S1B5 - Antibiotics: Mechanism of Action I & II Flashcards
Administering erythromycin to infants can cause what GI pathology?
Erythromycin in infants can result in hypertrophic pyloric stenosis, the proposed mechanism may be due to the gastrokinetic properties of erythromycin.
What antibiotic treats anaerobic infections below the diaphragm?
Metronidazole treats anaerobic organisms generally below the diaphragm. Contrast this with the indication for clindamycin, which is used to treat anaerobic infections above the diaphragm.
What is an example of a monobactam? What is its mechanism of action?
Aztreonam is the only monobactam commercially available. It is less susceptible to ß-lactamases and works by preventing peptidoglycan cross-linking by binding to penicillin binding protein 3.
When should vancomycin be used?
Vancomycin is reserved for serious, multidrug-resistant gram-positive organisms including
- MRSA
- S. epidermidis
- sensitive Enterococcus spp.
- C. difficile (via oral dose for pseudomembranous colitis)
What is the mechanism of action of macrolides? Is this bactericidal or bacteriostatic?
Macrolides bind to the 50S ribosomal subunit and blocks amino-acyl transpeptidation and translocation, and can be remembered with “macroslides.” Macrolides are bacteriostatic and acts to inhibit chain elongation and ultimately protein synthesis.
A patient with a postoperative ileus is started on intravenous erythromycin to enhance her gastrointestinal motility. Two days later, she develops the aberrant cardiac rhythm shown and is transferred to the ICU. Which is the likely explanation for these events?
A) Erythromycin-induced necrosis of the sinoatrial node
B) Aminoglycoside prolongation of her Q-T interval
C) Macrolide-induced 3rd degree heart block
D) Macrolide prolongation of her Q-T interval
E) Activation of an accessory cardiac pathway
Macrolide prolongation of her Q-T interval
Answer Explanation
Macrolides, especially erythromycin, are associated with QTc prolongation, which is the main risk factor for developing torsades des pointes (shown in this patient’s EKG).
What is the mechanism of resistance in Vancomycin-intermediate S. aureus?
VISA resistance to vancomycin occurs through the synthesis of an unusually thickened cell wall containing D-ala-D-ala.
How does VRSA achieve resistance against vancomycin?
Resistance to vancomycin occurs by D-ala-D-ala changes to D-alanyl-D-lactate or D-alanyl-D-serine.
What is the clinical use of penicillin G, V?
Mostly used for gram-positive organisms (S. pneumoniae, S. pyogenes, Actinomyces). Also used for gram-negative cocci (mainly N. meningitidis) and spirochetes (namely T. pallidum). Bactericidal for gram-positive cocci, gram-positive rods, gram-negative cocci, and spirochetes. Penicillinase sensitive.
What are the side-effects of cephalosporins?
Cephalosporins are generally well-tolerated. However some side effects can include
- Hypersensitivity reactions
- Vitamin K deficiency
- Disulfiram reaction
- Increased nephrotoxicity of aminoglycosides
- Hemolytic anemia
Describe the primary clinical role of penicillinase inhibitors.
Penicillinase inhibitors have negligible intrinsic antimicrobial activity, but are used in combination with penicillins to protect the antibiotic from destruction by ß-lactamase (penicillinase).
What is the function of the R-side group in penicillins?
In penicillin, the R-side group is variable, and different R-groups confer specificity and resistance to bacteria beta-lactamases.
What is the mechanism of action for the penicillins?
Bind penicillin-binding proteins (transpeptidases).
Block transpeptidase cross-linking of peptidoglycan in cell wall.
Activate autolytic enzymes.
What are common penicillin/penicillinase inhibitors combinations?
The common extended-spectrum penicillin and penicillinase inhibitor combinations include
- Amoxicillin - clavulanic acid
- Ampicillin - sulbactam
- Piperacillin - tazobactam
- Ticarcillin - clavulanic acid
Which side groups are modified in penicillins such as piperacillin and carbenicillin? What effect does this have on their spectrum of coverage?
Antipseudomonal penicillins rely on changes to their D-groups (not R-groups) to expand their coverage of Pseudomonas spp. These include
- Piperacillin
- Ticarcillin
- Carbenicillin
Which of the following is a contraindication to the use of erythromycin estolate?
A) Gout
B) Inhibition of prokaryotic 30S ribosomal subunit
C) Hypertension
D) Diabetes Mellitus
E) Hepatic disease
Hepatic disease
Answer Explanation
Erythromycin estolate is known to cause hepatic cholestasis. For this reason it is contraindicated in patients with liver dysfunction or liver disease. Erythromycin is not known to worsen the disease state in gout, diabetes mellitus, or hypertension.
A patient with severe, symptomatic gastroesophageal reflux disease despite maximal medical management is suspected of having a urinary tract infection. Which medication should not be prescribed?
A) Amoxicillin-clavulanate
B) Nitrofurantoin
C) Sulfamethaxole-trimethoprim
D) Moxifloxacin
Moxifloxacin
Answer Explanation
Fluoroquinolones are poorly absorbed in the setting of antacids and sucralfate. Given this patient’s severe GERD, it is likely that s/he is on either one or both. Another agent would be preferred as long as cultures indicate no bacterial resistance.
Are beta-lactams concentration dependent or time-dependent?
Beta-lactams are time-dependant
What are the toxicities and examples of aminoglycosides?
