B-lactams also activate a group of bacterial enzymes called autolysins which cause degradation of the cell wall.  Bacterial mutant that do NOT have autolysine are not killed.

1. Organisms have to be growing because only new forming cell walls are affected

2. Bacterial autolysin production is INCREASED

3. Weakened cell wall causes cell lysis:Bactericical

4. Time-dependent killing

Penicillins

Cephalosporins

Carbapenems

Monobactams

1. B-lactamase production.  B-lactamse are enzymes that hydrolyze the B-lactam ring of B-lactam antibiotics to carboxylic acids that have no antibacterial activity. 

B-Lactamases of Gm + bacteria are usually coded by a plasmid and are mostly commonly penicillinases. Able to secrete B-lactamase

B-lactamases of Gm - can be coded by plasmids, chromosome, and can be expressed consitutively or can be inducible. Typically the B-lactamases are broad spectrum and can hydrolyze several different substrates. Therefore they cause broader spectrum resisitance to B-Lactam antibiotics. B-lactamase is localized to the periplasmic space.

2. Decreased diffusion of the drugs through the pores ot the outer membrane of Gm - bacteria due to decreased pore size caused by expression of altered porin proteins.

3. Altered PBP that have either low or no affinity for the penicillins and most other B-lactam drugs. This includes methicillin resistant S. aureus (MRSA) and penicillin resistant S. pneumoniae

1. Derived from 6-aminopenicillanic acid

2. B-lactam Ring

3. Side chain R which affects acid stability, spectrum of activity, and resistance to penicillinase

4. Carboxyl group: Causes molecule to be polar.  Poor diffusion across lipid membranes

• Natural Penicillin
• Poor oral avaliability because it is destroyed by the stomach acid. (30% abs)
• Short 1/2 life (rapidly removed by the kidney)
• Peak plasma levels occur in 15 min
• Inactivation by B-lactamase (S. aureus)
• Narrow spectrum Gm+ mostly but some Gm - (Cocci, spirochetes, anaerobs of the oral cavity)
• Poor Penetration into the ocular, pericardial, and CSF. However in the presence of meningeal indlammation therapeutic concentrations of Penicillin G are achieved in the CSF.

Simultaneous administration of Probenecid prolongs the duration of action of penicillin G by blocking tubular secretion

Respiratory Form of Penicillin G

Low Blood levels but a longer 1/2 life

Respiratory Form of Penicillin G

Low blood level but longer 1/2 life

• Same antibacterial spectrum as Penicillin V
• Narrow spectrum Gm+ mostly but some Gm - (Cocci, spirochetes, anaerobs of the oral cavity)
• Poor Penetration into the ocular, pericardial, and CSF. However in the presence of meningeal indlammation therapeutic concentrations of Penicillin G are achieved in the CSF.
• Not as readily hydrolyzed in an acidic environment
• Oral Adminstration

Penicillinase-Resistant Penicillins

Resistant to S. aurues and S. epidermidis penicillinase

MRSA Designation

Penicillinase Resistant Penicillins

Resistant to S. aurues and S. epidermidis penicillinase

Penicillinase Resistant Penicillins

Resistant to S. aurues and S. epidermidis penicillinase

Penicillinase Resistant Penicillins

Resistant to S. aurues and S. epidermidis penicillinase

Excreted in the bile

Amino or Extended Spectrum Penicillins

• Effective against Gm + organisms
• Effective against some strains of E. coli, H. influenzae, Salmonella, Shigella, Proteus
• Hydrolyzed by penicillinase and other B-lactamases
• Incomplete absorption of ampicillin can result in disturbances of the endogenous flora of the bowel resulting in diarrhea
• Bacampicillin is a pro drug that releases ampicillin in the body. Better absorbed that ampicillin and therefore less likely to cause diarrhea

Amino or Extended Spectrum Penicillins

• Hydrolysed by penicillinase and other B-lactamases

Altered PBP.  Low affinity for B-lactam antibiotics

Plasmid mediates resistance to whole classes of drugs

Altered PBP.  Lowered affinity for B-lactam antibiotics

Resistance limited to B-Lactam antibiotics

More pathogenic

Antipseudomonal Penicillin

Hydrolyzed by penicillinase and other B-lactamases

Antipsudomonal Penicillin

• Also effective against Proteus, Enterobacter, and Pseudomonas
• Hydrolyed by penicillinase and other B-lactamases

Antipseusomonal Penicillins

• Hydrolyzed by penicillinase and other B-lactamases
• Active against bothe Gm + and Gm - organisms
• Increased activity against Pseudomonas and Klebisella

B-lactamse Inhibitors

Inactivate some B-lactamase and thereby prevent the inactivation of the penicillins. 

Extend the antibacterial spectrum against microorganisms  and had previously been resistant due to penicillinase production.

B-lactamse Inhibitors

Inactivate some B-lactamase and thereby prevent the inactivation of the penicillins. 

Extend the antibacterial spectrum against microorganisms  and had previously been resistant due to penicillinase production.

B-lactam

Inhibits cell wall synthesis

Intrinsically resistant to Gm + pencillinases but are inactivated by broad stectrum B-lactamases.

