IP 4 test 1 antibiotics
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Terms in this set (131)
- The gram negative cell wall consists of an Outer membrane (OM), peptidoglycan, and a plasma membrane.
- Due to the OM, certain drugs cannot pass through the cell wall. This is because the OM is a permeability barrier.
- Periplasmic space is where enzymes are stored.
- OM is where a lot of endotoxins are formed
- Due to the OM, certain drugs cannot pass through the cell wall. This is because the OM is a permeability barrier.
- Periplasmic space is where enzymes are stored.
- OM is where a lot of endotoxins are formed
- Gram stain (crystal violet) is a substance that selectively stains the cell walls of Gram-positive bacteria but is easily washed away from Gram-negative bacteria.
- Gram negative bacteria have an outer membrane of lipopolysaccharide that blocks stain from adhering to the peptidoglycan within the cell.
- Gram positive gram stain = blue
- To detect gram negative we stain with a red stain known as safranin.
- Gram negative bacteria have an outer membrane of lipopolysaccharide that blocks stain from adhering to the peptidoglycan within the cell.
- Gram positive gram stain = blue
- To detect gram negative we stain with a red stain known as safranin.
They are involved in the adaptive immune response and comprised of B and T cells among others.
- Viral infections
- Atypical lymphcytes
+ CMV
+ EBV
+ Toxoplasmosis
- Low in AIDS
- B lymphocytes - secrete antibodies
- T lymphocytes - mature in thymus gland; bind to to are involved in cytotoxic immunity - cell mediated immunity
- Natural killer cells - involved in killing cells that are infected with viruses
- Viral infections
- Atypical lymphcytes
+ CMV
+ EBV
+ Toxoplasmosis
- Low in AIDS
- B lymphocytes - secrete antibodies
- T lymphocytes - mature in thymus gland; bind to to are involved in cytotoxic immunity - cell mediated immunity
- Natural killer cells - involved in killing cells that are infected with viruses
What is the role of neutrophils?- Removal of debris / Removal of dead cells / Phagocytosis (ingesting bacteria)
- Bacterial infection
- Bands (developing neutrophils)
- Low in sepsis/drug reactions: when bacteria infects the body, the infections will proceed so quickly that neutrophils will be chewed through faster than they can be produced.What are the roles of bands?- developing neutrophils
- strong indicator of active sepsis infectionsWhat is the role of basophils?- found in bone marrow
- essential white blood cells
- secrete inflammatory mediatorsWhat is the role of humoral immunity?- factors that mediate the immune response were found in the humors (lymph nodes, serum, plasma)
- B-lymphocytes differentiate into plasma cells that secrete antibodies or become memory cells that interact with a specific pathogen that reacted to its surface immunoglobulin.
- Binding of a pathogen to the B- lymphocyte cell sig triggers production of IgA, IgD, IgE, IgG, or IgMWhat is the role of cell-mediated immunity?- T-lymphocytes are activated and specially designed to carry out cell-mediated immunity. They target intracellular infections, such as those caused by viruses.What is the role of innate immunity?- Immunity that exists without additional interventions
- First layer of defense - Includes skin, respiratory tract, mucous, cilia
- Second layer of defense - Phagocytes recognize, internalize, and digest pathogens using reactive oxygen species and digestive granules. Phagocytes include monocytes/macrophages, neutrophils, mast cells and eosinophils.
- Third layer of defense - Interferons cause cellular changes to help fight off viral infections (THE VIRUSES ARE COMING!)What are the most clinically significant gram positive pathogens?- Cocci
- Streptococci, Staphylococci, EnterococciWhat is catalase?- An enzyme that converts H2O2 into water and oxygen
- Some gram positive bacteria produce catalase to detoxify the ozonization process
- Present in Staphylococci not StreptococciWhat is a coagulase test?- Tests for the conversion of fibrinogen to fibrin, which walls bacteria from immune response
- Coagulase builds a suit of armor around Staphylococcus aureus so that it can travel through bloodstream and cause further infectionsWhat are the most important gram negative bacteria?BacilliPeptococcus/Peptostreptococcus- Gram positive cocci
- Anaerobic
- Ferment sugars after eating
- streptococci
- generally well covered with penicillin G or penicillin VKStaphylococcus aureus- Gram positive cocci
- Clusters
- Catalase +
- Coagulase + (due to this it is the only staph that has the potential for systemic infection)
- pneumonia, sepsis, skin infectionsStaphylococcus epidermidis/staphylococcus saprophyticus- Gram positive cocci
- Clusters
- Catalase +
- Coagulase -
- Skin infectionsStreptococcus viridans/Streptococcus pneumoniae- Gram positive cocci
- pairs/chains
- Catalase -
- alpha-hemolysis (green)
- pneumoniae - pneumonia, sensitive to optochin; waxy because of capsule; If the antisera has antibodies that bind to the capsule, the S. pneumoniae cells will swell due to an agglutination reaction.Streptococcus pyogenes/Streptococcus agalactiae- Gram positive cocci
- pairs/chains
- Catalase -
- beta-hemolysis (clear)
- pyogenes - skin infections and pharyngitis
- agalactiae - neonatal infectionsEnterococcus faecalis/Enterococcus faecium- Gram positive cocci
- pairs/chains
- Catalase -
- non-hemolysisClostridium- Gram positive bacilli
- Anaerobic
- difficile cause severe infections of the intestinal tract
- spp - necrotizing wounds, enterocolitisHACEK organisms- Gram negative bacilli
- aerobic
- Fastidious
- colonies the oropharynx
- associated with endocarditis 10% of casesWhat are morphological traits of Staphylococcus spp.?- Gram positive
- Spherical
- bunch like grapes
- Part of normal microbiota
+ GI tract
+ Respiratory
+ skin (S. Epidermis)
- Nonmotile
- Non-spore forming
- capsulated
- biofilm possible
- Catalase +
- Coagulase + only for S. aureusWhat is the role of protein A in S. aureus virulence and infection?- It is a cell wall component of S. aureus and surface protein that is part of the adhesions.