A mnemonic to remember the aminoglycosides, their toxicities and the fact that they do not cover anaerobes is “Mean GNATS caNNOT kill anaerobes”
Mean = Aminoglycosides
- Gentamicin
- Neomycin
- Amikacin
- Tobramycin
- Streptomycin
NOT = Toxicities
- Neuromuscular blockade
- Nephrotoxic
- Ototoxic
- Teratogen
What is the role of bacterial transpeptidases (penicillin binding proteins), and how are cephalosporins used to take advantage of their function?
Bacterial transpeptidases are important enzymes that cross-link peptidoglycan strands to create a thick peptidoglycan mesh layer. Transpeptidases are specific for the D-ala-D-ala sequence on peptidoglycan precursor strands. Cephalosporins mimic the D-ala-D-ala sequence and bind irreversibly.
What is the mechanism of linezolid?
Linezolid acts by inhibiting protein synthesis by binding to the 50S subunit and preventing formation of the initiation complex.
Which penicillinase inhibitor is often combined with ampicillin?
Sulbactam is an irreversible inhibitor that is combined with the aminopenicillin ampicillin (Unasyn).
Which drug is mainly used for anaerobes and C. diff?
Major uses of metronidazole include treatment or anaerobic infections, bacterial infections of the vagina, and treatment of Clostridium difficile infections.
What is the important thing that beta-lactam attaches to?
Beta-lactams attach to PBP (penicillin binding protein)
What’s the most important limitation to vancomycin therapy?
Limitations to Vancomycin Therapy
- Poor lung penetration
- Oral vancomycin is not absorbed systemically
- Creeping MIC’s of MRSA
What type of bacteria are fluoroquinolones used for?
Fluoroquinolones are used against
- Gram-negative bacilli of the genitourinary and gastrointestinal tracts (including Pseudomonas)
- Neisseria
- Legionella
- Gram-positive organisms
Describe 2 broad mechanisms of resistance to fluoroquinolones.
Mechanisms of resistance to fluoroquinolones occur via mutations in chromosomal genes or via acquisition of resistance genes on plasmids.
Why is cilastatin administered with imipenem?
Imipenem is rapidly degraded by the renal enzyme dehydropeptidase I, so it is always administered with cilastatin, a dehydropeptidase inhibitor.
What are bacterial targets of fifth generation cephalosporins?
Fifth generation cephalosporins (ceftaroline) have broad gram-positive and gram-negative organism covererage, however this class does not cover Pseudomonas. They are most notably used for
- Enteric gram-negative bacilli
- Penicillin-resistant pneumococci
- Oxacillin-resistant staphylococci
- Methicillin-resistant staph aureus (MRSA)
- Vancomycin-intermediate staph aureus (VISA)
What is the mechanism of action for daptomycin?
A) Binding 50S ribosomal subunit
B) Binding 30S ribosomal subunit
C) Hydrogen bond formation with bacterial N-acetylglucosamine
D) Hydrogen bond with bacterial N-acetylmuramic acid
E) Depolarization of bacterial cell membrane
Depolarization of bacterial cell membrane
Answer Explanation
Daptomycin, as a lipopeptide, rapidly depolarizes the bacterial cell membrane, leading to disruption of intracellular processes and cell death.
Carbapenems provide coverage against which gram-stain groups of bacteria? What organism is carbapenems the drug of choice for?
Carbapenems are ß-lactamase-resistant antibiotics that have a very broad activity against gram-positive and gram-negative bacteria. It is especially useful against resistant Pseudomonas, but no activity against MRSA or Enterococcus faecium. Considered to be the drug of choice for Enterobacter.
If a patient is about to undergo surgery (not abdominal), which antibiotic should prophylactically be given to prevent surgical wound infections?
Cefazolin is a drug of choice for antimicrobial prophylaxis for prevention of S. aureus surgical wound infection in adults.
Which has better Pseudomonas coverage, ciprofloxacin or levofloxacin?
Caveats
- Ciprofloxacin has better Pseudomonas coverage over Levofloxacin
- Moxifloxacin has better Streptococcus coverage than Levofloxacin
- Ciprofloxacin should not be used for community acquired pneumonia or outpatient pulmonary infections
- Unless severe beta-lactam allergy, these agents should be avoided in empiric therapy of urinary tract infections
How can bacteria be resistant to penicillin G, V?
Resistance
Penicillinase in bacteria (a type of β-lactamase) cleaves β-lactam ring.
What are the uses of tigecycline?
Covers MRSA, MDR-Acinetobacter, ESBL producing Gram negatives and VRE.
What are the adverse effects of quinupriston-dalfopristin?
Adverse Effects
- Hemolytic anemia, Pancytopenia
- Hyperbilirubinemia
Which is effective against C. diff and which isn’t?
- IV vancomycin
- Oral vancomycin
Treatment of Clostridium difficile
- IV Vancomycin – ineffective!!!
- Oral Vancomycin – this is the ONLY indication for oral vancomycin, it is not systemically absorbed, but concentrates well in the GI tract.
Name 4 bacteria that can be treated by second generation cephalosporins but not first generation cephalosporins.
Second generation cephalosporins (cefoxitin, cefaclor, cefuroxime) have broadened coverage over first generation, covering everything the 1st generation covers (“PEcK”) plus
- H. influenzae
- Enterobacter
- Neisseria spp.