As you proceed from the 1st to the 4th generation, the flux across the outer membrane of Gm - bacteria and the stability towards Gm - B-lactamases increases

• Active against Gm+
• Active against: E. coli, P. mirabilis, K. pneumoniae
• Ineffective against: enterococci, Listeria, MRSA, and penicillin-resistant Stepticocci
• Does not cross BBB even if inflammation is present

Drugs:

Cephalexin-oral admin only

Cefazolin-Eliminated primarily be renal glomerular filtration; tubular secretion and biliary secretion play secondary roles.  Long 1/2 life.  Used in surgery prophylaxis because it is active against staph and stepticocci

• Not as active against Gm+ as first generation
• Active against: E. coli, Klebsiella, Proteus, Haemophilus influenzae, Moraxella catarrhalis
• Does not cross BBB even if inflammation is present

Drugs

Cefuroxime

Cefaclor- oral admin

Cefotetan-Cephamycin that is more resistant to B-lactamases.  Additioanl activity against Bacteroides fragilis

• Activity against enterobacteriaceae, Serratia, Neisseria Gonorrhoeae
• Activity for S. aureus and S. pyogenes is comparable to first generation cephalosporins
• Expanded Gm - spectrum
• Some penetration into the CNS

Drugs

Cefotaxime-additional activity against Pseudomonas aeruginosa

Ceftazidime-DOC for N. gonorrhoeae

Ceftriaxone-excreted primarily the biliary tract

• Comparable to the thrid generation agents but with more resistance to some of the B-lactamases.
• Activity against enterobacteriaceae, Serratia, Neisseria Gonorrhoeae
• Activity for S. aureus and S. pyogenes is comparable to first generation cephalosporins
• Some penetration into the CNS

Drugs

Cefepime

• Carbapenem
• B-lactam-inhibts cell wall synthesis
• Formulated with Cilistatin which lacks antibacterial activity but serves to prevent the metabolic inactivation by dehydropeptidase.
• Dehydropeptidase is present in the brush borders of the kidney
• Improves efficacy of treatment of nosocomial UTIs
• Widest spectrum ofactivity of any B-lactam antibiotic
• Primarly used in the treatment of nosocomial infections however resistance is increasing due to broad spectrum B-lactamases.
• MRSA and Enterococcus faecium are resistant

Carbapenems

B-lacatam-Inhibits cell wall synthesis

Resistant to metabolism by dehydropeptidase

Carbapenems

B-lacatam-Inhibits cell wall synthesis

Resistant to metabolism by dehydropeptidase

Monobactams

• B-lactam-inhibits cell wall synthesis
• Only useful against Gm - bacteria. 
• Excellent stability to B-lactamase.
• Does not stimulate an immune response in patients allergic to other B-lactams. 
• Main use is in the treatment of noscomial Gm - pathogens

Penicillins

• Hypersensitivity reactions occur in 10%
• Mild Rash to life threatening anaphylaxis
• Most often a delayed allergic reaction characterized by maculopapular eruptions, fever or both. Eosinophilia may also be present
• IgE mediated hypersensitivity may also occur and symptoms include: ealy onset urticaria, laryngeal edema, or anaphylaxis.
• Serum sickness due to imune complexes
• May cause hemolytic anemia or allergic interstitial nephritis
• A hypersensitivity reaction to any penicillin places the patient at a higher risk of reaction to any other penicillin (cross-sensitivity)
• Ampicillin Rash-not immune mediate.  Can be cause by EBV, CMV or acute lymphoctic leukemia

Cephalosporins

• Hypersensitivity occurs in about 5 %
• Cross-sensitivity reaction to cephalosporins occurs in 10% of individuals who have experienced an hypersensitivity reacion in penicillins
• Cephalosporins are CONTRAINDICATED in individuals that have experienced immediate-type hypersensitivity or other serious allerigic reactions to penicillin
• High doses cause renal damage
• Cefaclor can cause a serum sickness like reaction in children
• Ceftriaxone casues pseudocholelithiasis
• Contain a methylthiotetrazole group and can frequently cause hypothrombinemia and bleeding disorders. Becuase of inhibition of Vit K epoxide reductase
• Admin of Vit K can prevent this
• Methylithiotetrazole ring can also cause severe disulfiram like reactions, due to inhibition of alcohol dehydrogenase. Thus alcohol containing medications and alcohol must be avoided

Carbapenems

• Cross sensitivity to penicillin and cephalosporins
• Allerigc reactions can occur
• Imipenem-seizures especially in those who have a pre-existing neurological condition. Or those receiving high doses in relation to renal function

