Selective Toxicity

(in relation to antibiotics)

1. Disruption of the bacterial cell wall - encased in rigid cell wall, drugs can weaken cell wall, promote cell death

2. Inhibition of an enzyme unique to bacteria - sulfonamides inhibit an enzyme meeded to make folic acid, a compound required by bacteria

3. Disruption of bacterial protein synthesis - drugs can impair protein synthesis in bacteria while leaving human protein synthesis untouched

Narrow Spectrum Antibiotic: effective against only a few microorganisms

Broad Spectrum Antibiotic: active against huge numbers of bacteria

*Narrow spectrum is preferred*

Bactericidal drugs are directly lethal to bacteria @ clinically achievable concentrations

Bacteriostatic drugs can slow bacterial growth but do not cause cell death

Drugs can...

1. decrease the concentration of a drug at its site of action (↓ active uptake or ↑ active export)

2. inactivate a drug (drug-metabolizing enzymes, ex: penicillinase)

3. alter the structure of drug target molecules (receptors)

4. produce a drug antagonist

Minimum Inhibitory Concentration,MIC: lowest concentration of antibiotic that produces complete inhibition of bacterial growth, but does not kill bacteria

Minimum Bactericidal Concentration,MBC: lowest concentration of drug that produces a 99.9% decline in the # of bacterial colonies, indicating bacterial kill

1. Initial therapy of severe infection - wide antimicrobial coverage is appropriate until infecting organism has been identified

2. Mixed Infections - infections may be caused by more than 1 microbe

3. Prevention of Resistance - w/ Tuberculosis, drug combos are used for the purpose of suppressing resistance

4. Decreased Toxicity - antibiotic combos can ↓ toxicity to host

5. Enhanced Antibacterial Action - at times combos of antibiotics can have ↑ effects than a single antiobiotic

*these agents are given for prevention*

1. Surgery - can ↓ incidence of infection during surgery

2. Bacterial Endocarditis - those w/ congenital or valvular ♥ disease/prothestic ♥ valves are susceptible & would need to be on antimicrobial meds before medical or dental procedures

3. Neutropenia - @ ↑ risk for infection, ↓ infection through antiobiotic prophylaxis

4. Ect - UTI's, Syphilis

• Attempted treatment of untreatable infection
• Treatment of FUO
• Improper dosage
• Treatment in the absence of adequate bacteriologic info
• Omission of surgical drainage

• Ideal antibiotic b/c they are active against a variety of bacteria & direct toxicity is low
• aka beta-lactam antibiotics due to their beta-lactam ring
• Disrupt the bacterial cell wall
• Generally bactericidal
• Active only against bacteria that are undergoing growth & division

By simultaneously inhibiting transpeptidases and activating autolysins, the penicillins (1) disrupt synthesis of the cell wall and (2) promote its active destruction. Result in cell lysis and death.

Molecular targets of the penicillins (transpeptidases, autolysins, other bacterial enzymes) are known as penicillin-binding proteins (PBPs).  Penicillins must bind to them to produce antibacterial effects

1. Inability of penicillins to reach their targets (PBPs)

Ex: Only certain penicillins can penetrate the outer membrane in gram-neg bacteria

2. Inactivation of penicillins by bacterial enzymes

Ex:Beta-lactamases (penicillinases) are enzymes that cleave the beta-lactam ring, and render penicillins inactive

3. Production of PBP's that have a low affinity for penicillins

Ex: MRSA has a production of PBP's w/ a low affinity for penicillins by aquiring these certain genes

Uses of Penicillins

(Pen G)

• Active against most gram-positive bacteria & gram-negative cocci, anaerobic bacteria, and spirochetes.
• With a few expections, gram-negative bacilli are resistant

Penicillin G Antibiotic

(PCN G)

Class: Penicillin antibiotic, narrow-spectrum penicillin

MOA: Interferes w/ cell wall replication of susceptible organisms; lysis is mediated by cell wall autolytic enzymes, results in cell death

Specific Uses: G+ and selected G- bacteria, spirochetes

Major ADRs: CNS- Coma, Seizures GI- pseudomembranous colitis GU- Oliguria, proteinuria, hematuria, glomerulonephritis, renal tubular damage HEMA- bone marrow depression, granulocytopenia, hemolytic anemia MISC- anaphylaxis, serum sickness, Stevens-Johnson syndrom

Precautions: Preg (B), breastfeeding, hypersensitivity to cephalosporins/carbapenem/sulfite, severe renal disease, GI disease, asthma

Considerations: very unstable @ low pH, 70% of druge is destroyed by gastric acid, excreted unchanged by the kidney, renal dosing

Func. Class: auntiinfective, antiulcer

Chem. class: aminopenicillin, broad-spectrum

MOA: interferes w/ cell wall replication of susceptible organisms; the cell wall, rendered osmotically unstable, swells and bursts from osmotiv pressure; bactericidal, lysis mediated by bacterial cell wall autolysis

