Antibiotic Intro & Penicillins & Cephalosporins

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Selective Toxicity

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inhibit or destroy pathogen without harming the host

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Bactericidal

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kills the pathogen

Ex: Penicillins, Cephalosporins, aminoglycosides, vanco,

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Bacteriostatic

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inhibits the growth of the pathogen

Ex: erythromycin, clindamycin, tetracycline, sulfa, trimeth

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Narrow Spectrum

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Gram Pos OR Gram Neg OR a specific grp

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Extended Spectrum

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effective against Gram Pos and some Gram Neg

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Broad Spectrum

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effective against a wide variety of both Gram Pos and Gram Neg

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5 Mechanisms of action on how antibacterials are classified

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1. inhibit synthesis of bacterial cell wall
2. alter cell membrane permeability
3. Inhibit bacterial protein synthesis (30s and 50s)
4. Inhibit nucleic acid synthesis
5. Block metabolic steps

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Emperical Therapy (Best Guess)

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*identity of infectious microbe is unknown*

1. usually includes a broad-spectrum antibiotic or combo
2. Use Gram-stain results, site of infection, clinical experience

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Rational Therapy

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*susceptibility of patient's bacterial isolate is performed*

1. Kirby-Bauer Disc diffusion test
2. MIC and MBC

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Minimum Inhibitory Concentration

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minimal concentration of an antibiotic that prevents visible growth

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Minimum Bactericidal Concentration

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miminum concentration of an antibiotic needed to kill the bacteria (99.9%)

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Minimum Inhibitory Concentration (MIC)

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test performed by diluting antibiotic in culture broth containing constant amount of the patient's bacterial isolate....first clear tube

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Minimum Bactericidal Concentration (MBC)

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test determined by taking an aliquot of a clear tube and plating it out onto an agar plate....no growth indicates killing effect

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Factors that cause or encourage Bacterial Resistance

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1. indiscriminate use
2. delay in optimal therapy
3. inability of drug to reach site of infection due to barriers
4. defective functional status of hte host defense mechanism
5. agricultural use of antibiotics in livestock

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Mechanisms by which microorganisms produce resistance

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1. Mutation & Selection
2. Genetic Exchange

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Mutations and Selection

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antibiotic serves as a selective agent for bacteria with random mutations which can be passed on to daughter cells

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Genetic Exchange

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horizontal transfer of resistance determinants from a donor cell via transformation, transduction, or conjugation

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Transduction

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bacteriophage has bacterial DNA in its protein coat obtained from a previous host bacterium that contains a gene for drug resistance

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Transformation

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DNA that is free in the environment and contains resistance genes is incorporated into the bacterial genome

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Conjugation

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Genes pass from cell to cell by direct contact of hte sex pilus

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Mechanism of Conjugation

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1. 2 sets of genes are transferred by plasmids (1 plasmid contains DNA and is the R-determinant)
2. other plasmid contains genes for bacterial conjugation (Resistance transfer factor)
3. plasmids can exist independently or in combo (complete R-Factor)

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Biochemical Mechanisms of drug resistance

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1. Decreased permeability of organism to drug (gram neg have porins which allow drugs to pass)
2. Inactivation of antibiotic by enzymes (beta lactamases)
3. Alteration of the drug target site (penicillin binding proteins)

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Goal of Combined Antibiotic Therapy

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to provide coverage for all organisms most likely involved in an infection

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Three possible interactions with the use of combined antibiotic therapy

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1. Synergism
2. Antagonism
3. No Effect

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Synergism

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*4-fold or greater reduction in the MIC or MBC when a drug combo is used*

1. Blockade of sequential steps in a metabolic pathway (Trimeth-Sulfa)
2. Inhibiting the enzymatic inactivation of an antibiotic (betalactam with betalactamase inhibitory)
3. Enhanced antibiotic uptake by bacteria (aminoglycoside + beta lactam)

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Antagonism

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*>50% of hte MIC of each drug is needed to produce an inhibition of growth

1. bacteriostatic agent will generally antagonize the action of a bactericidal agent

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Clinical Use of Combo antimicrobial agents

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1. treatment of mixed bacterial infections caused by more than on microorganism
2. empirical therapy of severe infections in which a specific cause is unknown
3. synergistic effect may be necessary to kill a microbe
4. may prevent the emergence of resistant microorganisms

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Prophylactic use of antibiotics

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used to prevent infection from occurring versus treating an established disease

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Reasons use to use antibiotics prophylactically

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1. protect healthy individuals from infection by specific microorganisms (gonorrhea or syphilis)
2. prevent recurrent disease in susceptible patients
3. antimicrobial prophylaxis in surgical procedures

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Superinfections

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appearance of a new infection during chemotherapy for another infection

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Misuses of Antibiotics

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1. Treat untreatable diseases (viral, fever)
2. Improper doses
3. antibiotic must reach site of action to be effective
4. Lack of adequate bacteriological info
5. Improper duration (completion of course)

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Natural Penicillins

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1. Penicillin G
2. Penicillin V Potassium
3. Penicillin G Procaine
4. Penicillin G Benzathine
5. Penicillin G Benzathing + Penicillin G Procaine

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Penicillinase Resistant Penicillins - Antistaphylococcal

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1. Methicillin
2. Nafcillin
3. Oxacillin

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Extended Spectrum Penicillins (Aminopenicillins)

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1. Ampicillin
2. Amoxicillin

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Antipseudomonal Penicillins

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1. Ticarcillin + Clavulanate potassium
2. Piperacillin + Tazobactam

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Other Beta-Lactam Drugs ----Monobactams

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Aztreonam

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Other Beta Lactam Drugs ----Carbapenems

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Imipenem + Cilastatin

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Beta-lactamase inhibitors

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1. Clavulanic Acid
2. Tazobactam

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Combo products containing Beta Lactamase inhibitors

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1. Augmentin (Amox + Clavulanic Acid)
2. Timentin (Ticarcillin + Clavulanic Acid)
3. Zosyn (Piperacillin + Tazbactam)

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Mechanism of action of the Penicillins

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**inhibit bacterial cell wall synthesis**

1. bacteria contain peptidoglycan cell wall (structure is lattice like)
2. enzymatic process of lattice like chain links --Transpeptidase
3. Beta-Lactams inhibit transpeptidase & cross linked peptidoglycan cell wall
4. only work on actively dividing cells

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Mechanisms of Bacterial Resistance to Penicillins

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1. Structural Differences
2. Inability to penetrate to its site of action
3. *Enzymatic Destruction of drug*

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Structural Differences that cause resistance to Penicillins

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*Penicillin-Binding Proteins (PBPs)

ex. highly penicillin-resistant Strep Pneumoniae has 4 out of 5 PBPs with decreased affinity

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Inability of Penicillin to penetrate to site of Action (resistance)

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1. Gram Pos - cell wall near surface - can easily penetrate to membrane
2. Gram Neg - out membrane can function as barrier
3. Porins - trouble diffusing thru

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Enzymatic Destruction of Penicillins (Resistance)

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*Beta - Lactamases - split beta-lactam ring to produce inactive product*

1. destroy the antibacterial activity
2. Gram Pos - large amounts of beta lactamases
3. Gram Neg - enzyme found between outer and inner membranes

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Absorption of Penicillins

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food impairs - administer 1-2 hours before or after a meal

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Which penicillin drug does food not impair absorption

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amoxicillin

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Tissue Distribution of penicillin

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1. concentration is similar to that of serum
2. bacterial meningitis - can pass into CSF

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Excretion of penicillins

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1. 10% GFR
2. 90% tubular secretion

Doses must be adjusted for renal function

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penicillins that do not need to be renally dosed

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1. nafcillin
2. oxacillin
3. dicloxacillin

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Major ADR of penicillins

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*Hypersensitivity*

1. anti-penicillin antibody present in most people
2. oral admin - less sensitizing and dangerous
3. topical use - highest degree
4. cross allergic and cross sensitizing

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Major determinant for hypersensitivity with penicillins

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*Benzylpenicilloyl* - degradation product

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Symptoms with immediate Type 1 hypersensitivity reaction to penicillin

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1. Skin rash, angioedema, urticaria, pruritis
2. Nausea, ab pain, vomiting, diarrhea
3. dyspnea or wheezing
4. hypotension, tachycardia, arrythmias
5. Fatality due to laryngeal edema or CV collapse

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Mechanism of Allergy to penicillin

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*Type 1 Reaction - Immediate/Anaphylaxis*

1. antibodies become fixed to mast cells of skin, GI, and respiratory tract & release histamine and other vasoactive mediators
2. skin testing most useful detection
3. occurs with 1-72 hours

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Most common type of Hypersensitivity reaction to penicillin

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Type 1 Reaction

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Methicillin

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Most common cause of acute allergic interstitial nephritis **Type IV Reaction**

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Other ADRs of penicillins

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1. ampicillin & amoxicillin non-allergy skin rash (1-28 days)
2. GI upset, nausea, vomiting, diarrhea
3. Excess Na and K - cardiac and renal toxicity
4. seizures - CNS toxicity

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Penicillin G is better administered

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parenterally (IM or IV)

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Penicillin G is good for

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1. Non-resisitant Staphylococcus and Streptococcus
(Pneumococcal pneumoniae and meningitis, strep pharyngitis)
2. Enterococcal infections
3. Spirochetes

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Penicillin V is administered

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orally

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Why can Penicillin V be administered orally

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1. modified side chain (phenoxymethyl penicillin)
2. makes it more stable in acidic condition and is better absorbed

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When is Penicillin V used

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less active against most microorganisms....used for minor infections

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Penicillin G Procaine AND
Penicillin G Benzathine

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provides a slow release from the injected area and allows a low persistent concentration of the drug - longer therapeutic effect

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Penicillin G procaine

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1. Given IM
2. Lasts several days
3. has local anesthetic effect
4. treats infections caused by Steptococcus pyogenes

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Penicillin G Benzathine

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1. Given IM
2. Lasts up to 26 days
3. has local anesthetic effect
4. treats streptococcal pharyngitis
5. provides satisfactory prophylaxis for rheumatic fever
6. treats syphilis

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Administration of Nafcillin and Oxacillin

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IV administration for serious systemic staphylococcal infections

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Nafcillin, Oxacillin, Methicillin dose adjustments

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doses do not need to be adjusted in renal disease but might need to be adjusted in liver impairment

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What makes Nafcillin, Oxacillin, Methicillin more resistant

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relatively resistant to destruction by staphylococcal B-lactamases due to a bulkier side chain (R group)

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What has caused the empirical use of Nafcillin and Oxacillin to drop

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MRSA

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Uses of Nafcillin, Oxacillin, Methicillin

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*Gram Positive cocci (Beta-lactamase producers*

1. skin infections
2. soft tissue infections
3. osteomyelitis
4. endocarditis

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Nafcillin, Oxacillin, Methicillin (Penicillinase Resistant Penicillins)

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Not effective against Gram Negative Aerobes

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First Generation Cephalosporins

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1. Cefazolin - parenteral
2. Cephalexin - oral

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Second Generation Cephalosporins

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1. Cefaclor - oral
2. Loracarbef - oral
3. Cefoxitin - parenteral
4. Cefuroxime - oral, parenteral
5. Cefprozil - oral

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Third Generation Cephalosporins

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1. Ceftriaxone - parenteral
2. Cefixime - oral
3. Ceftizoxime - parenteral
4. Ceftazidime - parenteral

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Fourth Generation Cephalosporins

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1. Cefepime - parenteral

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Fifth Generation Cephalosporins

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1. Ceftaroline - parenteral

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Mechanism of Action of Cephalosporins

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1. interfere with bacterial cell wall synthesis and are bactericidal

2. split in the beta-lactam ring structure destroys the activity

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Has the longest half life of all the cephalosporins

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ceftriaxone

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First and second generation cephalosporins

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1. do not have good penetration into the CNS
2. not recommended for meningitis or brain abscesses

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2nd generation cephalosporin Cefuroxime

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Does penetrate into the CNS but is less effective than 3rd generations...........not typically used for meningitis

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Generation of cephalosporins that doe enter the CNS and are used for meningitis

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3rd generation cephalosporins

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Cephalosporin that does not require dose adjustments in renal failure

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Ceftriaxone

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ADRs of Cephalosporins

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1. Hypersensitivity - urticaria, pruritis, angioedema
2. Bleeding disorders - prothrombin deficiency, thrombocytopenia, platelet dysfunction
3. Nephrotoxicity - synergistic with aminoglycoside
4. Superinfenction - GI
5. Seizures - higher doses in renal failure

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Immediate reactions with hypersensitivity of Cephalosporins

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1. urticaria
2. pruritis
3. angioedema
4. bronchospasm
5. maculopapular rash after several days
6. fever

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ADR of Cefaclor

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serum-sickness like reactions

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Alcohol with cephalosporins

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avoid - cause disulfiram-like reactions

should be avoided up to 72 hours after stopping the drug

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cephalosporin most likely to cause anticoagulation

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cefazolin

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most important resistance mechanism to cephalosporins

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destruction of the beta lactam ring

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Generation of cephalosporins that are inactivated by beta lactamase

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1st generation

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2nd generation ceph agent that is susceptible to breakdown by beta lactamase

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Cefaclor

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None of the cephalosporins are active against

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methicillin-resistant Staph aureus or Enterococci

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Very good activity against Gram Positive

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1st Generations (Cephazolin, Cephalexin)

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Gram Negatives that 1st Generation Cephalosporins are good for

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1. Proteus
2. E. Coli
3. Klebsiella

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drug of choice for surgical prophylaxis and still used

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Cefazolin

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Oral 1st Generation Cephalosporins are used

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1. Urinary Tract Infections
2. minor Staph infections
3. cellulitis and soft tissue abscess

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Gram Negatives that 2nd Generation Cephalosporins are good for

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1. Proteus
2. E.Coli
3. Klebsiella
4. H. Influenzae
5. Moraxella

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2nd generation cephalosporin CEFOXITIN

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activity against the anaerobe B. fragilis

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Clinical Uses for 2nd Generation Cephalosporins

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1. Sinusitis
2. otitis media
3. lower respiratory tract infection
4. peritonitis - mixed anaerobic infection
5. diverticulitis - mixed anaerobic infection

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3rd Generation Cephalosporin effective against Pseudomonas

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Ceftazidime

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3rd Generation Cephalosporins are good against

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Gram Negative Bacilli resistant to other generations

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Clinical uses for 3rd Generation Cephalosporins

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1. more serious infections that are resistant to other drugs
2. 1st line for gonorrhea (N. gonnorrhoeae)
3. Meningitis
4. Empirical therapy for Sepsis

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Listeria monocytogenes

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3rd generation cephalosporins are not useful against

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resistant against deactivation by plasmid and chromosomal beta lactamases

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4th generation Cephalosporin (Cefepime)

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Clinical uses of Cefepine (4th gen)

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*useful against Pseudomonas aeruginosa and enterobacteriaceae*

1. UTI - enterobacter
2. Penicillin-resistant Strep
3. Meningitis

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1st line Therapy for Gonorrhea

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a) Ceftriaxone 250mg IM + Azithromycin 1gm
b) Ceftriaxone 250mg IM + Doxycycline 100mg BID x7D