Aztreonam does not seem to have cross sensitization with other B-lactams

Common adverse effects

• Convulsions at high doses

Glycopeptide Antibiotics

• Inhibits cell wall synthesis by binding to D-alanyl-D-alanine protion of the peptidoglycan precursors as the emerge from the cytoplasmic membrane  
• This inhibits the transglycosylase preventing further elongation of the petidoglycan chain and prevents cross linking.
• Resistance is the result of enterococci substituting D-lactic acid for D-alanine
• Given IV
• Used to treat: MRSA, C. difficile (oral admin),
• Streptococcal endocarditis in conjuction with an aminoglycoside if the patient is allergic to penicillin
• Used to Treat penicillin resistant streptococcus
• Side efftects
• Redman/Red neck syndrome-Flushing of the upper body after rapid infuson
• Causes release of histamine from mast cells which causes the following side effects (ususally resolve within 20 min)
• Utricaria
• Puritus
• Hyoptension
• Wheezing
• Dyspnea
• Nephrotoxicity (rare)
• Ototoxicity (rare)

Lipoglycopeptides

• Inhibits Cell Wall synthesis-binds D-alanyl-D-alanine
• Lipid tail binds to the cytoplasmic membrane causing depolarization of the cytoplasmic membrane
• Exhibits concentration dependednt killing
• Approved for use in skin infections
• Women of childbearing potential should have a serum pregnancy test prior to admin of telavancin

• Inhibits cell wall synthesis-inhibits dephosphorylation of C55 isoprenylpyrophosphate
• Peptide antibiotic
•  Topical use only due to extreme nephrotoxicity

• Synthetic analog of Serine
• Used in the treatment of TB
• Inhibits alanine racemase-preventing conversion of L-alanine to D-alanine  

Inhibits cell wall synthesis at an early stage and is used for UTI  

Macrolide

• Generally considered bacterostatic but can be bactericidal depending on the organism and drug concentration
• Protein synthesis inhibitor via binding ot the 50S ribosome
• Binds to domian V of 23S subunit of 50S
• Binds Adenine in domain V
• Resistance Mechanisms
• Efflux pump (p-glycoprotein) that extrudes the macrolides
• Mutation of the ribosomal binding site
• Methylation of the ribosomal binding site by an inducable or constitutively expressed methylase
• Destroyed by the low pH of the stomach
• Concentrated in the liver and excreted in the bile 
• Metabolized by P450
• Inhibitor of CYP3A4
• Useful in patients who are allergic to penicillin
• Used in the treatment of :
• pneumococci
• streptococci
• staphylococci
• Mycoplasma pneumonia
• Legionella sp
• Side Effects
• Cholestatic hepatitis: 7-10 days of therapy and is primarily caused  by erythromycin estolate.  Subsides upon removal of drug  
• Abdominal cramping due to activation of motilin receptor causing increased GI motility.
• Drug interactions due to inhibition of p450 mediated metabolism

Macrolide

• Generally considered bacterostatic but can be bactericidal depending on the organism and drug concentration
• Protein synthesis inhibitor via binding ot the 50S ribosome
• Binds to domian V of 23S subunit of 50S
• Binds Adenine in domain V
• Resistance Mechanisms
• Efflux pump (p-glycoprotein) that extrudes the macrolides
• Mutation of the ribosomal binding site
• Methylation of the ribosomal binding site by an inducable or constitutively expressed methylase
• Destroyed by the low pH of the stomach
• Concentrated in the liver and excreted in the bile
• Metabolized by P450
• Inhibitor of CYP3A4
• Useful in patients who are allergic to penicillin
• Used in the treatment of : Broader spectrum than erythrommycin
• pneumococci
• streptococci-more active than erythromycin
• staphylococci-more active than erythromycin
• Mycoplasma pneumonia
• Legionella sp
• Less likely to cause GI problems
• Reported to cause CNS distrubanes (mania)
• Inhibitor of p450-drug interactions

Macrolide

• Generally considered bacterostatic but can be bactericidal depending on the organism and drug concentration
• Protein synthesis inhibitor via binding ot the 50S ribosome
• Binds to domian V of 23S subunit of 50S
• Binds Adenine in domain V
• Resistance Mechanisms
• Efflux pump (p-glycoprotein) that extrudes the macrolides
• Mutation of the ribosomal binding site
• Methylation of the ribosomal binding site by an inducable or constitutively expressed methylase
• Useful in patients who are allergic to penicillin
• Used in the treatment of :
• pneumococci
• streptococci
• staphylococci
• Mycoplasma pneumonia
• Legionella sp
• chlamydia
• Mycobacterium avium
• H. influenzae
• Tissue concentrations 10-100X higher than plasma concentrations
• Given for 5 days instead of 10 because tissue acts as a reservior of the drug
• Biliary Excretion

Ketolides

• Protein synthesis inhibitor:50s
• Binds to domain II and V on 23s of 50s
• Prevents resistance due to rRNA methylation
• The chemical modifications also makes telithromycin a poor susbstrate for the efflux pump
• Used in the treatment of Community Acquired Pneumonia (CAP)
• Acute hepatic failure and severe liver injury some cases fatal, have been reported
• Contraindicated in patients with a previous history of hepititis and or jaunice associated with use of telithromycin or any microlide antibiotic
• Should not be used in patients with myastenia gravis

Lincosamides

• Binds to 23s of 50s subunit of the ribosome thus inhibiting protein synthesis
• Mechanism of resistnace is methylation; however, clindomycin does NOT induce methylation
• Positive D Test
• Well absorbed with oral admin
• Most of the drug is metabolized to an inactive sulfoxide that is excreted in the urine and bile.
• Effective against Gm + including staphylococci and steptococci.
• Community aquired MRSA frequently respons to clindamycin
• Highly active against B. fragilis
• Side effects: pseudomembranous colitis