- Serratia marcescens (“HENS”)
What ABX class is tigecycline structurally similar to?
Structurally similar to the tetracyclines, Tigecycline has a broader spectrum of activity than most agents in this class.
What bacterial organisms are susceptible to first generation cephalosporins?
First generation cephalosporins (cefazolin, cephalexin) are effective against most gram-positive cocci, penicillin-resistant pneumococci, and methicillin-susceptible staphylococci.
- First generation cephalosporins cover
- Gram-positive cocci
- Penicillin-resistant pneumococci
- Methicillin-susceptible staphylococci (MSSA)
- Proteus mirabilis
- Escherichia coli
- Klebsiella pneumoniae (“PEcK”)
What are the major adverse effects of beta-lactams?
Beta-lactam Adverse Effects
- Allergy/Rash/Anaphylaxis
- If severe reaction, avoid ANY beta-lactam antibiotics, with the exception of aztreonam
- Seizures
- Avoid Imipenem-cilastatin in patients with history of seizure
- GI upset
- All antibiotics can cause, including antibiotic induced diarrhea. Must rule out super infection any time diarrhea presents with antibiotic administration.
- Super Infection
- Clostridium difficile, NO ANTIDIARRHEALS!!!!!!!!!!
- Anticoagulant Issues
- Certain cephalosporins
- Drug Interactions
- Birth Control
A 43-year-old female marathon runner develops a urinary tract infection and is prescribed an antibiotic. Two weeks later, she feels a “pop” in her left heel and is unable to plantarflex her foot. Which antibiotic was she most likely given?
A) Sulfamethoxole-trimethoprim
B) Amoxicillin
C) Ciprofloxacin
D) Erythromycin
E) Doxycycline
Ciprofloxacin
Answer Explanation
Spontaneous tendon rupture is associated with fluoroquinolones, which include a “black box warning” regarding this adverse reaction.
Name one potential adverse effect of chloramphenicol therapy that occurs due to inadequate UDP-glucuronyl transferase activity (limiting pt’s ability to metabolize the drug).
Toxicities of chloramphenicol include
- Bone marrow suppression (dose-dependent), which may lead to aplastic anemia (rare, fatal—dose-independent)
- Gray baby syndrome, where the baby exhibits blue/gray skin, vomiting, shock. Babies (especially premature babies) cannot adequately metabolize chloramphenicol due to inadequate UDP-glucuronyl transferase activity in addition to insufficient renal excretion of unconjugated chloramphenicol
Following a prolonged ICU stay for multi-organism sepsis, a patient complains of a persistent “ringing” sound in her left ear. If this is an adverse reaction to a medication, which medication is likely responsible?
A) Pristinamycin
B) Daptomycin
C) Clindamycin
D) Erythromycin
E) Gentamycin
Gentamicin
Answer Explanation
A persistent ringing sound suggests tinnitus, which is a sign of ototoxicity. Of the medications listed, aminoglycosides are the most frequently associated with ototoxicity. Gentamicin is an aminoglycoside antibiotic. Other aminoglycoside antibiotics include:
- Amikacin
- Capreomycin
- Paromomycin
- Nebramycin
- Neomycin
- Netilmicin
- Streptomycin
- Tobramycin
Despite their “-mycin” suffix, the following antibiotics are not aminoglycosides:
- Macrolides such as erythromycin, clarithromycin, and azithromycin
- Lincosamides such as clindamycin and lincomycin
- Streptogramins such as pristinamycin
- Vancomycin
- Daptomycin
Ciprofloxacin resistance in gonococcal strains is highly prevalent. What mechanisms are responsible?
A) Both increased active transport of quinolones out of the cell and alterations to topoisomerase amino acid sequences
B) Alterations to topoisomerase amino acid sequences
C) Mutations of the cell membrane porins
D) Alterations to the 23S ribosomal RNA binding site
E) Increased active transport of quinolones out of the cell
Both increased active transport of quinolones out of the cell and alterations to topoisomerase amino acid sequences
Answer Explanation
Increased efflux and changes to the fluoroquinolone binding sites are both mechanisms of fluoroquinolone resistance.
Which carbapenem has a decreased risk of seizures and does not require cilastatin?
Meropenem has a decreased risk of seizures and is stable to dehydropeptidase I.
What is the MOA of Colistimethate (Polymixin E)?
MOA
- Binds to LPS and causes permeability of the cell envelope and allows leakage
What are tetracyclines usually used to treat?
Tetracyclines are used to treat many intracellular organisms due to its accumulation within the cell. Examples include
- Vector-borne (Borrelia burgdorferi, Rickettsial organisms)
- Atypicals (Mycoplasma, Chlamydia, Legionella)
- Ureaplasma urealyticum
- Acne
- Helicobacter pylori quadruple therapy
What is the main toxicity of carbapenems?
Toxicities of carbapenems include
- GI distress
- Skin rash
- CNS toxicity, which include seizures at high concentrations
What’s the main adverse effect of Daptomycin that you need to know?
CPK elevations.
When treating a patient with Daptomycin, you need to monitor CPK levels.
What factors account for the limited use of chloramphenicol in the United States? When is it used?