Specific Uses: Have the same G+ spectrum w/ enhanced G- coverageTreatment of skin, respiratory, GI, GU infections, otitis media, gonorrhea, gram-positive cocci, gram-negative cocci, gram-positive bacilli, gram-negative bacilli, prophylaxis of bacterial endocarditis

Major ADRs: CNS- seizures, pseudomembranous colitis, bone marrow depression, granulocyopenia, hemolytic anemia, anaphylaxis, resp distress, serum sickness, Stevens-Johnson syndrome

Precautions: Preg (B), breastfeeding, neonates, hypersensitivity to cephalosporins, severe renal disease, acute lymphocytic leukemia

Routes: PO

Considerations: Better GI stability than Ampicillin, which makes for better absorption, make sure to use additional contraceptive method if on OCs, a macular rash will develop if a person has mononucleosis

MOA: interferes w/ cell wall replication of susceptible organisms; the cell wall, rendered osmotically unstable, swells and bursts from osmotiv pressure; bactericidal, lysis mediated by bacterial cell wall autolysis

Specific Uses: G+ and G-, biliary tract infection, shigellosis, typhoid fever

Major ADRs: CNS- coma, seizures GI- pseudomembranous colitis, hepatic necrosis/failure GU- glomerulonephritis HEMA- bone marrow depression, granulocyopenia, leukopenia, eosinophilia MISC- anaphylaxis, serum sickness, toxic epidermal necrolysis, Stevens-Johnson syndrome

Precautions: Preg (B), breastfeeding, neonates, hypersensitivity to cephalosporins, renal disease

Considerations: poor GI absorption, but is very well tolerated IV, make sure to use additional contraceptive method if on OCs, a macular rash will develop if a person has mononucleosis

Routes: IV, IM, PO

Procaine PCN-G: long-acting formulation that lasts for hrs (15-24)

Benzathine PCN-G: long-acting formulation that lasts for wks (1-4)

IM ONLY - no substitions, deep IM, Z-track injection, viscose formulation = inject very slowly

• Same spectrum as pen G, but has better stability in the low pH of the stomach
• ↑ absorption on empty stomach, food ↓ absorption
• This species of pen can also have K+ added to its structure to confer stability, pts w/ renal insufficiency might develop hyperkalemia
• Excreted unchanged by the kidney

Class: Extended Spectrum

MOA: Cell wall lysis mediated by cell wall autolytic enzymes

Specific Uses: G+, G-, UTIs, respiratory, soft tissue, bacterial septicemia

Major ADRs: CNS- coma, seizures GI- pseudomembranous colitis, hepatoxicity GU- glomerulonephritis HEMA- bone marrow depression, granuloctopenia INTEG- Stevens-Johnson syndrome SYST- anaphylaxis

Precautions: Preg (B), breastfeeding, hypersensitivity to cephalosporins, renal/GI disease, diabetes, electrolyte imbalances

Routes: IM, IV

• Beta-lactam antibiotics similar in structure and actions to penicillins
• bactericidal
• More resisitant to beta-lactamases
• ↓ toxicity
• 4 generations: as the generations goes ↑, so does the resistance to beta-lactamase destruction
  

1st Generation: great G+ coverage, limited G- coverage

2nd Generation: same G+ coverage, but more expanded G- coverage

3rd Generation: less G+ coverage, more G- coverage, and better anti-pseudomonal coverage

4th Generation: limited G+ coverage, much more activity against G-

• Allergic Rx - if allergic to penicillin most likely allergic to cephalosporins, not 100%
  
• Notorious for causing C. Diff diarrhea
• W/ selected antibiotics, there can be a heightened bleed risk from a ↓ in vit K
  
• Can cause thrombophlebitis

Cefalexin/Keflex

1st Generation

MOA: inhibits bacterial cell wall synthesis, rendering cell wall osmotically unstable, leading to cell deathl lysis mediasted by cell wall autolytic enzymes

Specific Uses: G- bacilli, G+, upper/lower respiratory tract, skin infections, UTIs, otitis media

Major ADRs: CNS- seizures GI- pseudomembranous colitis GU- nephrotoxicity, renal failure HEMA-

Route: PO

Elimination: Renal

Normal Renal Function: Half life = o.4 to 1

Severe Renal Impairment: Half life = 10-20

Cefaclor/Ceclor

2nd Generation

MOA: Inhibits bacterial cell wall synthesis, rendering cell wall osmotically unstable, leading to cell death by binding to cell wall membrane

Specific Use: G- bacilli, G+, respiratory tract, urinary tract, skin, bone, joint infections, otitis media