Quinupristin/Dalfopristin

Synercid

Steptogramins

• Synercid-30:70 combo of quinpristin (steptogramin B)and dalfopristin (streptogramin A)
• Synergistic: bind at different sides of the 50S ribosome
• No cross resistnace with other protein synthesis inhibitors because they bind at different sites.
•  Only acitive against Gm +
• VER Enterococcus faecium
• Sking and skin-structure infections caused by methicillin-susceptible S. aureus or S. pyogenes
• Not active against Enteroccus faecalis
• Extensively metabolized by CYP 3A4 (which is inhibited by erythromycin and clarithromycin, CYP 3A4 is induced by rifamicin
• Admin: central line
• Side Effects: Venous problems at the site of infusion
• Arthralgia and myalgia frequently occur

Nitrobenzenes

• Binds to 50S and inhibits protein synthesis
• Resistance is due to acetylaton which converts choramphenical to an inactive metabolite
• Rapidly absorbed from the GI tract 
• Widely distributed in body fluids including CFS, bilke, milk, and aqueous humor.
• Conjugated in the liver by glucuronosyl transferase to a nontoxic glucuronide that has no antibacterial effect
• Side Effects:
• Aplastic Anemia- resulting in pancytopenia is not dose related. Not reversible, even if the drug is withdrawn.  Usually associated with prolonged chloramphenicol therapy and more than one episode of treatment with chloramphenicaol.  Symptoms can start to appear as long as 6 months post treatment.  Often fatal
• BM supression/blood dyscasias-does dependent, reversible if drug is immediately discontinued
• Gray-baby syndrome- seen in neonates and premature infants who have been given a large dose of chloramphenicol.  Cyanosis and respiratory irregularities, vasomotor collapse, abdominal distention, loose green stools, and ashen gray color.  Neonate is not able to adaquately conjugate the drug bia glucuronidation and thus cannot eliminate it.  

Tetracyclines

• Can inhibit protein synthesis in both eukaryotic and prokaryotic cells but selective toxicity to eukaryotic cells because they have an active transport system
• Resistance is efflux pump
• Cross resistance among tetracyclines
• Abs is impaired by milk, and heavy metals therefore drug interactions with antacids containing heavy metals (Al, Ca, Mg), milk (Ca) or multivitamins (Fe)
• Removed from the blood by the liver, but undergoes enterohepatic circulation. Excretion is primarily by the glomerular filtration.
• Used in the treatment of Rickettsiae, chlamydiae, mycoplasms, H/pylori, plasmodia, amebas.
• Adverse Effects:
• Hyspersensitivity reactions: skin rash, drug fever
• Cross-sensitization among the various tetracyclines is common
• GI irritation
• Phototoxic reaction- resulting in severe skin lesions
• Hepatic dysfunction-exacerbated during pregnancy
• Children may develop yellow-brown discolorations of their teeth and suffer depressed bone growth.
• readily bind to Calcium deposited in newly forming bone and teeth.
• Admin between the ages of 2 months to 8 years
• Given during pregnancy can produce discoloration of deciduous teeth or bone malformation in the offspring.

Tetracyclines

• Can inhibit protein synthesis in both eukaryotic and prokaryotic cells but selective toxicity to eukaryotic cells because they have an active transport system
• Resistance is efflux pump
• Cross resistance among tetracyclines
• Abs is impaired by milk, and heavy metals therefore drug interactions with antacids containing heavy metals (Al, Ca, Mg), milk (Ca) or multivitamins (Fe)
• Removed from the blood by the liver, but undergoes enterohepatic circulation. Excretion is primarily by the glomerular filtration.
• Used in the treatment of Rickettsiae, chlamydiae, mycoplasms, H/pylori, plasmodia, amebas.
• Adverse Effects:
• Hyspersensitivity reactions: skin rash, drug fever
• Cross-sensitization among the various tetracyclines is common
• GI irritation
• Phototoxic reaction- resulting in severe skin lesions
• Hepatic dysfunction-exacerbated during pregnancy
• Children may develop yellow-brown discolorations of their teeth and suffer depressed bone growth.
• readily bind to Calcium deposited in newly forming bone and teeth.
• Admin between the ages of 2 months to 8 years
• Given during pregnancy can produce discoloration of deciduous teeth or bone malformation in the offspring.
• Vertigo and Dizziness
• Hyperpigmentation of skin--> used in the treatment of acene

Tetracyclines

• Can inhibit protein synthesis in both eukaryotic and prokaryotic cells but selective toxicity to eukaryotic cells because they have an active transport system
• Resistance is efflux pump
• Cross resistance among tetracyclines
• Abs is impaired by milk, and heavy metals therefore drug interactions with antacids containing heavy metals (Al, Ca, Mg), milk (Ca) or multivitamins (Fe)
• Removed from the blood by the liver 90% elimination in the feces  
• Used in the treatment of Rickettsiae, chlamydiae, mycoplasms, H/pylori, plasmodia, amebas.
• Adverse Effects:
• Hyspersensitivity reactions: skin rash, drug fever
• Cross-sensitization among the various tetracyclines is common
• GI irritation
• Phototoxic reaction- resulting in severe skin lesions
• Hepatic dysfunction-exacerbated during pregnancy
• Children may develop yellow-brown discolorations of their teeth and suffer depressed bone growth.
• readily bind to Calcium deposited in newly forming bone and teeth.
• Admin between the ages of 2 months to 8 years
• Given during pregnancy can produce discoloration of deciduous teeth or bone malformation in the offspring.