- Binds to the Fc portion of IgG molecules (except IgG3)
- The Fab portion of the IgG bound to protein A binds to a specific antigen.
- It can bind to the Fc domain of IgG and, therefore, inhibit opsonization that precedes phagocytosis.
- Furthermore, it can induce apoptosis in B-cells by binding to the Fab regions of the B-cell receptor and act as a B-cell superartigen.What is the role of Staphylocoagulase?- It activates fibrinogen into fibrin. It combines with thrombin to make Staphylothrombin molecule.
- This promotes clumping of Staphylococcus aureus into aggregates to form vegetations.
- These vegetations can form on the heart valves in endocarditis infection.What is the role of clumping factor in S. aureus?- Clumping factor binds to fibrinogen nonenzymatically, causes clumping and platelet aggregation
- Clumping factor is important for immune evasion
- Results in strong immunogenic response and has been the target of vaccine efforts.Describe the role of blaZ in penicillin resistance for MSSA.- blaZ is a chromosommally encoded beta lactamase in Methicillin Susceptible S. Aureus (MSSA) that hydrolyzes many penicillins.
- It catalyzes the opening of the beta lactam bond destroying the penicillin pharmacophore
- We can overcome blaZ or MSSA by using antistaphlococcal penicillins or combine penicillins with beta lactase inhibitors.
- Resistant to: penicillin G, Ampicillin, ticarcillin, piperacillinDescribe the role of mecA (PBP2a) in beta lactam resistance for MRSA.- Methicillin Resistant S. Aureus (MSSA) is resistant to most penicillins.
- The mecA gene encode a low affinity penicillin binding protein (PBP2a).
- PBP2a does not bind to penicillin or most cephalosporins, yet fully capable of assembling the cell wall.
- Resistant to: methicillin, naficillin, and oxacillin
- For gram positives altered penicillin binding proteins are the major resistant trait.Enterotoxins of S. aureus- Heat stable
- Resistant to degradation by gut enzymes
- Causative agents of food poisoning
- Emesis due to CNS stimulation after toxin binds to neural receptors in guttoxic shock syndrome toxin (TSST-1) of S. aureus- Enterotoxin type F, no food poisoning
- Multisystem disease for people with no antibodies to TSST-1
- Most common in young women who use tampons
- Fever, myalgia, vomiting, diarrhea, hypovolemic shock
- Desquamative skin rashExfoliative toxins S. aureus- Epidermolytic toxins (forms A and B)
- Cause skin erythema and separation
Produce scalded skin syndrome (SSSS)
- Part of a suite of lipases and hyaluronidase to strip back protective tissues
- Removes the protective skin coating to enhance spread of infection inside of the bodyWhat are the local skin/soft tissue infections caused by S. aureus?Folliculitis
Boils
Abcesses in any organ should be investigated for S. aureus
More common in diabeticsImpetigo (S. aureus)inflammatory skin disease with pustules that rupture and become crustedOsteomyelitis S. aureusinfection of the boneList symptoms of Staphylococcus aureus-induced endocarditis.- Infection of the lining of the interior of the heart or heart valve
- S. aureus endocarditis occurs in IV drug users, Contaminated needles, and Vegetation on tricuspid valve
- Hemodialysis recipients: Bacteremia and hematologous disseminationWhat is SCCmec in staphylococcus? What drug resistance genes does it encode?- SCCmec contains the broad spectrum beta lactam resistance encoded by mecA gene, which encodes PBP2a.
- SCCmec expresses drug resistance genes for clindamycin/erythromycin (erm), tetracycline (tet), staphylococcal penicillin (meca), and aminoglycosides (aac).
- Macrolids = erm (A), erm (C), msrA
- Tetracyclines = tetK and tetM
- Aminoglycosides = AAC(6')/APH(2')
- Staphylococcal penicillins = mecAExplain the mechanism of resistance for vancomycin in vancomycin-resistant Staphylococcus aureus.- Vancomycin resistance in S. aureus is encoded on an R factor(A transposable cassette that can be conjugated between different bacteria.)
- Due to altered cell wall precursor substrate
- VanA replaces D-ala-D-ala residues with D-ala-D-lactate. This causes 1000-fold lower binding of vancomycin.What is the drug of choice for MRSA?VancomycinvanHAX: Vanco resistance- Vanco binds to D-ala-D-ala that caps the peptidoglycan (5 H bonds)
- vanHAX
- vanH, vanX, vanA encode for dehydrogenase, ligase, dipeptidase that alter the D-ala, D-ala resides to D-ala, D-lactate (depsipeptide)
- vanH catalyses D-lactate synthesis
- vanA ligates D-lac to D-ala
- vanX cuts off D-ala-D-ala residuesD-zone test- If S. aureus is susceptible to clindamycin, there will be a halo effect around the clindamycin disk.