In the United States, chloramphenicol has limited use because of adverse effects, emergence of resistance, and availability of alternative antibiotics. Chloramphenicol is highly lipophilic, and is often used to treat Rocky Mountain spotted fever and meningitis caused by
- Haemophilus influenzae
- Neisseria meningitidis
- Streptococcus pneumoniae
What are the toxicities with linezolid use?
Toxicities of linezolid include
- Bone marrow suppression (especially thrombocytopenia)
- Peripheral neuropathy
- Serotonin syndrome
Aztreonam is synergistic with what group of antibiotics?
Aztreonam is synergistic with aminoglycosides.
Which has better Streptococcus coverage, Levofloxacin or Moxifloxacin?
Caveats
- Ciprofloxacin has better Pseudomonas coverage over Levofloxacin
- Moxifloxacin has better Streptococcus coverage than Levofloxacin
- Ciprofloxacin should not be used for community acquired pneumonia or outpatient pulmonary infections
- Unless severe beta-lactam allergy, these agents should be avoided in empiric therapy of urinary tract infections
What category of infections is daptomycin not effective against? Why?
Daptomycin is a cyclic lipopeptide and binds avidly to pulmonary surfactant, so it cannot be used in the treatment of pneumonia.
Dosing of aminoglycosides is carefully tailored to minimize nephrotoxicity.
How does the dosing schedule for aminoglycosides reflect the unique pharmacokinetics that aim to provide maximum efficacy, while preventing the development of nephrotoxicity?
Aminoglycoside nephrotoxicity is dose-dependent and toxicity relies more on trough levels, while peak serum concentrations are optimized for potential for efficacy. A once daily dosing regimen is recommended that aims at high peak serum concentrations, with low trough concentrations.
Describe the mechanism of action of doxycycline.
Tetracyclines are bacteriostatic and act by binding to the 30S bacterial ribosome subunit and preventing attachment of aminoacyl-tRNA.
What is the mechanism of resistance to chloramphenicol?
Mechanism of chloramphenicol resistance includes expression of chloramphenicol acetyltransferase (acetylating the antibiotic inactivates it).
What are the newer carbapenems (not imipenem)?
Newer carbapenems include
- Ertapenem (limited Pseudomonas coverage)
- Doripenem
- Meropenem
A 19-year-old female tests positive for gonococcal infection. She is prescribed a second generation cephalosporin. Which is the most appropriate?
A) Cephalexin
B) Cefuroxime
C) Cefazolin
D) Imipenem
E) Cefadroxyl
Cefuroxime
Answer Explanation
2nd-generation cephalosporins have better coverage of Neisseria than first generation cephalosporins. Of the answers, only cefuroxime is a 2nd-generation cephalosporin. Moreover, cefazolin is an IV formulation only, which would be excessive for outpatient gonococcal management. Imipenem is a carbapenem.
What are the major side effects of sulfonamides.
Toxicities of sulfonamides include
- Porphyria (sulfonamides are contraindicated in these disorders)
- Hypersensitivity reactions such as toxic epidermal necrolysis (Stevens Johnson syndrome)
- Kernicterus in infants
- Photosensitivity
- Hemolysis in G6PD patients
- Nephrotoxicity (tubulointerstitial nephritis)
- Displaces other drugs from albumin (e.g. warfarin)
- Crystalluria
What are the toxicities associated with metronidazole?
Toxicities of metronidazole include
- Disulfiram-like reaction (severe flushing, tachycardia, hypotension) with alcohol
- Metallic taste
- Headache
Which penicillinase inhibitor is often combined with amoxicillin?
Clavulanic acid is a suicide inhibitor that is combined with the aminopenicillin amoxicillin (Augmentin) or the antipseudomonal ticarcillin.
Name two aminopenicillins.
Aminopenicillins include ampicillin and amoxicillin. These act synergistic with aminoglycosides such as gentamicin.
Which fluoroquinolone should not be used for communitiy aquired pneumonia or outpatient pulmonary infections?
Caveats
- Ciprofloxacin has better Pseudomonas coverage over Levofloxacin
- Moxifloxacin has better Streptococcus coverage than Levofloxacin
- Ciprofloxacin should not be used for community acquired pneumonia or outpatient pulmonary infections
- Unless severe beta-lactam allergy, these agents should be avoided in empiric therapy of urinary tract infections
Which family of drugs has an adverse effect of a prolonged QT interval?
Some fluoroquinolones may prolong QT interval.
What antibiotic is added specifically for its ability to suppress toxin production in severe gram-positive infections?
Clindamycin is key in inhibiting toxin production in infections by gram-positives such as in scarlet fever and necrotizing fasciitis caused by S. pyogenes, and toxic-shock syndrome caused by S. aureus.
What risk factor increases the likelihood of tendon rupture with fluoroquinolone use? What other toxicities are associated with fluoroquinolones?
Toxicities of fluoroquinolones include
- GI upset
- Superinfections
- Skin rashes
- Headache
- Dizziness
- Spontaneous tendon rupture (with concomitant prednisone use or in people > 60 years old)
- Cartilage injury in neonates if given to pregnant women
- Cramps and myalgias in children
- Tendonitis
- Leg cramps
- Increase in QT interval
Monobactams provide coverage against which gram-stain groups of bacteria?
Aztreonam is used for gram-negative bacilli only, and has no activity against gram-positive or anaerobic organisms.
What bacterial species are targets of fourth generation cephalosporins?