Glycylcyclines

• 30s ribosome inhibitor: inhibits protein synthesis
• Addition of the glycine residue greatly enhances its binding affinity to the ribosomal receptor over tetracyclines
• The high affinity binding seems to aid in over coming bacterial resistance mechanism of changes in the binding site
• Unaffected by efflux pumps except in Pseudomonas aeruginosa
• No cross resistance with any other antibiotic classes
• Used to Treat
• MRSA
• VRE
• Penicillin-resistant S. penumoniae
• Acinetobacter spp resistant to carapenemns
• ESBL-producing Enterobacteriacae
• Side Effects: Nausea and vomiting

Aminoglycosides

• Exist as a cation at physiological pH
• Uptake by bacteria is biphasic and is oxygen dependent
• Inhibit protein biosynthesis by acting directly on the ribosome and are rapidly bactericidal. 
• Interfere with the proper attachment of mRNA to ribosomes
• Cause misreading of the genetic code
• Produce decreased or abnormal protein synthesis
• Synergistic with cell wall synthesis inhibitors
• More active in an alkaline environment
• Concentration dependent up to 10-12X above MIC
• Resistance is due to metabolism by the baceria to inactive compounds (phosphorylation or acetylation)
• Poor oral abs
• Rapid abs with intramuscular or subcutaneous admin and are distributed within the extracellular fluid
• Penetrate poorly into human cells because of the large size, low lipid solubility and high polycationic charge
• High concentrations of aminoglycosides in human cells only occurs in tubular renal cells of the renal cortex and hair cells of the ear which have an active transport mechanism of aminoglycosides.
• Excreted by glomerular filtration
• Active reabsorption by the proximal renal tubular cells.
• Requires dosage adjustment in renal failure
• Dosage is based on lean body mass
• Give 1/3 of daily dose every 8 hours
• OR 1 time daily dose
• Long Post antibiotic effect (PAE)
• Adverse Effects:
• Low therapeutic index
• Ototoxicity (vestibular or auditory)
• May be increased by duration of treatment
• Nephrotoxicity-acute renal insufficiency or tubular necrosis

Aminoglycosides

• Exist as a cation at physiological pH
• Uptake by bacteria is biphasic and is oxygen dependent
• Inhibit protein biosynthesis by acting directly on the ribosome and are rapidly bactericidal.
• Interfere with the proper attachment of mRNA to ribosomes
• Cause misreading of the genetic code
• Produce decreased or abnormal protein synthesis
• Synergistic with cell wall synthesis inhibitors
• More active in an alkaline environment
• Concentration dependent up to 10-12X above MIC
• Resistance is due to metabolism by the baceria to inactive compounds (phosphorylation or acetylation)
• Poor oral abs
• Rapid abs with intramuscular or subcutaneous admin and are distributed within the extracellular fluid
• Penetrate poorly into human cells because of the large size, low lipid solubility and high polycationic charge
• High concentrations of aminoglycosides in human cells only occurs in tubular renal cells of the renal cortex and hair cells of the ear which have an active transport mechanism of aminoglycosides.
• Excreted by glomerular filtration
• Active reabsorption by the proximal renal tubular cells.
• Requires dosage adjustment in renal failure
• Dosage is based on lean body mass
• Give 1/3 of daily dose every 8 hours
• OR 1 time daily dose
• Long Post antibiotic effect (PAE)
• Adverse Effects:
• Low therapeutic index
• Ototoxicity (vestibular or auditory)
• May be increased by duration of treatment
• Nephrotoxicity-acute renal insufficiency or tubular necrosis

Aminoglycosides

• Exist as a cation at physiological pH
• Uptake by bacteria is biphasic and is oxygen dependent
• Inhibit protein biosynthesis by acting directly on the ribosome and are rapidly bactericidal.
• Interfere with the proper attachment of mRNA to ribosomes
• Cause misreading of the genetic code
• Produce decreased or abnormal protein synthesis
• Synergistic with cell wall synthesis inhibitors
• More active in an alkaline environment
• Concentration dependent up to 10-12X above MIC
• Resistance is due to metabolism by the baceria to inactive compounds (phosphorylation or acetylation)
• Poor oral abs
• Rapid abs with intramuscular or subcutaneous admin and are distributed within the extracellular fluid
• Penetrate poorly into human cells because of the large size, low lipid solubility and high polycationic charge
• High concentrations of aminoglycosides in human cells only occurs in tubular renal cells of the renal cortex and hair cells of the ear which have an active transport mechanism of aminoglycosides.
• Excreted by glomerular filtration
• Active reabsorption by the proximal renal tubular cells.
• Requires dosage adjustment in renal failure
• Dosage is based on lean body mass
• Give 1/3 of daily dose every 8 hours
• OR 1 time daily dose
• Long Post antibiotic effect (PAE)
• Adverse Effects:
• Low therapeutic index
• Ototoxicity (vestibular or auditory)
• May be increased by duration of treatment
• Nephrotoxicity-acute renal insufficiency or tubular necrosis

