Cell Wall Synthesis Inhibitors Flashcards
Community-Acquired Pneumonia
What are the typical agents that cause it?
What are some atypical (not common) agents that cause it?
What is the treatment?
Typical: S. pneumonia, H. influenzae, M. catarrhalis, S. aureus
Atypical: Legionella, M. Pneumoniae, C. pneumoniae,
respiratory viruses
Treatment:
If patient is Healthy – you can use macrolides (these are 50S protein synthesis inhibitors) [Azythromycin-Clarithromycin] or doxycycline (30S subunit inhibitors).
Comorbidities – abx w/i 3 mos: Fluoroquinolones [Levofloxacin-Ciprofloxacin] or macrolide (or doxycycline) + beta lactam (amoxicillin ± clavulanic acid).
ICU (pseudomonas): Piperacillin-Tazobactam + FQ (cipro-levo) or AG
ICU (MRSA): vancomycin or linezolid
Acute Sinusitis
What causes it?
Treatment for symptomatic patients usually consists of OTC analgesics, systemic-topical decongestants, nasal corticosteroids, saline nasal lavage. However, If symptoms > 10 days or worsening, consider________.
If the patient has penicillin allergy consider_____.
Etiology
**Viruses are most common cause
-S. pneumoniae-H. influenzae-M. catarrhalis
1st choice: Amoxicillin
Recent abx: Amox-clav, FQ (2nd – 3rd Ceph*)
PCN allergy: Macrolides
Acute Bronchitis
Etiology
**Viruses are most common cause
Less common: M. pneumoniae, C. pneumoniae, Bordetella pertussis
Pharyngitis
Etiology
**Viruses are most common cause
S. pyogenes (most common treatable cause)
Acute Otitis Media
What causes it?
What is the first choice treatment?
What if there is Penicillin allergy?
If treatment with amoxicillin-clavulanate fails, what is the next option?
**Viruses are most common cause
S. Pneumoniae - H. influenzae - M. catarrhalis
Pyodermas
What causes it?
What is the treatment for MSSA infection?
What is the treatment for MRSA infection?
Etiology
*Methicillin-sensitive Staph Aureus (MSSA)
*Methicillin-resistant Staph Aureus (MRSA)
*Β-hemolytic Streptococci
Penicillins
Explain the general structure of penicillins:
They are a cysteine and valine condensation product.
Once in the body, the products of penicillins have different functions/properties that allows them to act differently.
Compounds with different R groups have different properties such as:
Amount of penicillin doses is given in _____, except for penicillin G, which can be expressed in ____.
Production (via fermentation process).
Semi-synthetic penicillins: Hydrolysis of side-chain with bacterial amidases to produce 6-amino-penicillanic acid followed by chemical addition of side chains, using acyl chlorides.
Compounds with different “R” groups have different properties including those that can:
–>Increase acid stability (in GI tract)
–>Decrease renal excretion, increase metabolic stability
–>Minimize bacterial resistance (since bacteria use β-lactamase or amidase to break penicillins)
–>Increase antibacterial spectrum by increasing bacterial penetration.
Early dosage of penicillin expressed in units. With advent of pure penicillins, this measure of penicillin quantity is outmoded. Used only for penicillin G. Amount of all other penicillins stated in mg. [1 mg Penicillin G = 1667 units OR 250 mg = 400,000 units]
Bacterial wall synthesis:
- The primary mechanism of antibacterial action of the penicillins involves inhibition of:
A.Beta-lactamases
B.Cell membrane synthesis
C.N-acetylmuramic acid synthesis
D.Reactions involving transpeptidation (affects cross-linkin of peptidoglycans by targeting transpeptidase, carboxypeptidase, and Penicillin binding proteing (PBP)
E.Porin insertion into membranes
Mechanism of action:
During bacterial cell wall synthesis, at what level do penicillins interfere?
Are penicillins bactericidal or bacteristatic?
At Stage 3, preventing cross-linking of peptidoglycan polymers occurring at the cell wall (inhibited by penicillins and cephalosporins [5]).
Penicillins are bactericidal to growing organisms. Lysis of spheroplasts depends on osmotic pressure difference between inner/outer environments. Satisfactory explanation for lysis is lacking.
Action of Penicillin G mainly confined to gram-positive organisms and gram-negative cocci, some spirochetes. Acts on gram-negative bacilli, but much higher concentrations required.
For penicillin actions, why are Penicillin Binding Proteins (PBPs) important?
How do penicillins inhibit transpeptidase enzymes?
In binding to PBP uniform?