Fourth generation cephalosporins (cefepime) have similar activity as third generation (broad-spectrum gram-negative coverage), plus effectiveness against gram-positive organisms and Pseudomonas aeruginosa.
What is the mechanism of action of metronidazole?
Metronidazole contains a nitro group that acts as an electron sink, capturing electrons and creating free radicals, resulting in cytotoxic intermediates that inhibit bacterial DNA synthesis.
What are macrolides most importantly used for?
Macrolides are used for
- Atypical pneumonias (Mycoplasma, Chlamydophila, Legionella)
- STIs (Chlamydia)
- Gram-postiive cocci (an alternative to streptococcal infections in patients allergic to penicillin)
- B. pertussis
- Mycobacteria
Describe the 3 mechanisms of resistance against sulfonamides.
Mechanisms of resistance of sulfonamides include
- Increased PABA synthesis (competitive inhibition)
- Mutation in bacterial dihydropteroate synthase
- Decreased uptake
What is the mechanism of resistance to aminoglycosides?
Mechanism of resistance to aminoglycosides include the presence of bacterial transferase enzymes that inactivate the drug by
- Acetylation
- Phosphorylation
- Adenylation
How do cephalosporins cause bacterial cell death?
Destruction of the peptidoglycan cell wall disrupts the bacterial cell’s osmotic stability and causes subsequent bacterial cell death
Are beta-lactams bacteristatic or bactericidal?
Beta-lactams are bactericidal, they effectively “kill” the bacteria by cell lysis.
If a patient is about to undergo abdominal surgery, which antibiotic should prophylactically be given?
A subset of the second generation cephalosporins is the cephamycin group (cefoxitin). Cephamycins are used for their activity against gram-negative gut anaerobes (usually given before abdominal surgery), which include
- B. fragilis
- E. coli
- Klebsiella
- Proteus
What organisms are typically not covered by cephalosporins?
Organisms typically not covered by cephalosporins can be remembered by the mnemonic LAME
- Listeria
- Atypicals (Chlamydia, Mycoplasma)
- MRSA (ceftaroline is the exception)
- Enterococci
Which penicillin-class antibiotic is most effective against Pseudomonas species?
A) Cefuroxime
B) Amoxicillin
C) Dicloxacillin
D) Nafcillin
E) Ticarcillin
Ticarcillin
Answer Explanation
Antipseudomonal PCNs (piperacillin, ticarcillin, carbenicillin) have altered D-groups that expand their coverage of Pseudomonas spp.
Nafcillin, while providing good coverage against MSSA (methicillin-sensitive S. aureus), does not provide good coverage against Pseudomonas. Cefuroxime is a cephalosporin, not a penicillin.
What is the mechanism of action of cephalosporins?
Cephalosporins inhibit bacterial transpeptidases (aka penicillin binding proteins, or PBP).
What is the cross-reactivity rate between monobactams and penicillins?
Monobactams have minimal toxicity and cross-reactivity with cephalosporins and penicillins, making them an alternative to penicillin-sensitive patients.
Name 2 serious toxicities of daptomycin.
Toxicities of daptomycin include rhabdomyolysis and myopathy.
How can you prevent red man syndrome from happening with vancomycin treatment?
Red man syndrome (can largely prevent by pretreatment with antihistamines and slow infusion rate).
An 87-year-old woman with S. pneumoniae pneumonia is found to have an erythromycin-resistant strain. What is the mechanism of the resistance?
A) Post-transcriptional methylation of the 30S subunit
B) Alterations to cell wall peptidoglycans
C) Pre-transcriptional methylation of the 30S subunit
D) Post-transcriptional methylation of the 50S subunit
E) Post-transcriptional methylation of the 50S subunit
Post-transcriptional methylation of the 50S subunit
Answer Explanation
Macrolides like erythromycin target the 50S subunit, preventing tRNA translocation. Resistance involves post-transcriptional methylation (in RNA, there is no such thing as “pre-transcriptional” methylation) of the macrolide binding site (which is actually the 23S rRNA subunit of the 50S ribosomal subunit).
Describe some of the potential side effects of macrolide toxicity. (Name at least 3).
Toxicities include MACRO:
- Motility issues by acting on the motilin receptors, thereby stimulating the smooth muscle of the gastrointestinal tract
- Arrhythmia caused by QT prolongation
- Cholestatic hepatitis
- Rash
- eOsinophilia
In addition, macrolides such as clarithromycin and erythromycin inhibit P-450, which increases serum levels of other drugs that are metabolized by CYP3A4 (e.g., coumadin, theophylline).
Gentamicin is ineffective against Bacteroides fragilis, a gram-negative anaerobe found in the colon. What explains this finding?
A) Gentamycin is ineffective against gram negative organisms
B) Bacteroides fragilis transports gentamycin out of the cell
C) Bacteroides fragilis uses a different ribosomal subunit
D) Bacteroides fragilis doesn’t uptake gentamycin
Bacteroides fragilis doesn’t uptake gentamicin
Answer Explanation
Aminoglycosides like gentamicin require oxygen for uptake and are thus more effective against aerobic organisms. They are ineffective against anaerobes.
What are the dosing strategies for beta-lactams?
Dosing strategies
- More frequent dosing
- Larger doses
- Continuous infusion (best)
Are aminoglycosides useful against gram-negative or gram-positive bacteria?
Aminoglycosides are useful against gram-negatives. Aminoglycosides are synergistic with some β-lactams (especially aminopenicillins or monobactams).
