Week 4: Anti-Microbials Flashcards
Describe selective toxicity
ability of a drug to injure a target cell or target organism without injuring other cells or organisms in contact with the target
Selective toxicity is achieved by targeting _____________________
differences in cellular chemistry of microbes and mammals
Antimicrobials include __________, __________ and __________ drugs.
Antibacterial
Antifungal
Antiviral
What are some of the mechanisms of action employed by antimicrobials?
Inhibitors of cell wall synthesis: Penicillins, Cephalosporins, Imipenem, Vancomycin, Caspofungin
Drugs that disrupt the cell membrane
Inhibitors of protein synthesis
Drugs that interfere with DNA and RNA
Antimetabolites
Drugs that suppress viral replication
Describe the difference between bactericidal and bacteriostatic
bactericidal : directly lethal to bacterial
Bacteriostatic: slow bacteria growth but do not cause death – elimination of bacteria must ultimately be accomplished by immune system
There are two primary ways in which microbes can acquire drug resistance – what are they?
Spontaneous mutation – creates resistance to 1 drug
Conjugation – bacteria of different species can share DNA including R factors (resistance factors). R factors can be passed from normal flora to pathogens. Causes multiple drug resistances
What are some microbial mechanisms of drug resistance?
Reduction of drug concentration at site of action: cease active uptake of drugs or increase active transport
Alter structure of drug target molecules
Produce a drug antagonist
Cause drug inactivation. Ex. Bacteria produce enzymes that inactivate penicillin
True or false - there is no benefit to drug resistance unless drugs are present
True
Explain how antibiotics promote drug resistance.
Mutation and conjugation are random events. There is no benefit to drug resistance unless drugs are present. Antibiotics kill all but those that are resistant, remove the competition for resources and create selection pressure favoring overgrowth of resistant microbes
True or false - Broad spectrum kill more competing organisms than narrow spectrum and facilitate less antibiotic resistance
False
Broad spectrum kill more competing organisms than narrow spectrum and facilitate MORE antibiotic resistance
A secondary infection that develops during the course of treatment for a primary infection is called a ________
Superinfection
Goal of therapy is to provide maximal antimicrobial effects with minimal harm to host. What are some factors to consider in the selection of therapy?
the infecting organism
drug-sensitivity of the organism
host factors (1. Site of infection – difficult to get antibiotics across BBB, to abscesses, to heart vegetations. Also prosthetics cause phagocytes to focus on attacking them and make them less effective against pathogens. 2. host defenses – if immune system impaired the antibiotics may not be enough to save people ex. HIV, chemo)
In antimicrobial selection, what are factors that may require the use of second-line agents?
Allergy
inability of drug to penetrate site
heightened patient susceptibility to toxicity
Other considerations: age, pregnancy, breastfeeding
Typically it is preferable to use a single antimicrobial to avoid developing multidrug resistant microbes, what are some scenarios which multiple antimicrobials may be indicated for?
initial therapy of severe infection
mixed microbe infections
prevention of resistance in TB
decreasing doses to limit toxicity
synergistic responses
What are examples of situations where prophylactic antibiotics may be indicated?
Surgery: cardiac, peripheral vascular, orthopedic, GI, hysterectomy, emergency c-section, contaminated surgery (perforated abdominal organs, compound fractures, animal bites)
Bacterial endocarditis: patients with congenital or valvular heart disease are susceptible to bacterial endocarditis following dental procedures or anything that can release bacterial into the bloodstream
Neutropenia (controversial)
Women with recurrent UTI, exposure to STI organisms
What are some examples of misuse of antimicrobials?
Viral infections – patients get all the risks of the drugs and no benefits
Treatment of fever of unknown origin (exception: antibiotics indicated in severely immunocompromised patients with fever)
Treatment without identifying organism and testing sensitivity
Drugs that weaken the cell wall include ..
B-lactams (Penicillins and Cephalosporins)
Vancomycin
Telavancin
Fosfomycin
Penicillin drugs weaken the bacterial cell wall. What is the mechanism of action? Are they bactericidal or bacteriostatic?
Inhibition of transpeptidases – enzymes critical for cell wall synthesis – which disrupts synthesis of cell wall
Disinhibition (activation) of autolysins – bacterial enzymes that break down cell wall to permit growth – which actively destroys cell wall
Usually bactericidal
Penicillins bind to _____ on microbes.