- If it has inducible resistance genes (erm genes - resistance to clindamycin and erythromycin), the erythromycin will induce the expression of the erm genes on the left side of the plate give rise to the formation of a D shape. Meaning: do not use clindamycin.What is Panton-Valentine leukocidin?- Pore forming toxin secreted by S. aureus that kills leukocytes
- Community acquired MRSA cases have type 4 SCCmec. It contains PVL which is very toxic. It lyse white blood cells by causing pore formation in the cellular membranes and increase cation permeability. It leads to massive release of inflammatory mediators, causing necrosis and severe inflammation.Why is one blood culture of S. aureus enough to warrant weeks of IV antibiotics?It shows a significant risk of endocarditis and because vancomycin gets such poor distribution to the heart values where the infection occurs.What are morphological traits for Streptococcus spp?- Gram positive
- Spherical
- Grow in pairs or chains
- Widespread, diverse bacteria
- Part of normal microbiota
+ Throat
+ Skin
+ Colon
+ Female genital tract
- Capsulated
- Lancefield antigens
- penicillins are very good against streptococcoi
- Facultatively anaerobicWhat are examples of group A streptococcus spp?S. pyogenes
- Beta hemolysis
- Common diseases: Necrotizing fasciitis, pharyngitis, rheumatic fever
- important traits: streptokinase, M protein, streptolysins, erythorgens
- susceptible to bacitracin
- can occur at site of minimal trauma or postoperative incisionWhat are examples of group B streptococcus spp?S. agalactia
- Beta hemolysisWhat are examples of group C streptococcus spp?S. dysgalactiae
- beta hemolysis (infectious)What are examples of Group D streptococcus spp?S. bovis
- No hemolysisS. pneumoiaeno grouping
- common disease: pneumonia, meningitis, endocarditis
- important traits: susceptible to optochin; quellung+Alpha hemolysin on blood agaroxidation of iron in hemoglobin, partial hemolysis results in green appearanceBeta hemolysin on blood agarComplete rupture of erythrocytes
Wide areas of cleared blood cells surrounding bacteriaGamma hemolysin on blood agarNo hemolysis on plate (nonhemolytic)Viridans group streptococci-found in upper respiratory tract/ throat
- They are optochin resistant and are not soluble in bile which distinguishes them from pneumococcus.
- Group D - streptococcus
- Viridans group streptocci are increasingly resistant to penicillin G or penicillin VK. (especially S. mitis group)
- Treatment (severe endocarditis) usually uses a penicillin + aminoglycoside (gentamycin)/or other synergistic drug.necrotizing fasciitis from Streptococcus spp- Extensive necrosis of skin, fascia.
- Can especially occur at site of minimal trauma or postoperative incision
- Prevention of spread of the S. pyogenes via surgical means
- PK/PD limitations of drugs do not always allow them to be first treatment option - hard to treat because blood vessels are destroyed. This means there is no way for drug to travel.Rheumatic fever from Streptococcus spp- Autoimmune disease that occurs after 2-3 wks after pharyngitis
- school aged kids/early adolescents
- molecular mimicry (type II hypersensitivity)
- Body still has antibodies from pharyngitis. Antibodies bind to muscle filaments in heart. This can lead to endocarditis.
- Clinical presentation: fever, rash, join pain swelling, Sydenham chorea (emotional instability, quick jerky movements of hands and face), heart valve disorders (arrhythmia), HFStreptococcal toxic shock syndrome- Disease of any organ associated with onset of shock and organ failure
- Associated with surgical procedures
- Supported with IV, fluids, antibioticsPuerperal fever and sepsis (Streptococcal)Initiated during or shortly after:
- Delivery of a newborn
- Abortion
Streptococcal colonization of the patient herself or transmitted from medical personnel:
- Septicemia
- Mother is often systemically illS. Pyogenes virulence factors- M protein: Hairlike antigenic structure, causes many episodes of infection
- Rhamnosyl-N-acetylglucosamine
- Protein F (like the coagulase of S. aureus)
- Protein G (prevents opsonization)
- Teichoic acid (adhesion to cells)
- Erythrogens (Cause scarlet fever)
- Streptolysins (Release lysosomal enzymes from host cells to destroy tissue)
- Various exotoxins( Cause toxic shock syndrome, proteases)
- Streptokinase: Converts plasminogen to plasmin, and lyses thrombus. Causes disseminationList and describe virulence proteins for Streptococcus spp.- M protein: Hairlike antigenic structure, causes many episodes of infection; no M protein antibodies - S. Pneumonia evades phagocytosis by polymorphonuclear leukocytes; inhibits the activation of alternative complement pathway; >150; also plays a role in S. pyogenes related to rheumatic fever
- Streptokinase
Converts plasminogen to plasmin, and lyses thrombus. Causes dissemination; plasminogen → plasmin (plasmin digest fibrin and other proteins); results in bacteria escaping from blood clots
- Streptolysins: lyse membranes of cells; Streptolysin O is only activated when it is in the reduced state (cysteines reduced to -SH); Inactivated in presence of O2.; Inactivated by antistreptolysin O; Streptolysin S is responsible for hemolytic zones around beta hemolytic streptococci.Streptococcus pyogenes capsules- Capsules are composed of hyaluronic acid and M protein - Also has M, T, R antigens, and carbohydrates
- Capsules impede phagocytosis
- Capsule binds to hyaluronic-acid-binding protein, CD44.
- Binding disrupts intercellular junctions
- Streptococcus remains extracellular as it progresses through epitheliumWhat disease does strep. pneumoniae cause?- Community acquired pneumonia (CAP): Most common bacterial cause in elderly patients
- Otitis media - most common bacterial disease in children
- Bacteremia/septicemia and sepsis
- Primary peritonitis
- Sinusitis (acute)
- Bacterial meningitis: Most common contemporary cause
Infections occurs:
- Endogenously - insufficient host response (immunocompromised patients are always at risk) - spleen significant defense
- Exogenously - transmission from aerosolized infected droplets
Treatment: detection by culture; bacterial agents; vaccinationstrep. pneumonia virulence factors- Capsules (antigenic and antiphagocytic; > 85 subtypes) vaccine target
- Autolysin - Cell lysis of S. pneumoniae and release internal factors
- Pneumolysin - causes cell lysis of host cell
- Pneumococcal surface proteins A (disrupt complement & iron activities)
- Pneumococcal surface proteins C (translocation across epithelial cells)How do you test for encapsulated strep?- Culture - waxy green Strep. pneumonia
- quelling reaction (swelling)
- optochin sensitivityWhat antibiotics are effective in covering MSSA?If the antibiotic covers MRSA, it covers MSSA. Although, this is not true when thinking backward (MSSA antibiotics do not cover MRSA).