How are aminoglycosides administered?
Aminoglycosides are usually administered parenterally because of poor gut absorption. However, neomycin is an exception in that it is applied topically or ingested as an ammonium detoxicant.
Which 2 forms of -lysis occur in bacteria that are killed by penicillins?
Penicillins inhibits the ability of bacteria to generate a cell wall, which causes death by osmolysis. In addition, penicillins allow accumulation of peptidoglycan precursors, which activates bacterial autolysis.
What is the current indication for lipopeptide antibiotics?
Daptomycin is used for multi-resistant gram-positives such as
- VRE
- MRSA-related skin infections
- Corynebacteria
- Bacteremia from Staphylococcus aureus
- Right-sided infective endocarditis
What is the mechanism of chloramphenicol?
Chloramphenicol inhibits peptidyltransferase function of the 23S rRNA of the 50S ribosomal subunit, making the action bacteriostatic.
Which foods should not be taken with metronidazole?
A) Unpasteurized cheese
B) Alcohol
C) Fava beans
D) Grapefruit
Alcohol
Answer Explanation
Metronidazole + EtOH can lead to an unpleasant disulfiram-like reaction (nausea, flushing).
Which carbapenem does not cover Pseudomonas?
Carbapenems cover pseudomonas well except for Ertapenem.
What is the mechanism of action of aminoglycosides?
Mechanism of action of aminoglycosides include
- Binding to the 30S ribosomal subunit, causing irreversible inhibition of initiation complex
- Causing misreading of mRNA, leading to mistranslated proteins.
- Blocking translocation
What is the mechanism of action of penicillins?
Mechanism of penicillins is inhibition of penicillin-binding protein transpeptidase activity, which cross-links peptidoglycans and can eventually lead to suicide inhibition.
Name 2 toxicities of chloramphenicol.
Toxicities of chloramphenicol include
- Bone marrow suppression (dose-dependent), which may lead to aplastic anemia (rare, fatal—dose-independent)
- Gray baby syndrome, where the baby exhibits blue/gray skin, vomiting, shock. Babies (especially premature babies) cannot adequately metabolize chloramphenicol due to inadequate UDP-glucuronyl transferase activity in addition to insufficient renal excretion of unconjugated chloramphenicol
Why should tetracyclines not be taken with meals?
Tetracyclines bind strongly to divalent cations (Mg2+, aluminum, Fe2+, Ca2+) such as those found in antacids, which limits oral absorption so they are often not recommended with milk and food.
What microbes can be treated with clindamycin?
Lincosamides (eg, clindamycin, lincomycin) are useful against:
- Anaerobic infections above the waist (e.g. B. fragilis, C. perfringens) in aspiration pneumonia, lung abscesses, and oral infections.
- Gram-positives infections such as S. pyogenes infections, especially in penicillin-allergic patients
- Some protozoa such as Plasmodium spp.
What is the mechanism of bacterial resistance to cephalosporins?
Mechanisms of bacterial resistance to cephalosporins include structural changes in pencillin-binding proteins (transpeptidases).
A 16-year-old male with copious volume watery diarrhea after a camping trip is suspected of having a Giardia infection. Which antibiotic should be prescribed?
A) Metronidazole
B) Gentamicin
C) Ciprofloxacin
D) Polymyxin B
E) Piperacillin-tazobactam
Metronidazole
Answer Explanation
Metronidazole is used for some protozoal infections, notably Giardia and Entamoeba.
Describe 6 clinical indications for metronidazole.
Metronidazole indications can be remembered by the mnemonic GET GAP on the Metro:
- Giardia
- Entamoeba
- Trichomonas
- Gardnerella vaginalis
- Anaerobes (Bacteroides, C. difficile)
- H. Pylori (as part of triple therapy with proton pump inhibitor and clarithromycin)
Why would you not use tigecycline for bacterimia (blood infection)?
Tigecycline has a high volume of distribution.
A 29-year-old man presents with shortness of breath. His medical history is significant for recent incision & drainage of a staphylococcal abscess on his thigh. He was treated with an unknown antibiotic. His chest X-ray is shown. Labs included a WBC of 8,900 cells/mm3, and a hematocrit of 27%. A venipuncture sample of the patient’s blood is washed, and when the isolated erythrocytes are incubated with antihuman globulin, they form clumps. Which antibiotic was likely prescribed?
A) Norfloxacin
B) Oxacillin
C) Tetracycline
D) Clindamycin
E) Streptomycin
Oxacillin
Answer Explanation
If washed RBCs agglutinate when incubated with antihuman globulin (aka Coombs’ reagent), it is a positive direct Coombs’ test. In the setting of symptomatic anemia and recent new medication use, this suggests drug-induced hemolytic anemia. While almost any medication can cause hemolytic anemia, this reaction is classically associated with PCNs, cephalosporins, quinidine, and levodopa/methyldopa. The CXR shown is normal.
Describe 2 mechanisms of penicillin resistance in bacteria.
Resistance of penicillins comes from production of β-lactamases (“penicillinases”) that cleave the β-lactam ring, or changes to penicillin binding proteins (confers methicillin resistance in MRSA).
Which macrolide doesn’t increase serum levels of coumadin?
Azithromycin does not inhibit P-450.
What drug is Televancin similar to?
Vancomycin
What is an example of a lincosamide and what is its mechanism of action?
Lincosamides are a class of antibiotics that include clindamycin and lincomycin with multiple mechanisms of action:
- Lincosamides inhibits bacterial protein synthesis by specifically binding on the 50S subunit and affecting the process of peptide transfer (translocation).
- Clindamycin also suppresses peptidyltransferase activity.
Why are aminoglycosides ineffective against anaerobes?
Uptake of aminoglycosides is oxygen-dependent, which means aminoglycosides have no effect on anaerobes because they lack the uptake mechanism.
What is the primary drug of choice for PJP infections and Stenotrophomonas infections?
Clincal Uses (Sulfamethoxazole/Trimethoprim)
- Skin/Soft Tissue Infections
- Urinary Tract Infections
- PJP (formerly PCP) infections
- Agent of choice for Stenotrophomonas infections
What are the symptoms of gray baby syndrome?
Toxicities of chloramphenicol include
- Bone marrow suppression (dose-dependent), which may lead to aplastic anemia (rare, fatal—dose-independent)
- Gray baby syndrome, where the baby exhibits blue/gray skin, vomiting, shock. Babies (especially premature babies) cannot adequately metabolize chloramphenicol due to inadequate UDP-glucuronyl transferase activity in addition to insufficient renal excretion of unconjugated chloramphenicol
What are some examples of tetracyclines?
Examples of tetracyclines include
- Tetracycline
- Doxycycline
- Minocycline
What is the MOA of quinupristin-dalfopristin?
Quinupristin-dalfopristin
MOA
- Binds to 50s subunit of bacterial ribosomes. Synergistic: dalfopristin inhibits early phase of protein synthesis, quinupristin inhibits late phase. Individually they are bacteriostatic, but together are considered bactericidal.
What is the mechanism of action of daptomycin?
Daptomycin is a cyclic lipopeptide that functions to cause rapid depolarization of the cell membrane. This acts to cause disruption of protein, DNA, RNA synthesis and eventual cell death.
What are some examples of aminoglycosides?
Examples of aminoglycosides include (GNATS)
- Gentamicin
- Neomycin (used in bowel prep)
- Amikacin
- Tobramycin
- Streptomycin
Unless the patient has a severe beta-lactam allergy, which family of antibiotics should be avoided in empiric treatment of urinary tract infections?
Caveats
- Ciprofloxacin has better Pseudomonas coverage over Levofloxacin
- Moxifloxacin has better Streptococcus coverage than Levofloxacin
- Ciprofloxacin should not be used for community acquired pneumonia or outpatient pulmonary infections
- Unless severe beta-lactam allergy, fluoroquinolones should be avoided in empiric therapy of urinary tract infections
What are the clinical uses for quinupristin-dalfopristin?
Clinical Uses
- Gram-positive infections.
- Use has fallen with increased resistance and adverse effect profile.
What disease and etiology has never had resistance to the original penicillin and is still treated with it?
Penicillin
- Narrowest spectrum of all
- Group A strep (Strep Throat), Drug of Choice, never had resistance
What gram staining species is linezolid used against?
Linezolid is used against gram-positive species including MRSA and VRE.
Which penicillin drug has a better spectrum against gram-negative bacteria?
Aminopenicillin
- Better spectrum against Gram-negative bacteria
Name 4 toxicities of vancomycin.
Toxicities of vancomycin usage includes
- Nephrotoxicity
- Ototoxicity
- Thrombophlebitis
- Red man syndrome
Name the 4 primary toxicities of aminoglycosides.
Toxicities for aminoglycosides include
- Neuromuscular blockade
- Nephrotoxicity
- Ototoxicity
- Teratogen
An IV antibiotic is administered for a serious infection. The patient soon develops flushing and an erythematous rash across the face, neck and torso. What drug is responsible? What is the mechanism behind the patient’s reaction?
Red man syndrome is characterized by flushing, erythema, pruritus, and sometimes hypotension. The mechanism of red man syndrome is caused by a rapid infusion from the first dose of vancomycin caused by direct activation of mast cells, and it is not a IgE-mediated Type I hypersensitivity reaction. Slow infusion minimizes risk. Red man syndrome can also be caused by other antibiotics (e.g., ciprofloxacin, amphotericin B).
Which antibiotic class causes teeth discoloration in children?
Adverse effects of tetracyclines include photosensitivity and teeth discoloration in children. Tetracyclines are contraindicated in children, pregnant women, and breastfeeding women.
What is an important distinction of third generation cephalosporins compared to earlier generations?
Third generation cephalosporins (ceftriaxone, ceftazidime, cefotaxime) have broad-spectrum gram-negative coverage and can penetrate the CNS.
Why did Colistimethate (Polymixin E) stop getting used?
Because of the neurotoxicity.
Adverse Effects
- Neurotoxicity – has decreased with “cleaner product”
- Nephrotoxicity
What is the major limitation of tigecycline?
GI upset is a major limitation of Tigecycline, and has been associated with affecting dosing regimens.
Which penicillin derivative has the bulkiest R-side group?
A) Ampicillin
B) Carmenicillin
C) Amoxicillin
D) Penicillin G
E) Dicloxacillin
Dicloxacillin
Answer Explanation
Bulky R-side groups confer penicillinase resistance. The most penicillinase resistant PCNs are methicillin, dicloxacillin, and nafcillin.
Which tetracycline is safe to use in patients with renal failure?
Tetracyclines are relatively contraindicated in patients with renal failure, except doxycycline, which is fecally excreted.
What are general differences among different generations of cephalosporins?
There are 5 different generations of cephalosporins with varying properties and coverage. As a general rule, progressive generations migrate from gram-positive to gram-negative coverage.
Why is vancomycin ineffective against gram negative bacteria?
Vancomycin has no activity against gram negatives because the drug is too large to cross the outer cell membrane and inhibit the inner peptidoglycan.
Which penicillinase inhibitor is piperacillin often combined with?
Tazobactam is a irreversible inhibitor that is combined with antipseudomonal piperacillin (Zosyn).
How does having an positively-charged amino R-group affect penicillins?
Aminopenicillins have an positively-charged amino R-group, creating an extended spectrum. Aminopenicillins are still sensitive to penicillinase, so they are usually coupled with a β-lactamase inhibitor. The extended spectrum can be remembered by the mnemonic “ampicillin/amoxicillin HHELPSS kill Enterococci”
- Haemophilus influenzae
- Helicobacter pylori
- Escherichia coli
- Listeria monocytogenes
- Proteus mirabilis
- Salmonella
- Shigella
- Enterococci
Which antibiotic that targets the 50S ribosomal subunit is most closely associated with fatal aplastic anemia?
A) Chloramphenicol
B) Neomycin
C) Erythromycin
D) Clindamycin
E) Azithromycin
Chloramphenicol
Answer Explanation
Antibiotics that target the 50S subunit include: macrolides, clindamycin, streptogramins, chloramphenicol, and linezolid. Of these, only chloramphenicol is known for inducing aplastic anemia. Erythromycin can cause cholestatic jaundice. Clindamycin is associated w/ C. diff colitis. Neomycin is an aminoglycoside and therefore targets the 30S (not the 50S) subunit.
Name 3 commonly used macrolide antibiotics.
Examples include:
- Clarithromycin
- Erythromycin
- Azithromycin
What is the mechanism of macrolide resistance?
Mechanisms of resistance to macrolides occurs through post-transcriptional methylation of the 23S bacterial rRNA, a component of the 50s subunit.
What is the mechanism of resistance to linezolid?
Mechanism of resistance of linezolid includes point mutation of the ribosomal RNA.
What type of antibiotic are cephalosporins?
Cephalosporins are ß-lactam antibiotics that target a broad range of bacterial infections, from gram-negative to gram-positive.
Which antibiotic class inhibits dihydropteroate synthetase?
Sulfonamides act as competitive inhibitors of dihydropteroate synthase (DHPS). In bacteria, DHPS converts PABA into dihydrofolate (DHF), which is then reduced by dihydrofolate reductase (DHFR) into tetrahydrofolate (THF). Sulfonamides effectively deplete methionine, purines, and thymidine.
What microorganisms are targeted by third generation cephalosporins?
Third generation cephalosporins are used for
- Pneumococcal meningitis
- Enterobacteriaceae
- Gonorrhea from Neisseria spp.
- Haemophilus influenzae
- Disseminated Lyme disease
- Pseudomonas aeruginosa (ceftazidime only)
Name the 3 mechanisms of tetracycline resistance.
Mechanisms of tetracycline resistance include
- Tetracycline efflux
- Tetracycline modification
- Ribosomal protection (via soluble GTPase analogues)
What are some examples of fluoroquinolones?
Examples of fluoroquinolones include
- Moxifloxacin
- Levofloxacin
- Sparfloxacin
- Enoxacin
- Norfloxacin
- Ciprofloxacin
- Gatifloxacin
- Nalidixic acid (a quinolone)
What are the contraindications, if any, of cephalosporins?
Cephalosporins were contraindicated in patients with severe allergic reactions to other beta-lactams like penicillin. However, recent studies suggest that there is minimal cross-reactivity with penicillin allergy.
What is the molecular target of fluoroquinolones?
Fluoroquinolones are bactericidal and act by direct entry via cell membrane porins and inhibition of DNA gyrase (topoisomerase II) and topoisomerase IV.
Which antibiotic class mimics the structure of para-aminobenzoic acid?
Sulfonamides are chemically similar to PABA (para-aminobenzoic acid) and act as antimetabolites.
Which antibiotic is most associated with antibiotic-associated C. difficile colitis?
C. difficilis colitis classically linked to clindamycin use.
Which penicillin-class antibiotic has the broadest gram-negative coverage?
A) Ceftazidime
B) Carbenicillin
C) Nafcillin
D) Ampicillin
E) Dicloxacillin
Carbenicillin
Answer Explanation
Of the penicillins, carbenicillin has the broadest gram-negative coverage. Note, however, that Klebsiella and enterococci are often resistant.
Aminopenicillins have extended-spectrum coverage. These include ampicillin and amoxicillin. Ceftazidime, as a 3rd-generation cephalosporin, also has good gram-negative coverage, but it is not a penicillin.
How does having a bulkier R-group affect penicillins? What are some examples of these type of penicillins?
Bulkier R-group confers penicillinase resistance but a narrower spectrum and is used for penicillin-resistant S. aureus (not MRSA). These include
- Oxacillin (which has replaced the no longer manufactured methicillin)
- Nafcillin
- Dicloxacillin