Penicillin Binding Proteins (PBP) - which are only expressed during growth and division, therefore only active against bacterial under growth and division
How does bacterial resistance to penicillins occur?
Inability of penicillins to reach targets. Gram-negative bacteria have an additional outer membrane that some penicillins cannot penetrate
Inactivation of penicillins by bacterial enzymes – b-lactamases/penicillinases can be produced by bacteria to inactivate penicillins and other b-lactam drugs
Production of PBPs that have a low affinity for penicillins
Can you think of a famous example of a microbe that is resistant to penicillins?
MRSA – methicillin resistant staph. Aureus – resistant to all penicillins and most cephalosporins
Where is MRSA commonly found and what types of infections does it cause?
Often colonizes skin and nostrils of healthy people
Usually infects skin/soft tissues causing abscesses, boils, cellulitis and impetigo. Can cause fatal lung and bloodstream infections
How can we treat MRSA infections?
Healthcare associated HCA-MRSA usually treated with IV vancomycin, linezolid, daptomycin, telavancin, clindamycin, ceftaroline
Community associated CA-MRSA generally less dangerous than HCA. 20-30% of population is colonized. Causes many skin/soft tissue infections. Rarely causes necrotizing fasciitis, necrotizing pneumonia and severe sepsis. Usually treated with trimethoprim/sulfamethoxazole, minocyline, doxycycline, clindamycin.
True or false – Penicillins are broad-spectrum
False. Can be narrow or broad spectrum
Narrow spectrum penicillins, penicillinase sensitive: Penicillin G, Penicillin V
Narrow spectrum penicillins, penicillinase resistant (antistaphylococcal penicillins): Nafcillin, Oxacillin, Dicloxacillin
Broad-spectrum penicillins (aminopenicillins): Ampicillin, Amoxicillin
Extended-spectrum penicillin (antipseudomonal penicillin): Piperacillin
Penicillin G was the first penicillin. It is well distributed, undergoes minimal metabolism and is excreted by the kidneys mostly unchanged. Which pathogens are sensitive to Pen G?
Bactericidal to most gram-positive bacteria, gram-negative cocci, anaerobic bacteria and spirochetes
What is the primary adverse effect of Pen G?
The least toxic of all antibiotics and among the safest of all medications, allergic reactions are the principle concerns
True or false, penicillins are the most common drug allergy
True! Penicillins are the most common drug allergy. 0.4-7% of patients who receive penicillins experience an allergic reaction ranging from minor rash to anaphylaxis
Reactions can be immediate (2-30 minutes), accelerated (1-72 hours) or delayed (days to weeks)
Anaphylactic reactions are rare – incidence 0.004-0.04%, but they have a 10% mortality rate
True or false: patients can experience an allergic reaction to a penicillin even if they have never received a penicillin antibiotic
True! Prior exposure could occur from penicillins produced by fungi or present in foods of animal origin
True or false, patients allergic to one penicillin should not be considered allergic to all penicillins
False!
Patients allergic to one penicillin should be considered allergic to all penicillins. 1% display a cross-sensitivity to cephalosporins, more likely with a severe penicillin allergy
What is a difference between Pen G and Pen V?
Similar to pen G except is stable in stomach acid and can be used for oral therapy
Must be taken with food
What are the two broad spectrum Penicillins (Hint: they are Aminopenicillins)
Ampicillin: useful for enterococcus fecalis, proteus mirabilis, E. coli, salmonella, shigella and h.influenzae. More likely to cause rash and diarrhea than any other penicillin
Amoxicillin: similar to ampilicillin but more acid-stable, therefore preferred for oral therapy
Combination medications are available of Ampicillin/Sulbactam and Amoxicillin/Clavulanic acid. What is the benefit of these additives?
inhibitors of b-lactamases – decreasing inactivation and therefore resistance
There is one Extended-Spectrum Penicillin. It targets everything the aminopenicillins target and pseudomonas aerginosa, Enterobacter species, proteus species, bacterocides fragilis and many klebsiella species.