- Linezolid (Zyvox®)
- Methicillin (IV)
- Nafcillin (IV)
- Oxacillin
- Cloxacillin (PO)
- Dicloxacillin (PO)
- Ampicillin/sulbactam
- Amoxicillin/clavulanate
- Piperacillin/tazobactam
- Ticarcillin/clavulanate
- Cefazolin
- Cephalexin
- Cefadroxil
- cefaclor
- Cefuroxime
- cefprozil
- cefoxitin
- cefotetan
- Cefepime
- Ceftaroline
- Vancomycin
- Telavancin
- Dalbavancin
- Oritavancin
- Tedizolid
- Tigecycline
- DaptomycinWhat are the antibiotics that are effective in covering MRSA?- Vancomycin
- Telavancin
- Dalbavancin
- Oritavancin
- Tedizolid
- Linezolid
- Tigecycline
- Daptomycin
- Ceftaroline Fosamil (only cephalosporin that covers MRSA)What are the ADME+toxicity properties for vancomycin?- Vancomycin has only one oral indication (C.Diff in GI tract) because oral absorption is extremely poor. Most administration is intravenously.
- Distribution: Vancomycin obeys 2 compartment pk; appears CSF with inflamed meninges, bile, pleural, pericardial, synovial, and ascitic
- Elimination: 90% of Vanco is eliminated via glomerular filtration; impaired in renal dysfunction; ADR = nephrotoxicity (esp with other aminoglycosides)
- Major ADR: vancomycin infusion reaction - IV administration can sometimes result in an erythematous rash or flushing. (not an allergic rxn)What is the MAO of vancomycin?- Binds to D-ala-D-ala residues of peptidoglycan in the cell wall (5 hydrogen bonds)
- inhibits the transpeptidase reaction by covering D-ala-D-ala residues so cell wall of bacteria cannot be cross linked and falls apart. The cell will die
- It is too large to cross the outer membrane of gram negatives.
SAR:
- Sugars: D-glucose and D-epivancoasmine make drug water soluble and enhances penetration (enhances potency)
- Six peptide linkages: These are crucial for binding to D-ala-D-ala residues
- Aryl ether bonds for peptide linkages add ridigity and strengthWhat is the MOA of telavancin?- Binds to D-ala-D-ala residues of peptidoglycan in the cell wall (5 hydrogen bonds)
- inhibits the transpeptidase reaction by covering D-ala-D-ala residues so cell wall of bacteria cannot be cross linked and falls apart. The cell will die.
- Also disrupts cell wall integrity (binds to both D-ala-D-ala residues and the cell membrane causing cell leakage and membrane rupture.
SAR:
- Lipophilic side chain enhances membrane binding activity and enhances half life.
- The phosphonomethyl group helps enhance renal clearanceWhat is the MOA of Dalbavancin?- Two dose regimen given weekly (1000 mg first week, 500 mg second week)
- Lipoglycopeptide approved for ABSSSI (Same MOA)
- t1/2 of 8.5 days.
- Renal impairment requires dosage adjustmentWhat is the MOA of Oritavancin?Three mechanisms of action:
- Inhibits transglycosylation by binding to peptide residue
- Inhibits transpeptidase reaction by binding to bridging segments of cell wall
- Disrupts membrane integrity through binding of chlorobiphenylmethyl group
- Single dose regimen (1200 mg dose)
- Covers MRSA, Enterococcus, and C. difficile (even VRSA and VRE!)
Resistance is rareWhat is the MOA of linezolid?- Linezolid binds to initiation complex of ribosome (binds at 50S site)
- Linezolid prevents protein synthesis from ever starting.
- Binds to tRNAfMet (the first tRNA)
- Bacteriostatic- MRSA, MSSA, streptococci (S. pneumoniae), Enterococci
- Why does linezolid not work with gram negatives? Many gram negatives have efflux pumps
that can pump linezolid out of the cell
- Is also a MOAI due to having similar chemical structures as MOAIs.
- ADR: dizziness, depression, suicide, psychoses, serotonin syndrome (tx: benzodiazepines, paralysis, intubation, filtration)What is the MOA of Tedizolid?- Tedizolid phosphate is a prodrug activated by serum phosphatases
- oxazolidinoneWhat is the MOA of tigecycline?- It changes shape of rRNA binding cavity in 30S ribosome.
- OR it fosters new interaction with G 1053 phosphate
- Also helps avoid being pumped out by tetracycline efflux pumps.
***Either way, this helps it to overcome tetracycline resistance.***What is the MOA of daptomycin?- Daptomycin is incorporated into the membrane as a phosphatidylglycerol building block
- It aggregates, corrupt the shape of the membrane
- This results in holes that leak out essential ions
- The cell membrane depolarizes and the bacterium dies
- This decanoic acid side chain is incorporated
in place of phosphatidylglycerol.What is the MOA for Chlorhexidine?- Chlorhexidine binds electrostatically and strips back the bacterial cell wall, which leads to intracellular leakage of small ions and chemicals (i.e. potassium ions, etc.).
- skin disinfectantWhat is the MOA for Mupirocin?- It inhibits bacterial protein synthesis by reversible binding and inhibition of isoleucine-tRNA synthase. (Isoleucyl tRNA synthase inhibitor (block isoleucine incorporation in proteins))
- decolonizing agent
SAR:
- Mupirocin competitively inhibits isoleucyl-tRNA synthase via binding of the methyl end to the amino acid binding site.
- The methyl end of the molecule resembles isoleucine.
- The tail end of mupirocin binds to the ATP binding site.What is the MOA for Retapamulin (Altabax®)?- Retapamulin has potential use as a nasal decolonizing agent for treatment of mupirocin-resistant MRSA.
- Mechanism of action: Retapamulin inhibits peptide synthesis via binding to the 50S ribosomal subunit at a unique site.
SAR:
- Pharmacophore: The tricyclic pleuromutilin core composes the pharmacophore and occupies the A site.
- The C-14 side chain extends to the P site and inhibits the peptidyl transferase center of the 50S ribosomal subunit.
- This binding disrupts the translation of mRNA.
- Incorporation of a thioether at C-14 increases the antibiotic activity of pleuromutilins.What is the MOA for Lefamulin (Xenleta®)?- Lefamulin inhibits peptide synthesis via binding to the 50S ribosomal subunit at a unique site.What is the MOA for Rifampicin (Rifadin®)?- Rifampicin inhibits DNA-dependent RNA polymerase transcription. It binds to rpoB. (It cuts through biofilm like hot knife through butter allowing greater penetration of antibiotics)
- It is metabolized by deacetylation and CYP3A4.
- IT IS A POTENT CYP3A4 INDUCER.
- It can turn urine and tears red.
- Resistance is easy to get. This is why it is never used as mono therapy.
SAR:
- Rifampicin features a piperazine ring that enhances oral bioavailability.
- This piperazine ring also enhances the basicity of the molecule and makes it more water soluble.Rifampicin SAR of two aromatic rings- Rifampicin features two aromatic rings that compose the pharmacophore.
- These aromatic rings form pi-bond stacking interactions within RNA polymerase.
- It binds deep in the DNA/RNA channel and inhibits elongation of mRNA when it is 2 to 3 nucleotides long.
- The hydroxyl groups on the aromatic rings help to chelate Zn2+. RNA polymerase uses zinc as a cofactor.Rifampicin SAR of two hydroxyl groups- These additional hydroxyl groups bind within the active site of bacterial RNA polymerase.
- They help anchor the drug within the DNA/RNA channel.
- Resistance: Single point mutations in the rpoB (RNA polymerase B) gene can lead to resistance. Rifampicin should not be used as a monotherapy.What is the MOA for Rifabutin (Mycobutin)?- MOA is the same as rifampicin (inhibits DNA-dependent RNA polymerase transcription.)
- Rifabutin is more potent than rifampicin, and therefore inhibits Staphylococcus isolates at MICs lower than rifampicin.What is the MOA for Rifapentine (Priftin)?- MOA is the same as rifampicin (inhibits DNA-dependent RNA polymerase transcription.)
- Structural analogue of Rifampin (4-fold greater half-life than rifampin
More active than Rifampin)What is the MOA for Quinupristin-dalfopristin (Synercid®)?- Quinupristin and dalfopristin bind to different sites of the 50S ribosomal subunit and inhibit peptide elongation.Penicillin G (IV); penicillin V (PO)- Penicillins
- Spectrum of activity: T. palladium (Pen G is drug of choice. T. palladium causes syphillis), Streptococcus, oral anaerobes
- MOA: Beta lactams irreversibly and selectively destroy the penicillin binding proteins involved in cell wall synthesis (inhibiting peptidoglycan synthesis)
- ADR: NVD, rash, hives, anaphylaxis, interstitial nephritis, SJS/TENs
- Interactions Probenecid ↑ β-lactam concentrations, may ↑ Warfarin anticoagulation effectMethicillin (IV)
Nafcillin (IV)
Oxacillin (IV)
Cloxacillin (PO)
Dicloxacillin (PO- beta lactamase resistant penicillins
- Spectrum of activity: Oral anaerobes, Streptococcus, MSSA
- DOES NOT COVER GRAM NEGATIVES
- MOA: Beta lactams irreversibly and selectively destroy the penicillin binding proteins involved in cell wall synthesis (inhibiting peptidoglycan synthesis)
- ADR: rash, hives, anaphylaxis, SJS/TENS, acute interstitial nephritis
- Interactions: Probenecid ↑ β-lactam concentrations; Nafcillin, Dicloxacillin: ↓Warfarin anticoagulation(others increase it); Nafcillin = CYP3A4 inducer (moderate); Dicloxacillin = CYP2C19 inducer (moderate), CYP2C9 & 3A4 inducer (weak)Penicillin G Procaine/ Penicillin G Benzathine- This formulation of Pen G maximizes its time dependent killing. The natural penicillins have a short half-life. The concentration independent antimicrobial activity (AUC>MIC) for upwards of ~26 days from a single dose.
- Probenecid can block OATPs and extend t1/2 for penicillins- but it is not used for this!
- injected IM where it is slowly released into the circulation.
- The positively-charged amino groups on benzathine causes low concentration and continuous absorption into the blood stream.
- These formulations are used to treat syphilis or uncomplicated streptococcal pneumoniaAmpicillin (IV)
Amoxicillin (PO)- Extended spectrum penicillins
- Spectrum of activity (adds gram negatives and gets better coverage of enterococcus): (gram-negative) E. coli, Salmonella, Shigella, Proteus,(gram-positive) oral anaerobes, Streptococcus, Enterococcus
- MOA: Beta lactams irreversibly and selectively destroy the penicillin binding proteins involved in cell wall synthesis (inhibiting peptidoglycan synthesis)
- ADR: rash, hives, anaphylaxis, SJS/TENS, acute interstitial nephritis
- Interactions: Probenecid ↑ β-lactam concentrations, may ↑ Warfarin anticoagulation effectPiperacillin (IV)- Extended Spectrum Penicillins
- GORILLACIN - very broad spectrum because of acylureiod side chain the mimics longer segment of peptidoglycan
- No staph (MSSA); Not BL stable (no penicillinase producing-gram negatives)
- Spectrum of activity:
Klebsiella, E. coli, SPACE (very spotty, check sensitivities), Also covers aminopenicillin and natural penicillin bacteria.
- MOA: Beta lactams irreversibly and selectively destroy the penicillin binding proteins involved in cell wall synthesis (inhibiting peptidoglycan synthesis)Ampicillin/Sulbactam (I.V.)
Amoxicillin/Clavulanate (P.O.)- Penicillin/Beta-lactamase Inhibitor
- Spectrum of activity: (gram-negative) Klebsiella, Moraxella, Neisseria, Haemophilus, E. coli, Salmonella, Shigella, Proteus, (gram-positive) oral anaerobes, Streptococcus, Enterococcus, MSSA
- MOA: Beta lactams irreversibly and selectively destroy the penicillin binding proteins involved in cell wall synthesis (inhibiting peptidoglycan synthesis); Beta lactamase inhibitors blocks action of penicillinases.
- ADR: rash, hives, anaphylaxis, SJ/TENS. acute interstitial nephritis
- interactions: Probenecid ↑ β-lactam concentrations, may ↑ Warfarin anticoagulation effectPiperacillin-tazobactam (IV)
Ticarcillin-clavulanate (Timentin®, IV)- Penicillin/Beta-lactamase Inhibitor
- Spectrum of activity:(gram-negative) Klebsiella, Moraxella, Neisseria, Haemophilus, SPACE, E. coli, Salmonella, Shigella, Proteus, (gram-positive) oral anaerobes, Streptococcus, Enterococcus, MSSA, Enterococcus faecalis
- MOA: Beta lactams irreversibly and selectively destroy the penicillin binding proteins involved in cell wall synthesis (inhibiting peptidoglycan synthesis); Beta lactamase inhibitors blocks action of penicillinases.
- ADR: rash, hives, anaphylaxis, SJ/TENS. acute interstitial nephritis
- interactions: Probenecid ↑ β-lactam concentrations, may ↑ Warfarin anticoagulation effect,Zosyn may ↑ nephrotoxic effects of vancomycinWhat are the 4 penicillins that do a great job inhibiting enterococcus?amoxicillin
ampicillin
ticarcillin
PiperacillinHow are beta lactams interrelated?- The β-lactam (azetidinone) is a four-membered cyclic amide.
- The β-lactam ring is part of the pharmacophore of β-lactam antibiotics. The ring is sterically hindered, which potentiates its mechanism of action.
- Penicillins have a thiazolidinone ring attached to the β-lactam core. This is also part of the pharmacophore.
- This structure roughly gives penicillins a distinctive "V" shape in 3D space.Gram positive cell wall and penicillinThe peptidoglycan layer is the site of action. Beta lactams want to get to the cell wall. Pencillin will bind to Penicillin binding proteins (targets of beta lactams). This will inhibit the cross linking of peptidoglycan.Gram negative cell wall and penicillinIn order for penicillin to cross the cell wall, it must be able to passively diffuse (impossible) or exploit cell transports. The drug targets are found inside the periplasmic space. This is where beta lactamases and penicillin binding proteins are present.What is the mechanism of beta lactamase degradation?Beta-lactamases
destroy beta lactams
by opening the beta lactam ring.
- Certain beta lactamase genes, for example, are induced by administration of cephalosporins (e.g. cefoxitin).What cephalosporin kills Enterococcus?No cephalosporin kills Enterococcus.What are the first generation cephalosporins?Cefazolin (IV)
Cephalexin (PO)
Cefadroxil (PO)
- broader spectrum than penicillins. At baseline cephalosporins already get some gram - and +s. They are also resistant to penicillinases.What are the second generation cephalosporins?Cefuroxime (PO/IV)
Cefoxitin (IV)
Cefotetan (IV)
Cefprozil (PO)What are the third generation cephalosporins?Ceftriaxone (IV, Poster child)
Cefotaxime (IV)
Cefpodoxime (PO)
Cefdinir (PO)
Ceftazidime (IV)What are the fourth generation cephalosporins?Cefepime (IV)What are the fifth generation cephalosporins?Ceftaroline fosamil (IV)Cefazolin (IV)
Cephalexin (PO)
Cefadroxil (PO)- First gen cephalosporins
- Spectrum of activity: Oral anaerobes, Streptococcus, Staphylococcus (MSSA), E. coli, Salmonella, Shigella, Proteus, P. mirabilis
- MOA: Binds to PBPs inhibiting peptidoglycan synthesis, thus inhibiting cell wall biosynthesis
- ADR: NVD, rash, hives, anaphylaxis, interstitial nephritis, SJS/TENS
- Interactions: Probenecid ↑ β-lactam concentrations, may ↑ Warfarin anticoagulation effect, May ↑ nephrotoxic effects of aminoglycosides
- Pearls: High cross-sensitivity with penicillin allergies (except for cefazolin)Cefuroxime (PO) axetil (IV)
Cefprozil (PO)
Cefaclor- Second gen Cephalosporins
- Spectrum of activity: Oral anaerobes, Streptococcus, Staphylococcus (MSSA), E. coli, Salmonella, Shigella, Proteus, Moraxella, amp-resistant Haemophilus, Neisseria
- MOA: Binds to PBPs inhibiting peptidoglycan synthesis, thus inhibiting cell wall biosynthesis
- ADR: NVD, rash, hives, anaphylaxis,interstitial nephritis, SJS/TENS
- Interactions: Probenecid ↑ β-lactam concentrations, may ↑ Warfarin anticoagulation effect, May ↑ nephrotoxic effects of aminoglycosides
- Pearls: High cross-sensitivity with penicillin allergies (except for cefazolin)Cefoxitin (IV)
Cefotetan (IV)- Second gen Cephalosporins
- Spectrum of activity: Oral anaerobes, Streptococcus, Staphylococcus (MSSA), E. coli, Salmonella, Shigella, Proteus, Moraxella, amp-resistant Haemophilus, Neisseria, Bacteroids fragilis
- MOA: Binds to PBPs inhibiting peptidoglycan synthesis, thus inhibiting cell wall biosynthesis
- ADR: NVD, rash, hives, anaphylaxis,interstitial nephritis, SJS/TENS; cefotetan has a MTT side chain, do not use with alcohol due to disulfiram like reaction
- Interactions: Probenecid ↑ β-lactam concentrations, may ↑ Warfarin anticoagulation effect, May ↑ nephrotoxic effects of aminoglycosides
- Pearls: High cross-sensitivity with penicillin allergies (except for cefazolin)Cefpodoxime (PO)
Cefdinir (PO)- Third gen cephalosporins
- Spectrum of activity:Oral anaerobes, Streptococcus, E. coli, Salmonella, Shigella, Proteus, Moraxella, amp-resistant Haemophilus, Neisseria, SPACE (spotty P and A aren't covered), Klebsiella
- MOA: Binds to PBPs inhibiting peptidoglycan synthesis, thus inhibiting cell wall biosynthesis
- ADR: NVD, rash, hives, anaphylaxis,interstitial nephritis, SJS/TENS;
- Interactions: Probenecid ↑ β-lactam concentrations, may ↑ Warfarin anticoagulation effect, May ↑ nephrotoxic effects of aminoglycosides, PPIs, H2RA, antacids ↓ PO bioavailability for both medications
- Pearls: Cefdinir for infections above diaphragm, cefpodoxime for infections below the diaphragm.Ceftriaxone (IV, Poster child)
Cefotaxime (IV)- Third gen cephalosporins
- Spectrum of activity: Oral anaerobes, Streptococcus, E. coli, Salmonella, Shigella, Proteus, Moraxella, amp-resistant Haemophilus, Neisseria, SPACE (spotty P and A aren't covered), Klebsiella
- MOA: Binds to PBPs inhibiting peptidoglycan synthesis, thus inhibiting cell wall biosynthesis
- ADR: NVD, rash, hives, anaphylaxis,interstitial nephritis, SJS/TENS;
- Interactions: Probenecid ↑ β-lactam concentrations, may ↑ Warfarin anticoagulation effect, May ↑ nephrotoxic effects of aminoglycosides, Calcium Salts with Ceftriaxone, forms precipitate
- Contraindications: Concurrent use with calcium-containing IV products in neonates < 28 days old; Hyperbilirubinemia neonates; causes biliary sludging/kernicterus. Use cefotaxime instead.Ceftazidime (IV)
Ceftazidime + avibactam (IV)- Third gen cephalosporins/ third gen Cephalosporin/Beta-lactamase Inhibitor Combos
- Spectrum of activity: Oral anaerobes, Streptococcus, E. coli, Salmonella, Shigella, Proteus, Moraxella, amp-resistant Haemophilus, Neisseria, SPACE, Klebsiella, Pseudomonas
- MOA: Binds to PBPs inhibiting peptidoglycan synthesis, thus inhibiting cell wall biosynthesis
ADR: NVD, rash, hives, anaphylaxis, interstitial nephritis, SJS/TENS
- Interactions: Probenecid ↑ β-lactam concentrations, may ↑ Warfarin anticoagulation effect, May ↑ nephrotoxic effects of aminoglycosides
- Pearls: Avycaz: Typically reserved for MDR gram-negative organisms (including Pseudomonas)
- Unique because Exhibits good activity against P. aeruginosaCefiderocol (IV)- Siderophore cephalosporin
- Spectrum of activity: E. coli, Salmonella, Shigella, Proteus, Klebsiella, Moraxella, Neisseria, amp-resistant Haemophilus, SPACE, Pseudomonas
- MOA: Chelates ferric iron, where it then utilizes the iron transport system of gram-bacteria to be delivered across their outer membrane. It then binds to PBPs inhibiting peptidoglycan synthesis, thus inhibiting cell wall biosynthesis
- ADR: NVD, rash, hives, anaphylaxis, interstitial nephritis, SJS/TENS
- Interactions: Probenecid ↑ β-lactam concentrations, may ↑ Warfarin anticoagulation effect, May ↑ nephrotoxic effects of aminoglycosides
- Pearls: Typically reserved for MDR gram-negative organisms (including Pseudomonas, Acinotobactera, klebsiella)cefepime (IV)- fourth generation cephalosporin
- Spectrum of activity: Oral anaerobes, Streptococcus, E. coli, Salmonella, Shigella, Proteus, Moraxella, amp-resistant Haemophilus, Neisseria, SPACE, Klebsiella, Pseudomonas, Staphylococcus (MSSA)
- MOA: Binds to PBPs inhibiting peptidoglycan synthesis, thus inhibiting cell wall biosynthesis
- ADR: NVD, rash, hives, anaphylaxis, acute interstitial nephritis, SJS/TENS
- Interactions: Probenecid ↑ β-lactam concentrations, may ↑ Warfarin anticoagulation effect, May ↑ nephrotoxic effects of aminoglycosides
- Pearls: Covers Pseudomonas. Broadest-spectrum cephalosporinCeftaroline fosamil (IV)- Fifth-generation cephalosporin
- Spectrum of activity: Oral anaerobes, Streptococcus, E. coli, Salmonella, Shigella, Proteus, Moraxella, amp-resistant Haemophilus, Neisseria, Serratia, Citrobacter, Enterobacter, Klebsiella, Staphylococcus (MRSA)
- MOA: Binds to PBPs inhibiting peptidoglycan synthesis, thus inhibiting cell wall biosynthesis
- ADR: NVD, rash, hives, anaphylaxis,acute interstitial nephritis, SJS/TENS
- Interactions: Probenecid ↑ β-lactam concentrations, may ↑ Warfarin anticoagulation effect, May ↑ nephrotoxic effects of aminoglycosides
- Pearls: Ceftaroline: only β-lactam with activity against MRSACeftolozane + tazobactam (IV)- Fifth-generation cephalosporin + beta-lactamase inhibitor
- Spectrum of activity: Oral anaerobes, Streptococcus, E. coli, Salmonella, Shigella, Proteus, Moraxella, amp-resistant Haemophilus, Neisseria, SPACE, Klebsiella, Pseudomonas
- MOA: Binds to PBPs inhibiting peptidoglycan synthesis, thus inhibiting cell wall biosynthesis
- ADR: NVD, rash, hives, anaphylaxis, acute interstitial nephritis, SJS/TENS
- Interactions: Probenecid ↑ β-lactam concentrations, may ↑ Warfarin anticoagulation effect, May ↑ nephrotoxic effects of aminoglycosides
- Pearls: Typically reserved for MDR gram-negative organisms (including Pseudomonas)Why shouldn't you give Ceftriaxone to neonates?- Ceftriaxone interacts with calcium-containing medications
- Negatively charged carboxylate group and oxygens of side chain have electrostatic interactions with Ca2+ - Can crystallize in liver/kidneys, which can be fatal
- Also leads to biliary sludging and hyperbilirubinemia in neonates.
- Biliary sludging results in contraindication of ceftriaxone in pediatric populations. We use cefotaxime for neonates instead.Cefiderocol indication- Indication: Cefiderocol is indicated for complicated urinary tract infections, pyelonephritis, and acute uncomplicated urinary tract infections in hospitalized adults.
- Cefiderocol covers many gram-negative bacteria, including carbapenem non-susceptible and carbapenemase-producing bacteria.
MDR gram negatives:
- Acinetobacter baumannii
- Pseudomonas aeruginosa
- Klebsiella pneumoniae
- Streptophomonas maltophilaWhat is the only cephalosporin that covers MRSA?Ceftaroline (5th gen)Aztreonam-Monobactam
- It only has the four membered ring of the azetidinone pharmacophore.
- Has the exact same side chain as ceftazidime!!!
- **As it turns out, it can be safe to give patients with penicillin allergy.**
Unless that allergy is to ceftazidime!!!
- It functions exactly the same as ceftazidime
- Good gram negative aerobe activity
- ***Kills Pseudomonas***
- Loses gram positive activity
- Loses anaerobes
- Lacks hypersensitivity reaction for some patients with true penicillin allergy. (due to the monobactam ring)
- Aztreonam binds to penicillin binding protein 3
- Aztreonam is drawn to the PBP-3 of aerobic gram negatives.
- Gram positives do not really have this PBP3, so the activity against these suffers.What is the mechanism of action for sulfadiazine and sulfamethoxazole?- Sulfa drugs inhibit dihydropteroate synthase.
- Dihydropteroate synthase forms dihydropteroic acid from para-aminobenzoic acid (PABA) and dihydropteroate pyrophosphate.
- Sulfa drugs are condensed with PABA to form junk metabolites
- These junk metabolites fail to get converted to tetrahydrofolate by downstream enzymes.
(basically 1. inhibits dihydropteroate synthase and 2. forms false metabolites that inhibit folic acid synthesis)What is the spectrum of activity of Sulfadiazine/pyrimethamine, Sulfamethoxazole/trimethoprim, and Dapsone?Pneumocystis jirovecii
Staphylococcus aureus (including MRSA)
Haemophilus influenzae
Stenotrophomonas maltophilia
Listeria monocytogenes
Toxoplasma gondiiWhat is the mechanism of action for pyrimethamine and trimethoprim?Inhibits Dihydrofolate reductase
- it gets the PABA that leaks through; prevents recyclingWhat is the rationale for drugging the bacterial folic acid synthesis pathway?Folic aid is very important for synthesizing DNA. In humans, we get folic acid from our diet while bacteria synthesize their own folic acid. This pathway allows us to selectively address the bacteria while having significant less ADRs.
- Sulfa drugs competes with PABA and DHFR inhibitor inhibits DHFR - This allows us to get PABA that leaks through and allows us to prevent some development of resistance from the bacteria.Trimethoprim/Sulfamethoxazole (Bactrim®)- Dual-inhibitor that is effective against bacterial (Staphylococcus aureus-MRSA) and parasite/fungal infection (to due to Toxoplasma gondii and Pneumocystis jirovecii) shared targets.
- Sulfa allergy can result in type IV hypersensitivities (Stevens Johnson syndrome)
- Dosed based on TMP component (in 1:4 ratio).
- metabolism CYP2C9What can cause resistance to Bactrim?Sunscreen used to have PABA in it. If you're taking a sulfa drug, you can cause treatment failure because PABA would out compete the sulfa drug.Sulfasalazine (Azulfidine)- Poorly absorbed, distributes to distal bowel.
- Used to treat ulcerative colitis or Crohn's disease.
- Not used as an antibiotic. (Why?) The primary metabolite is 5- aminosalicylate. It inhibits NF-kappa. This prevent a inflammatory response.Sulfadiazine + pyrimethamine- Drug of choice for Toxoplasmosis
- Hits two targets (like Bactrim)
- Pyrimethamine = DHFR inhibitor
- Sulfadiazine= dihydropteroate synthaseDapsone- Dapsone is a second-line therapy for treatment of P. jirovecii prophylaxis.
- Dapsone is used to treat leprosy (Hansen's disease) due to Mycobacterium leprae.
- Dapsone is also used for treatment of dermatitis herpetiformis.
- Mechanism of action: Same as sulfamethoxazole.
- Resistance mechanism: Same as sulfamethoxazole.Explain the true incidence and mechanism behind sulfa antibiotic allergy.- Roughly ~3-5% of the population report allergies to sulfa drugs. Highest incidence with antibiotic sulfas.
- TMP/SMX frequently causes rash, usually because of the sulfamethoxazole component. Rash is much more common in HIV/AIDS patients. Although these rashes are usually not severe, life-threatening dermatologic reactions such as toxic epidermal necrolysis and Stevens- Johnson syndrome also occur.
- Sulfonamide drugs (-SO2NH2) drugs are notorious for allergies e.g:
+ Antibiotics
+ Thiazides
+ Loop Diuretics
+ Oral hypoglycemic
+ Carbonic anhydrase inhibitors
- 10% of the population has "also allergies": these people are allergic to drugs in general and can have cross-reactivity between structurally unrelated drugs. (these pts are more likely to be cross-allergic to penicillin as a sulfonamide drug)
- AIDs patients are 50-80% more likely to be hypersensitive to sulfa drugs. This is due to their unique immune system. This is important because sulfa antibiotics are used in AIDs patients for opportunistic infections (Pneumocystis jirovecii; Toxoplasma gondii). These infections can be deadly to a person who has AIDs.
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