What does “autolytic” activity refers to?
Penicillin Binding Proteins (PBPs)
β-lactam antibiotics have a complex mechanism of action. They acylate several bacterial proteins termed penicillin binding proteins (PBPs).
-PBPs include but are NOT LIMITED to transpeptidase enzymes (D-alanine carboxypeptidase, endopeptidase). Penicillins inhibit these enzymes by an **irreversible covalent interaction.
Particular β-lactam antibiotics bind to distinct PBPs. Binding is NOT uniform. The antimicrobial spectrum of action of certain β-lactam antibiotics is distinctive and related to their binding to some but not all PBPs.
–Autolytic Activity. The presence of endogenous autolytic enzymes (murine hydrolases) is required for bactericidal lytic effect. β-lactams “trigger” this activity by depressing the natural inhibitory action of autolysins.
Kinetics of penicillin bactericidal action. Penicillin may also activate autolytic action of enzymes. Why is this relevant to clinical use?
–>Effect persists when drug is gone as penicillin exerts a persistent injurious action due to its covalent binding to bacterial proteins
–Maximal killing rate is a function of the growth rate of the organism****
Resistance to penicillins:
What are the different ways resistance can occur?
What is a B-lactamase? What stimulates their production by bacteria?
Alteration of PBP is important since it prevents binding of penicillin to its targets. This is notoriously seen in____.
Production of penicillinase enzyme occurs via a plasmid.
- Production of the β-lactamase is induced in the presence of penicillin. May be transmitted to sensitive organisms by bacteriophages (transduction).
Major problem with staphylococcus***.
NOTE: β lactamase is the generic term for enzymes that hydrolyze β-lactams, includes penicillinases and cephalosporinases.
- Another problem is alterations in penicillin-binding proteins. Responsible for methicillin resistance in staphylococci (MRSA) and penicillin resistance in pneumococci.
- Inability to penetrate into the bacterial cell. E.g., penicillin G can’t enter many gram-negative bacteria (e.g., Pseudomonas) due to presence of outer membrane.
- “Escape or Persisters. Metabolically inactive organisms or “L” forms can survive in a hypertonic environment like the kidney.
Resistance to penicillin:
Beta-Lactamase inhibitors
Resistance to penicillin:
Resistance to penicillins:
Resistance to penicillins:
In what kind of organisms is it found?
Allows passages of what kind of compounds?
Resistance to penicillins:
Pharmacokinetic properties of penicillins:
Absorption
Why does chemical modification of R groups improves absorption? What are some examples?
Penicillins are moderately strong acids. Highly water-soluble. Acid-lability impairs oral absorption of many types of penicillin (penicillin G [about 20%], methicillin, carbenicillin, ticarcillin).
Thus, optimal absorption from an empty stomach (1 hr ac or 2 hrs pc). Oral doses must be much higher than parenteral doses for penicillin G.
–Chemical modification of R-group improves absorption by increasing acid stability (amoxicillin, penicillin V).
-Rapidly absorbed from IM parenteral sites. Use of insoluble salts to reduce absorption and extend duration of action. For example, procaine penicillin G and benzathine penicillin G.
Distribution of penicillins:
What type of tissues can they enter more readily than normal?
Distribution
Distribute throughout body. Penetrate into tissues poorly (largely ionized at physiological pH). Highest concentration in liver, kidney, skin. Variable binding to plasma proteins.
Can enter inflamed tissues or membranes (CSF, joint, eye) more readily than normal.
Metabolism of Penicillins:
Most excretion (90%) is by ______.
What can prolong duration of activity by blocking secretion of penicillins?
Metabolism - Excretion
Most penicillins excreted as active drug via the kidney (t1/2 < 1 hr).
90% by tubular secretion
Blocked by **probenecid (can prolong duration of activity).
Metabolism often increases to compensate in cases of renal failure (oxacillin-type).
**Excreted in breast milk (consider risk / benefit in use).
Individual Penicillins
Prototype Penicillins
Narrow or wide spectrum?
Penicillin G is limited to what patients? Given via what route? Is it hydrolyzed by acid and peninillinase?
Penicillin V is given mostly via what route? Efficacy less or more than Penicillin G?
Relatively narrow spectrum of antimicrobial activity.
–Penicillin G (Benzyl penicillin) [Pen G Benzathine: Bicillin, Permapen, Pen G Procaine: Wycillin, Crysticillin]. The prototypical penicillin. Powerful and inexpensive. Previously penicillin of choice in most circumstances, but use today limited to hospitalized patients with serious infections given via the parenteral route. However, hydrolyzed by acid and penicillinase enzyme. About 30-50% bound to plasma protein.