What is this drug? (Hint: we use it a lot in acute care in combination with a b-lactamase inhibitor)
Piperacillin/ Tazobactam
What do the drugs cephalosporins, vancomycin, telavancin and fosfomycin have in common with the penicillins ?
disrupt the bacterial cell wall and cause lysis and death
All are b-lactam drugs with the exceptions of vancomycin, telavancin and Fosfomycin
What is the most widely used group of antibiotics?
Cephalosporins
Outline the MOA of cephalosporins. (hint: similar to penicillins)
bind to PBPs - disrupt cell wall synthesis and activate autolysins causing death by lysis - Bactericidal
Most effective against cells undergoing active growth and division
What is the most common cause of resistance to cephalosporins?
Resistance most often caused by b-lactamases, sometimes referred to as cephalosporinases. 1st generation sensitive to b-lactamases, 2nd generation less sensitive, 3rd, 4th, and 5th generation highly resistant
Can also be caused by altered PBPs with low affinity for cephalosporins. Ex. MRSA resistant to most cephalosporins, except 5th generation Ceftaroline
True or False, cephalosporins are broad spectrum
True. 1st- 5th generation drugs, named in order of development
As progress from 1st to 5th there is increasing activity against gram-negative bacteria and anaerobes, increasing resistance to destruction by b-lactamases and increasing ability to reach CSF
Can you think of a few drug names in the cephalosporin family? (Hint, they all start with Cef-)
Listed by generation…
1st: Cefadroxil, Cefazolin, Cephalexin
2nd: Cefaclor, Cefotetan, Cefoxitin, Cefprozil, Cefuroxime
3rd: Cefdinir, Cefditoren, Cefixime, Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftriaxone,
4th: Cefepime, Ceftolozane
5th: Ceftaroline
True or false, Cephalosporins must be administered parenterally (IV or IM)
False. Many must be parenterally administered (IM or IV). 10 cephalosporins can be administered po, only one can be administered po or parenterally – cefuroxime
Outline the general pharmacokinetics of cephalosporins
Poor GI absorption
Distributes well to most tissues/body fluids except for ocular fluids. 1st and 2nd generation have low CSF penetration
Eliminated mostly by the kidneys. Reduce doses in renal insufficiency. Ceftriaxone is eliminated by the liver and does not require dose adjustment in renal insufficiency.
The primary adverse effect of cephalosporins is the same as penicillins, as they are all b-lactams. What is it?
Hypersensitivity reactions most common adverse reactions
Similar structure to penicillins, cross-sensitivity happens in 1% of patients allergic to penicillins. Safe for patients with mild penicillin allergies, unsafe for severe penicillin allergies
Well tolerated, one of safest groups of antimicrobials
All cephalosporins can promote c.diff infection
What are some drug interactions of note for cephalosporins?
Alcohol can dangerously interact with cefazolin and cefotetan
Cefotetan, cefazolin and ceftriaxone can promote bleeding as they contain a side chain that interferes with vit k metabolism and can inhibit the formation of clotting factors. Caution needed if given with other drugs that promote bleeding (anticoagulants, thrombolytics, NSAIDS, other anti-platelets) — INTERESTING – I often give ceftriaxone and anticoags and had no idea of this risk.
Penicillins, Cephalosporins and ________ are all b-lactam antibiotics
Carbapenems
Can you think of any carbapenems? (hint: they end in “-penems”)
Imipenem, meropenem, ertapenem, doripenem
Parenteral administration only
True or false, carbapenems are very broad spectrum, including coverage for MRSA
False – Carbapenems are very broad spectrum but none are active against MRSA
What is the MOA for carbapenems? (hint – same as penicillins and cephalosporins)
binds to PBP, cell wall weakening, lysis and death
Of note: resistant to b-lactamases, can penetrate gram-negative cell envelope.
Outline basic carbapenem pharmacokinetics
not absorbed by GI, IVonly, well distributed, including to CSF, primarily renal elimination – reduce dose in renal impairment
True or false, there are many serious adverse effects/drug reactions to be aware of for carbapenems
False
well tolerated, GI effects (nausea, vomiting, diarrhea)
Bacterial or fungal superinfections in 4% of patients
Cross sensitivity with penicillin allergies – 1%.
Drug reaction: reduces blood levels of valproate. Avoid combination or provide supplemental anti-seizure therapy