Fluoroquinolones "floxacin"

• Inhibits bacterial DNA gyrase Gm -
• Inhibits topoisomerase IV of Gm +
• DNA gyrase uses ATP to cut DNA, ligate DNA to form + supercoil DNA --> - supercoil DNA.
• Binds to DNA gyrase when it is bound to to the DNA.  It does not prevent the cutting of the DNA but rather the ligation of the cut DNA 
• Mutations in the gene coding for A subunit lead to decreased binding affinity. 
• Identifiedin many strains to E. coli and other Gm - bacilli
• Muation in the B subunit are less common and cause low level resistance.
• Resistance can also be due to a change in the porin protein in Gm - bacteria
• Resitance can also be due to active efflux of the drug
• High oral bioavailability
• 40-50% excreted in urine
• Drugs tend to accumulate in renal failure
• Large Vd --> increased levels in neutrophils and macrophages, kills intraceullar bacteria.
• Adverse Effects
• GI disturbance
• Rash
• Produce CNS disturbances: headache, vertigo, excitement, visual disturbances
• Tendon rupture following vigorous exercise
• Not recommended for use in children since they may damage cartilage
• Inhibits metabolism of theophylline and warfarin
• Hypoglycemia with glyburide
• Concentration dependent killing

Fluoroquinolones "floxacin"

• Better for respiratory infections than Ciprofloxacin
• L-isomer of ofloxacin 
• Inhibits bacterial DNA gyrase Gm -
• Inhibits topoisomerase IV of Gm +
• DNA gyrase uses ATP to cut DNA, ligate DNA to form + supercoil DNA --> - supercoil DNA.
• Binds to DNA gyrase when it is bound to to the DNA. It does not prevent the cutting of the DNA but rather the ligation of the cut DNA
• Mutations in the gene coding for A subunit lead to decreased binding affinity.
• Identifiedin many strains to E. coli and other Gm - bacilli
• Muation in the B subunit are less common and cause low level resistance.
• Resistance can also be due to a change in the porin protein in Gm - bacteria
• Resitance can also be due to active efflux of the drug
• High oral bioavailability
• 40-50% excreted in urine
• Drugs tend to accumulate in renal failure
• Large Vd --> increased levels in neutrophils and macrophages, kills intraceullar bacteria.
• Adverse Effects
• GI disturbance
• Rash
• Produce CNS disturbances: headache, vertigo, excitement, visual disturbances
• Tendon rupture following vigorous exercise
• Not recommended for use in children since they may damage cartilage
• Inhibits metabolism of theophylline and warfarin
• Hypoglycemia with glyburide
• Concentration dependent killing

Fluoroquinolones "floxacin"

• Better for respiratory infections than ciprofloxacin 
• Inhibits bacterial DNA gyrase Gm -
• Inhibits topoisomerase IV of Gm +
• DNA gyrase uses ATP to cut DNA, ligate DNA to form + supercoil DNA --> - supercoil DNA.
• Binds to DNA gyrase when it is bound to to the DNA. It does not prevent the cutting of the DNA but rather the ligation of the cut DNA
• Mutations in the gene coding for A subunit lead to decreased binding affinity.
• Identifiedin many strains to E. coli and other Gm - bacilli
• Muation in the B subunit are less common and cause low level resistance.
• Resistance can also be due to a change in the porin protein in Gm - bacteria
• Resitance can also be due to active efflux of the drug
• High oral bioavailability
• 40-50% excreted in urine
• Drugs tend to accumulate in renal failure
• Large Vd --> increased levels in neutrophils and macrophages, kills intraceullar bacteria.
• Adverse Effects
• GI disturbance
• Rash
• Produce CNS disturbances: headache, vertigo, excitement, visual disturbances
• Tendon rupture following vigorous exercise
• Not recommended for use in children since they may damage cartilage
• Inhibits metabolism of theophylline and warfarin
• Hypoglycemia with glyburide
• Concentration dependent killing

Fluoroquinolones "floxacin"

• Inhibits bacterial DNA gyrase Gm -
• Inhibits topoisomerase IV of Gm +
• DNA gyrase uses ATP to cut DNA, ligate DNA to form + supercoil DNA --> - supercoil DNA.
• Binds to DNA gyrase when it is bound to to the DNA. It does not prevent the cutting of the DNA but rather the ligation of the cut DNA
• Mutations in the gene coding for A subunit lead to decreased binding affinity.
• Identifiedin many strains to E. coli and other Gm - bacilli
• Muation in the B subunit are less common and cause low level resistance.
• Resistance can also be due to a change in the porin protein in Gm - bacteria
• Resitance can also be due to active efflux of the drug
• High oral bioavailability
• 40-50% excreted in urine
• Drugs tend to accumulate in renal failure
• Large Vd --> increased levels in neutrophils and macrophages, kills intraceullar bacteria.
• Adverse Effects
• GI disturbance
• Rash
• Produce CNS disturbances: headache, vertigo, excitement, visual disturbances
• Tendon rupture following vigorous exercise
• Not recommended for use in children since they may damage cartilage
• Inhibits metabolism of theophylline and warfarin
• Hypoglycemia with glyburide
• Concentration dependent killing

Rifamycin

• Inhibit DNA-dependent RNA polymerase- thus inhibiting RNA biosynthesis
• Used in combination with other antibacterials to prevent resistance which develops rapidly when used alone
• EXCEPTION: used alone to treat carriers of N. meningitidis 
• Treatment of TB
• Treatment of Leprosy
• Potent inducer of CYP3A4
• MRSA: rifamycin + vancomycin
• Legionella: macrolide + rifamycin
• Adverse effects: usually reversible
• GI
• Hepatic

Rifamycin

• Inhibits DNA dependent RNA polymerase-inhibiting RNA biosynthesis  

Sulfonamides

• Dihydropteroate synthase catalyzes bond formation between p-aminobenzoic acid (PABA) and dihydropteridine
• Sulfonamides are structural analogs of PABA and act as a competitive inhibitor of dihydropteroate synthase
• This depletes the bacteria of folic acid, a cofactor.
• Acts as a methyl donor
• This inhibits the synthesis of DNA, RNA, and protein biosyntesis  
• Resistnace can occur due to increased PABA synthesis, synthesis of an altered dihydropteroate synthase that does not bond sulfonamides, or utilization of exogenous folic acid.
• Short acting
• Oral abs
• Renal elimination within 24 hrs
• Distribute in the extracellular body water and CSF
• Metabolized by acetylation of the N4 nitrogen
• UTI treatment
• Treatment of nocardiosis
• Adverse Effects:
• Steven-Johnson Syndrome
• About 75% of adverse effects involve skin, with sensitization often being responsible,
• Cross sensitization with other sulfonamides
• Drug Fever
• Blood dyscrasias
• Eosinophilia
• Crystalluria is seen with other manifestations of hypersensitivity
• Hepatitis causing focal diffuse necrosis of the liver occurs rarely
• Kernicterus can occur in newborns becuase of displacement of bilirubin from plasma albumin

Sulfonamides

• Dihydropteroate synthase catalyzes bond formation between p-aminobenzoic acid (PABA) and dihydropteridine
• Sulfonamides are structural analogs of PABA and act as a competitive inhibitor of dihydropteroate synthase
• This depletes the bacteria of folic acid, a cofactor.
• Acts as a methyl donor
• This inhibits the synthesis of DNA, RNA, and protein biosyntesis
• Resistnace can occur due to increased PABA synthesis, synthesis of an altered dihydropteroate synthase that does not bond sulfonamides, or utilization of exogenous folic acid.
• Short acting
• Oral abs
• Renal elimination within 24 hrs
• Distribute in the extracellular body water and CSF
• Metabolized by acetylation of the N4 nitrogen
• UTI treatment
• Treatment of nocardiosis
• Adverse Effects:
• Steven-Johnson Syndrome
• About 75% of adverse effects involve skin, with sensitization often being responsible,
• Cross sensitization with other sulfonamides
• Drug Fever
• Blood dyscrasias
• Eosinophilia
• Crystalluria is seen with other manifestations of hypersensitivity
• Hepatitis causing focal diffuse necrosis of the liver occurs rarely
• Kernicterus can occur in newborns becuase of displacement of bilirubin from plasma albumin

Sulfonamides

• Dihydropteroate synthase catalyzes bond formation between p-aminobenzoic acid (PABA) and dihydropteridine
• Sulfonamides are structural analogs of PABA and act as a competitive inhibitor of dihydropteroate synthase
• This depletes the bacteria of folic acid, a cofactor.
• Acts as a methyl donor
• This inhibits the synthesis of DNA, RNA, and protein biosyntesis
• Resistnace can occur due to increased PABA synthesis, synthesis of an altered dihydropteroate synthase that does not bond sulfonamides, or utilization of exogenous folic acid.
• Used to prevent colonization of burns by bacteria
• Not effective in treating bacterial infection
• Adverse Effects:
• Steven-Johnson Syndrome
• About 75% of adverse effects involve skin, with sensitization often being responsible,
• Cross sensitization with other sulfonamides
• Drug Fever
• Blood dyscrasias
• Eosinophilia
• Crystalluria is seen with other manifestations of hypersensitivity
• Hepatitis causing focal diffuse necrosis of the liver occurs rarely
• Kernicterus can occur in newborns becuase of displacement of bilirubin from plasma albumin

Sulfonamides

• Not used to treat bacterial infections
• Used to treat ulcerative colitis
• Therapeutic action may reside in 5-aminosalicylic acid a metabolite

Trimethoprim

TMP

Folic Acid Reducatase Inhibitor

• Bacteristatic
• Inhibitor of dihydrofolate reducatse 
• dihydrofolate reducatse reduces dihydrofolate to tetrahydrofolate  
• Synergistic with sulfonamides
• Bactericidal
• TMP can interfere with folate metabolism in malnorished individuals (megaloblastic anemia, leukopenia, and granulocytopenia)

• Sulfonamide + Folic Acid Reducatase Inhibitor
• Most important formulation
• Replaced single use of sulfomamides
• Effective in the treatment of conditions where sulfonamide alone are ineffective
• Treatment of Bronchitis, otitis media
• DOC for Pneumocystis jiroveci
• Common in AIDS patients
• AIDS patients may experience side effects severe enough that treatment must be disconinued.  

• Treatment of acute cystitis, and prophylaxis  UTI
• MAO unknown
• Appears to be involved with reductive metabolism of nitro group to form reactive species which forms an active oxygen metabolite.
• No systemic activity because it is excreted by kidney
• Commonly causes GI disturbances and headache
• Acutely affects the lungs: allergic reaction that produces chills, cough, and pulmonary infiltrations
• Chronic lungs affects: Generally occur after 6 months or more of therapy.  Irreversible. Causes pulmonary fibrosis and may be due to a reactive metabolite
• E. coli is susceptible
• Gm - is resistant
• High urine concentration, low serum concentration

• Co-polymer of ammonia and formaldehyde that decomposes is acidic urine to release formaldehyde
• Used for prophylaxis to prevent recurrences of cystitis
• If you have an increased rate of urine loss then formaldehyde sits in the bladder for a shorter amount of time and is less effective  

• Inactivation of the enzyme enolpyruvyl transferase
• Blocking the condensation of uridine diphosphate-N-acetylglucosamine with p-enolpyruvate
• One of the first steps in bacterial cell wall synthesis
• Reduces adherence of bacteria to uroepithelial cells
• Treatment of uncomplicated UTI (acute cystitis) in women due to susceptible strains of E. coli and E. faecalis
• Inferior to 7 days of ciprofloxacin or 10 days of TMP/SMZ
• Equivalent to 10 days of nitrofurantoin
• Advantage is it is taken as a single dose.  

Lipopeptides

• 13-member amino acid lipopeptide that has a lipophilic tail. 
• The agent binds to the bacterial cell membrane of Gm + organisms via the lipophilic tail in a calcium dependent process. This disrupts the cell membrane potential.
• Spectrum similar to vancomycin except that it maintains activity against organisms that are vancomycin resistant
• MRSA
• VRSA
• VRE
• Bactericidal
• Concentration dependent killing 

• Antiprotozoal agent (Flagyl)
• Highly active against many anaerobic bacteria including C. Diff (DOC), H. pylori, B. fragilis
• Includes a nitro group that may be reduced to a free radical species that damages the bacterial DNA
• Adverse Effects:
• Headache
• Produces a metallic taste
• Disulfuram-like reaction in patients who consume alcohol while taking drug
• Lipid soluble and pentrates CNS 

• Used as an alternatice drug to N. gnorrhea including penicillinase-producing strains in patients allergic to other drugs
• Not active against T. pallidum so this organism must be treated separately if both organisms are prestent simultaneously  

Treatment of C. diff associated diarrhea

Equivalent to vancomycin in effectivness

Vancomycin

Telavancin

Bacitavcin

Quinupristin/Dalfopristin

Linezolid

Daptomycin

Aztreonam

Polymyxin B or E

Isoniazid

Rifampin

Pyrazinamide

Ethambutol

Streptomycin

• Multiple drugs are always used to treat active TB cases.  This decreases the change of the organism developing TB
• Isoniazid can be used alone for prophylaxis treatment  

• Primary agent used in the treatment of TB
• Only drug approved for prophylaxis of TB
• Bactericidal for growing organisms and bacteriostatic for resting organisms
• isoniazid is activated by catalase/peroxidase enzyme and then inhibits synthesis of mycolic acids.
• Mutation of catalase/peroxidase causes resistance
• Rate limiting step for elimination is metabolism, primarily by acetylation
• Slow aceytlators have a higher concentration of isoniazid in plasma and are more prone to develop peripheral neuropathy.
• Presents similar to pyridoxine deficiency (B6)
• Related to increased excretion of pyridoxine
• Supplement the diet with pyridoxine
• Hepatotoxicity
• Chances increase with age.  By the age of 35 the rish of hepatitis increases and may out weigh the benifit  

• TB treatment
• MOA unknown
• May cause uni or bilateral ocular toxicity
• Dose-related
• Reversible
• Manifested by gradual loss of visual acuity, decrease in visual fields, and loss of red/green color discrimination
• Hyperuricemia

• TB treatment
• Postulated to interfere with the role of nicotinamide as a cofactor in mycobacterial dehydrogenase systems
• Dose related hepatotoxicity
• Hyperuricemia  

• Aminoglycoside antibiotic
• TB Drugs
• Given by injection typically 1 X week
• Ototoxicity-vestibular mainly
• Less nephrotoxic than other aminoglycosides  

Dapsone

Clofazimine

Rifampin