–Acid resistant penicillin: Penicillin V (Phenoxymethyl penicillin) [PenVee K, V-Cillin]. Better absorbed than penicillin G, but still incompletely absorbed. Many prefer Penicillin V for oral therapy because of higher reliability of absorption. Antimicrobial efficacy generally less than penicillin G but still suitable for many mild-to-moderate infections.
Individual penicillins
Penicillinase-resistant penicillins
Are they more potent than penicillin G? When are they used?
Apart from being penicillinase-resistant, are they resistant to acids?
Eliminated via what routes?
In general order of efficacy (greatest first, but efficacy will vary depending on the particular organism): Methicillin [obsolete] > Nafcillin (parenteral, erratic oral) > Oxacillin (oral) > Cloxacillin (oral) and Dicloxacillin (oral).
Considerably less potent against Penicillin G-sensitive organisms. Not substitutes for penicillin G, except when penicillinase-producing organisms are encountered (but emergence of MRSA has greatly limited current clinical use). Variable protein binding, high with oxacillin, cloxacillin and dicloxacillin.
NOTE: Acid resistance varies among the penicillinase resistant penicillins as noted above. These penicillins are less susceptible to β-lactamase than are the cephalosporins.
As a group the isoxazole penicillins are eliminated by both **renal and **hepatic routes improving their safety profile in patients with renal insufficiency.
All are relatively narrow spectrum agents: Gram-positive, gram-negative cocci.
Individual Penicillins:
Extended Spectrum Penicillins
What gives them an increased hydrophilicity?
Amoxicillin and ampicillin have additional activity against gram-negative______.
Are they acid resistant? What about penicillinase?
What can be given along with amoxicillin and ampicillin to increase their efficacy?
Anti-pseudomonal penicillins such as ____ and ___ must be given parenterally. Are they resistant to pecinillinase?
Extended Spectrum Penicillins
- Increased hydrophilicity [due to NH2 or COOH] –> penetration through porins of gram-negative organisms
- NOT penicillinase-resistant –> thus given w/β-lactamase inhibitors.
Amoxicillin and Ampicillin
- Acid resistant, good oral absorption
- Amoxicillin absorbed better –> less frequent dosing-diarrhea
Piperacillin and Ticarcillin - anti-pseudomonal penicillins
- Must be given parenterally**
- Useful in anaerobic infections caused by B. fragilis
- Effective against Pseudomonas and enterococci (+ AG)
- Select the FALSE statement concerning use of ampicillin:
A.Antibacterial activity is enhanced by sulbactam
B.Causes maculopapular rashes (true it causes hypersensitivity reactions, rash, pseudomembranous colitis).
C.Drug of choice for Listeria monocytogenes infections (HHELPS: H. influenza, H. pylori, E. Coli, Listeria monocytogenes, Proteus mirabilis, Salmonella, Shigella, enteroccoci).
D.Eradicates most strains of methicillin-resistant Staphylococcus aureus
May cause pseudomembranous colitis with extended use
Spectrum and clinical uses of penicillin:
Spectrum and clinical uses of penicillins:
Antipseudomonal penicillins
B-lactamase inhibitors
Gram-positive bacilli
Toxicity and adverse reactions of penicillins:
Other Toxicities
Rarely, encephalopathy or seizures can occur with intrathecal penicillin or massive parenteral doses of penicillin, especially if associated renal insufficiency.
Beware of potassium or sodium intoxication when massive doses of salts and penicillin are administered parenterally. Especially a problem if renal insufficiency or CHF.
Jarisch-Herxheimer reaction during treatment of syphilis (via spirochetal antigens).
Look at penicillins
Vancomycin
MOA:
Structure / Mechanism of Action:
Tricyclic glycopeptide acts by inhibiting cell wall synthesis at site different from penicillin (blocks linear polymerization, Stage 2 of cell wall synthesis).
•Stage 2 –> blocks glycopeptide polymerization via binding tightly to D-alanyl-D-alanine portion of cell wall precursor
Resistance to Vancomycin
Vancomycin antimicrobial spectrum:
For what situations is it used?
For clostridum difficile, which is the 1st choice if not severe infection?
-Use reserved for situations when less toxic agents are ineffective or not tolerated (e.g., penicillin allergy).
Gram positive cocci
Methicillin Resistant Staphylococcus Aureus (MRSA) –> severe skin and soft tissue infections.