Route: PO

Major Route of Elimination: Renal

Normal Renal Function: half-life = 0.6-0.9

Severe Renal Impairment: half-life = 2-3

Ceftriaxone/Rocephin

3rd Generation

MOA: Inhibits bacterial cell wall synthesis, rendering cell wall osmoitcally unstable, leading to cell death

Specific Uses: G- bacilli, G+, serious lower/upper respiratory tract, urinary tract, skin, gonococcal, intraabdominal infections, septicemia, meningitis, bone, joing infections, otitis media, PID

Routes: IM, IV

Major Route of Elimination: Hepatic

Normal Renal Function: half-life = 5.8-8.7

Severe Renal Impairment: half-life = 15.7

Cefepime/Maxipime

4th Generation

MOA: Inhibits bacterial cell wall synthesis, rendering cell wall osmoitcally unstable, leading to cell death

Specific Uses: G- bacilli, G+, lower respiratory tract, acute bronchitis, uncomplicated gonorrhea

Routes: IM, IV
Major Route of Elimination: Renal

Normal Renal Function: half-life = 2

Severe Renal Impairment: increased

Imipenem

Carbapenem

Class: Very Broad spectrum

MOA: interferes w/ cell wall replication of susceptible organisms; osmotically unstable cell wall swells, bursts from osmotic pressure; addition of cilastatin prevents renal inactivation that occurs w/ high urinary concentrations of imipenem

Specific Uses: serious infections caused by G+, enterococcus, group A ß-hemolytic streptococci

Major ADRs: renal toxicity/failure, seizures, hepatitis, allergic Rx

Considerations: Preg (C)

Routes: IV, IM

• Narrow-Spectrum Antiobiotics
• Used against aerobic G- bacilli
• Can cause serious inury to inner ear (ototoxicity) and kidney (renal toxicity)
  
• Not absorbed into the GI tract
• Bactericidal
• Low therapeutic index
• Must monitor serum drug level to find right dosage
  
• Rapidly excreted by the kidneys as unchanged drug
  

Aminoglycosides disrupt bacterial protein synthesis.  These drugs bind to the 30S ribosomal unit, and cause (1) inhibition of protein synthesis, (2) premature termination of protein synthesis, and (3) production of abnormal proteins

↑ the concentration, the more rapidly the infection will clear

• Limited esclusively to aerobic G- bacilli
• E. Coli, Klebsiella pneumoniae, Serratia marcescens, proteus mirablilis, pseudomonas aeruginosa
• Inactive against G+ bacteria
• Cannot kill anaerobes b/c lack of O₂ and cannot cross cell membrane
• Only used against really serious infections
  

• Ototoxicity- impairment of hearing is caused by damage to sensory hair cells in the cochlea, disruption of balance is caused by damage to sensory hair cells of the vestibular apparatus. The risk of ototoxicity is related primarily to excessive levels trough levels (lowest level between doses, occurs prior to administering next does) of drug--rather than excessive peak levels. Largely irreversible
  
• Nephrotoxicity- can injure cells of the proximal renal tubules, drugs are taken up by tubular cells and achieve ↑ intracellular concentrations. Correlates w/ total cumulative dose of drug and w/ ↑ trough levels. Serum creatinine & BUN should be monitored

• For therapy to be both safe & effective, serum drug levels should be maintained within a narrow therapeutic range
• Peak and Trough- peak levels are blood levels of the drug taken 30 mins to 1 hr after admin, trough levels are blood levels of drug taken just prior to next dose
  
• Monitoring of serum drug levels provide the best basis for adjustment of the dosage, which means drawing blood to measure antibiotic levels @ various times
• Dosage needs to be adjusted so that peak levels are high enough to kill bacteria but not so high as to be toxic
  

Gentamicin

Aminoglycoside

Class: Narrow-spectrum

MOA: interferes w/ protein synthesis in bacterial cell by binding to ribosomal subunit, causing misreading of genetic code; inaccurate peptide sequence forms in protein chain, causing bacterial death

Specific Uses: Severe systemic infections of CNS, respiratory, GI, urinary tract, bone, skin, soft tissues caused by susceptible strains, acute PID

Warnings: Preg (D), severe renal disease, hearing deficits, Parkinson's Disease

Routes: IM, IV

• Ubiquitous
• Eukaryotic, rigid cell wall made up of chitin & polysaccharide
• Ergosterol is principal lipid, humans is cholesterol
• Like warm/dark/moist

• Class: Polyenes
• Drug of choice for severe, systemic fungi infections, b/c is broad spectrum, very effective, but unfortunately carries toxicities that make it the agent of last choice
• Depending of concentration can be fungistatic or fungicidal

• Infusion Reactions- fever, chills, rigors, nausea, headache
• Nephrotoxicity- renail impairment occurs in practically all patients
• Hypokalemia- damage to kidneys, potassium supplements may be needed to correct problem
• Hematologic- bone marrow suppression, resulting in normocytic, normochromic anemia