Staphylococci and streptococci –> meningitis, pneumonia, endocarditis, sepsis
Enterococci –> (**ampicillin resistant) –> bacteremia, endocarditis
Anaerobes
**Clostridium difficile –> pseudomembranous colitis [vancomycin is used orally - parenteral route does not deliver to GI tract]; **metronidazole 1st choice if NOT severe infection.
Vancomycin adverse reactions:
Adverse Reactions
Chills-fever-skin rash (infusion-related-pretreat with acetaminophen/diphenhydramine)
***Ototoxicity most severe.
More highly purified preparations now available display fewer adverse effects
Daptomycin
How does it lead to bacterial death?
It is active against methicillin and vancomycin resistant strains of staphyloccoci such as_______ and _______.
Need to reduce dose if____.
Mechanism. Action at bacterial membrane and loss of intracellular ions leading to cell death.
B.Pharmacokinetic Properties. Given once daily via infusion; reduce dose if CrCl < 30 ml/min
C. Antimicrobial Spectrum / Clinical Syndrome. Active against methicillin and vancomycin resistant strains of staphylococci (MRSA and VRSA) and vancomycin resistant enterococci (VRE).
***An option for treatment of severe purulent skin and skin structure infections (MRSA).
D. Adverse Reactions: Minor side effects (GI disorders, fever, HA, dizziness).
Lipoglycopeptides
Cephalosporins
Relative to penicillins G and V, cephalosporins have:
Classification of Cephalosporins:
1st generation
First Generation: Cefazolin (Ancef), Cefadroxil (po-Duricef), Cephalexin (po-Keflex)
Effective against many gram-positive cocci (except low activity against enterococci and methicillin-resistant staphylococci) commonly found on the skin, gram-negative cocci, and some gram-negative bacilli (Proteus, E. coli, Klebsiella). Rarely drugs of first choice. Antibacterial spectrum like amoxicillin.
I **More stable than penicillins to many beta-lactamases.
Cefazolin is now the prototype for reasons of cost, lower toxicity, good penetration into most tissues and lengthened t1/2 (90 min)
Compared to penicillin G and later generation cephalosporins, the first generation cephalosporins have greater activity against S. aureus (MSSA).
2nd Generation
Second Generation: Cefuroxime (Zinacef, po-Ceftin), Cefotetan (Cefotan), Cefoxitin (Mefoxin), Cefprozil (po-Cefzil), Cefaclor (po-Ceclor).
Maintain gram positive coverage similar to 1st generation agents, but greater activity against gram-negative bacteria (Hemophilus influenzae, M. catarrhalis, Neisseria species), especially respiratory pathogens. Little or no activity against Pseudomonas species.
Increased spectrum of activity is attributable to increased penetration of gram-negative envelope and increased affinity for penicillin-binding proteins
Active against cefazolin (1st generation)-resistant strains of E.coli, Klebsiella, Proteus mirabilis
Active against anaerobes, including Bacteroides fragilis: – cefoxitin, cefotetan
3rd Generation
Third Generation: Cefdinir, (po-Omnicef), Cefotaxime (Claforan), **Ceftriaxone (Rocephin), Cefotaxime (Claforan),Ceftazidime (Fortaz), Cefixime (po-Suprax), Cefpodoxime (po-Vantin).
Maintain varying degrees of gram positive coverage, excellent activity against pneumococci (cefotaxime and ceftriaxone)
Compared with 2nd generation agents, they have expanded gram negative coverage. More active against enteric gram-negative bacilli; also Enterobacter, Hemophilus, Neisseria
Ceftazidime has moderate antipseudomonal activity, but much less active against gram +
4th and 5th generation
Cephalosporins antimicrobial spectrum
Cephalosporin antimicrobial spectrum
- A major distinction between 1st and 3rd generation cephalosporins is:
A.3rd generation agents have less activity against Pseudomonas
B.3rd generation agents have increased activity against chlamydia
C.1st generation agents have increased penetration into the CNS
D.3rd generation agents have increased activity against resistant gram-negative organisms
E.1st generation agents have greater activity against methicillin-resistant Staphylococcus aureus
Cephalosporins antimicrobial function:
.A 65-year-old man with a 2-day history of sore throat, nasal congestion, and cough comes to your office because his wife told him he needs to take an antibiotic. You could tell him that:
A.He should be treated with a single IM injection of ceftriaxone (Rocephin)
B.He should be treated with 5 days of azithromycin (Z-Pak)
C.Most cases of acute sinusitis and pharyngitis are viral and should not be treated with antibiotics
D.He should be treated with oseltamivir for 5 days
Cephalosporins adverse reactions:
