IID 04: Pharmacology of Beta Lactams Flashcards

Question

Penicillinase-Resistant Penicillin (Antistaphylococcal Penicillins)

Answer 1

- relatively acid stable and well absorbed - absorption impaired by food - beta-lactamase-resistant due to bulky residues on their R side chains that prevent binding by the staphylococcal beta-lactamase - not as effectives as penicillin G or penicillin V - semi-synthetic penicillins with a narrow spectrum – used to treat infections caused by penicillinase-resistant staphylococci

Answer 2

methicillin resistant bacteria - have altered penicillin binding proteins - vancomycin is the drug of choice in such infections

Answer 3

infections caused by staphylococci, with the exception of MRSA

Answer 4

extended-spectrum penicillins – ampicillin and amoxicillin - similar activity against organisms targeted by penicillin G - greater activity against gram-negative bacteria - beta-lactamase sensitive

Answer 5

urinary tract infections, respiratory infections

Answer 6

should not be taken on an empty stomach – food impairs absorption of drug

Answer 7

- similar activity against organisms targeted by ampicillin - side chains allow for greater penetration into gram-negative bacteria than aminopenicillins - generally, more resistant to cleavage by gram-negative beta-lactamase than aminopenicillins - show activity against Pseudomonas aeruginosa, Klebsiella - effective against some Staph. Aureus

Answer 8

urinary tract infections, respiratory infections

Answer 9

no – generally non-toxic

Answer 10

- GI upset (large oral doses) – nausea, vomiting, diarrhea, abdominal pain - rash - fever - bronchospasm (abnormal smooth muscle contraction, respiratory obstruction) - vasculitis (inflammation of blood vessel) - exfoliative dermatitis (severe inflammation of entire skin) - anaphylaxis – rare, about 0.5-1 of 10,000 patients

Answer 11

- 5% ranging from maculopapular rash (common rash with ampicillin hypersensitivity) to angioedema (marked swelling of the lips, tongue, and periorbital area) and anaphylaxis - patients with mononucleosis and treated with ampicillin – incidence of maculopapular rash approaches 100%

Answer 12

- patients with renal failure: high doses → seizures - penicillins are irritating to neuronal cells, provoke seizures if injected intrafecal or if very high blood levels are reached - epileptic patients are particularly at risk - high doses of penicillin causes seizures by inhibiting GABA

Answer 13

- common problem - disruption of the normal balance of intestinal microorganisms with drugs - also pseudomembranous colitis with some other antibiotics

Answer 14

all penicillins, but particularly methicillin, are potential cause of acute interstitial nephritis - note: methicillin is therefore no longer available

Answer 15

- penicillins are generally sodium or potassium salt - toxicities due to large quantities of Na or K - Na excess may result in hypokalemia (rare) -0 this can be avoided by using the most potent antibiotic, which permits lower doses of drug and accompanying cations - hyperkalemia (rare) – increased potassium load due to rapid IV doses of penicillin G potassium in patients with renal failure

Answer 16

benzyl penicilloyl (95%) formed when the beta-lactam ring is opened

Answer 17

penilloate, penicilloate, and benzyl-n-propylamine formed by drug degradation in GI tract

Answer 18

major and minor determinants of metabolism

Answer 19

- minutes to hours - offending drugs – IgE (histamine and other proinflammatory from mast cells and basophils) - anaphylaxis, urticaria, angioedema, pruritus, hypotension, respiratory distress/bronchospasm

Answer 20

- 72 hours cytotoxic reaction - IgG directed against haptenized proteins - antibody bind to renal intestinal cells or RBC complement system - hemolytic anemia, thrombocytopenia, cytopenia, proteinuria, and/or hematuria

Answer 21

- 10-21 days hypersensitivity to penicillin - delayed immune complex reactions mediated by IgG and IgM - circulating immune complexes complement deposited in blood vessels of kidneys, joints, or skin - fever, serum sickness, vasculitis, erythema multiform, interstitial nephritis, lymphadenopathy, splenomegaly, arthralgias

Answer 22

- 2-4 days or more - induction of T cells interacting with an antigen - proinflammatory cytokines, tissue inflammation, and clinical manifestations - morbilliform eruptions or contact dermatitis - Stevens-Johnson syndrome or toxic epidermal necrolysis

Answer 23

- penicillin allergy testing – skin testing - desensitization - severe non-IgE-mediated reactions related to penicillin use requires strict avoidance of penicillin

Answer 24

- decreased coagulation with the antipseudomonal penicillins and, to some extent, with penicillin G - in patients who are predisposed to hemorrhage (ie. uremic) or those receiving anticoagulants - additional toxicities include eosinophilia

Answer 25

associated with: - longer hospital admissions, higher rates of readmission, treatment failure, and intensive care unit admission - increased risk of exposure to significantly more antibiotics associated with Clostridium difficile, vancomycin-resistant Enterococcus, and methicillin-resistant S aureus (MRSA)

Answer 26

- antibiotic is inactivated by beta-lactamase produced by the bacteria itself (very common) - modification of target PBPs - impaired penetration of drug to target PBPs - efflux pump mechanism to remove drug

Answer 27

- over 300 beta-lactamases (penicillinase) identified - specificity can be variable - large amounts often secreted by gram-positive bacteria - gram-negative bacteria tend to secrete less penicillinase - weak correlation between a given antibiotic’s bactericidal action and its susceptibility to beta-lactamase - beta-lactamase may also hydrolyze cephalosporin

Answer 28

- PBPs may have low affinity for binding to beta-lactam antibiotics - inhibition of bacterial growth occurs only with high drug concentrations – very rare but common with Staphylococci, Pneumococci, Enterococci, and Neisseria gonorrhoeae - clinical usefulness of beta-lactam may be compromised - MRSA expresses a new PBP

Answer 29

- peptidoglycan layer in (G+) bacteria is near the cell surface - small beta-lactam drugs easily penetrate the outer layer of cytoplasmic membrane and bind to PBP - outer membrane in gram negative (G-) bacteria forms an impenetrable barrier to certain antibiotics - aqueous channels (porins) in (G-) bacteria allow access to certain hydrophilic antibiotics - pore size and density can vary among different (G-) bacteria

Answer 30

- certain gram negative bacteria possess protein components for efflux pumps - efflux pumps transport beta-lactam antibiotics back across the outer membrane - ie. nafcillin extrusion by Salmonella tyhinurium

Answer 31

- semi-synthetic derivatives from a fungus - structurally and pharmacologically related to penicillins - generally, beta-lactamase resistant (not totally) - high therapeutic index

Answer 32

bactericidal action – dose-related - inhibit cell wall synthesis and bind to the same proteins as penicillin

Answer 33

wider/broad spectrum that may work against penicillin-resistant bacteria

Answer 34

- mechanism of action - mechanisms of resistance - absorption and excretion - toxicity

Answer 35

- gram positive bacteria - E. coli - Klebsiella - Proteus

Answer 36

- enterococci - methicillin-resistant staphylococcus aureus (MRSA)

Answer 37

- cephalexin - cefazolin - cefadroxil

Answer 38

- stronger antimicrobial action against G+ bacteria than G- bacteria - nephrotoxic (to a certain degree) - not effective against pseudomonas - stable against beta-lactamase (penicillinase) - cefazolin does not penetrate CNS and cannot be used to treat meningitis

Answer 39

- cefoxitin - cefotetan - cefaclor - cefuroxime - cefprozil

Answer 40

- less effective against G+ bacteria than 1st generation with enhanced antimicrobial action against G- bacteria - stable against beta lactamases and exert less nephrotoxicity than 1st generation - cefuroxime has ability to cross the blood-brain barrier and suitable for the treatment of meningitis, especially H. influenzae meningitis, and sepsis

Answer 41

- cefixime - cefotaxime - ceftriazone - ceftazidime

Answer 42

broadest spectrums of all cephalosporins - highest activities against G- bacteria - lowest activities against G+ bacteria - highest resistance to beta-lactamase - best penetration into the CSF – almost no nephrotoxicity

Answer 43

has longest half-life (8 hr) of any cephalosporin

Answer 44

oral preparation

Answer 45

best anti-pseudomonal cephalosporin

Answer 46

eliminated (70%) in the bile – therefore very useful in patients with renal failure

Answer 47

- cefepime

Answer 48

- greater stability against beta-lactamases - extended spectrum of activity against gram-positive organisms – similar to ceftriaxone - effective against Pseudomonas aeruginosa - very good activity against penicillin resistant strain of streptococci and it may be useful in the treatment of Enterobacter infections - otherwise, clinical role is similar to third generation cephalosporins

Answer 49

first and second generation cephalosporins are used with aminoglycosides to treat serious gm(-) infections

Answer 50

third generation cephalosporins are effective against gm(-) meningitis and in multi-resistant gm(-) infections – pneumonias, UTI, osteomyelitis, pelvic and intra-abdominal infections

Answer 51

similar to penicillins - hypersensitivity - diarrhea - nephritis - neurotoxicity - hematologic toxicities - cation toxicity third generation cephalosporins may decrease thrombin → increase bleeding

Answer 52

- anaphylaxis (rare) - rash (maculopapular, urticarial) (1-3%) - serum sickness-like reaction (especially with cefaclor) - some cross-sensitivity with penicillin (5-10% – perhaps as low as 1%) - if a patient develops urticaria, anaphylaxis, or angioedema with penicillin or a cephalosporin, avoid using any of the other cephalosporin

Answer 53

- associated with methylthiotetrazole ring - common with cefoperazone, cefamandole, and cefotetan – occurs in 20-60% of patients - give Vitamin K (menadione) as preventative measure – less bleeding problems with cefotetan - cephalosporins may also cause bleeding due to reduction of gut flora

Answer 54

- flushing, sweating, headache, tachycardia associated with alcohol ingestion - associated with methylthiotetrazole-containing cephalosporin only (cefoperazone, cefamandole, cefotetan)

Answer 55

diarrhea more common with cefixime, cefdinir, and cefoperazon

Answer 56

- precipitation of ceftriaxone in bile leads to biliary sludge - may require surgery

Answer 57

- major concern in neonates - occurs with ceftriaxone and cefoperazone

Answer 58

- most common with cephalothin and cephapirin - may also occur with cefotaxime

Answer 59

- some produce disulfiram-like reactions with alcohol (symptoms include flushing of the skin, accelerated heart rate, SOB, nausea, vomiting) - H2 antagonists and antacids decrease absorption - probenecid increases/prolongs cephalosporin’s effect - false-positive glucosuria testing with a copper reduction test (clinitest) may occur with many cephalosporins - depletion of gut flora resulting in decreased vitamin K synthesis (problem with 2nd and 3rd generation cephalosporins)

Answer 60

- aminoglycosides - anticoagulant

Answer 61

aminoglycoside nephrotoxicity may be potentiated with the use of certain cephalosporins – especially cephalothin

Answer 62

- hypoprothrombinemic effects of anticoagulants are increased - bleeding complications may occur

Answer 63

structural similarities - originally theorized that the common beta-lactam ring was the cause of cross sensitivity, but further research suggests the cause to be similar side-chains - penicillins contain a single side-chain at the 6-position, while cephalosporins have two side-chains at the 7- and 3-position - when the penicillin side-chain is similar to either of the cephalosporin side-chains, the likelihood of cross-sensitivity increases - many first- and second-generation cephalosporins have similar side-chains to penicillin antibiotics, thus increasing the chance of cross-sensitivity - the other generation agents have structurally different side-chains, and therefore patients have a lower likelihood of experiencing cross-sensitivity

Answer 64

- ceftaroline - ceftobiprole

Answer 65

- active against a wide range of both gram-positive and gram-negative organisms including methicillin resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae, pseudomonas aeruginosa

Answer 66

- prodrug form of a new semi-synthetic cephalosporin - effective against MRSA and multidrug-resistant Streptococcus pneumonia, as well as some gram-negative organisms

Answer 67

- binds to the penicillin-binding protein (PBP)2a, an MRSA-specific protein, which makes it unique among the cephalosporins - efficacy against endocarditis, pneumonia, myositis, and osteomyelitis has been demonstrated in animal models - efficacy in the treatment of complicated skin and soft tissue infections and community-acquired pneumonia has been confirmed in humans

Answer 68

broad spectrum with bactericidal activity - effective against many resistant gram-positive bacteria as well as gram-negative bacteria - retains activity against isolates with reduced susceptibility to vancomycin or linezolid - inactive against ESBL-producing or AmpC-over-expressing Enterobacteriaceae - limited activity against non-fermenting gram-negative bacilli such as Pseudomonas aeruginosa and Acinetobacter baumannii

Answer 69

- ability to bind to PBP2a, demonstrating superior affinity as compared with cefozopran and other beta-lactams - high affinity for S. aureus PBPs correlates well with its low minimum inhibitory concentration (MIC) for MRSA or methicillin-susceptible S. aureus (MSSA) strains

Answer 70

- following IV infusion, ceftaroline prodrug is rapidly converted to its bioactive metabolite, ceftaroline, by plasma phosphatases - no drug accumulation at therapeutic doses upon IV administration in healthy volunteer - comparable bioavailability when administered IM or IV – IV more expensive - upon conversion of ceftaroline fosamil in the plasma to the active metabolite, ceftaroline, a small fraction is converted to an inactive metabolite, ceftaroline-M-1 - half-life of active ceftaroline is 2.6 h and that of the ceftaroline-M-1 metabolite is 4.5 h in healthy volunteers - ceftaroline and ceftaroline-M-1 are eliminated primarily through the kidney and half of the dose is excreted in the urine as an active drug, with a small amount excreted in the urine as ceftaroline-M-1 - dosage adjustment may be needed in patients with moderate but not mild renal impairment

Answer 71

- generally mild - nausea, headache, pruritus, and rash (which infrequently require discontinuation of therapy) - occurrence of Clostridium difficile-induced diarrhea is rare with this novel cephalosporin - no evidence of hepatic, renal, or cardiac toxicity or any infection/fatalities - ceftaroline should not be used in cephalosporin sensitive patients

Answer 72

- no clinical drug-drug interaction studies have been conducted with ceftaroline fosamil - neither ceftaroline fosamil nor ceftaroline inhibits the major cytochrome P450 isoenzymes - neither ceftaroline fosamil nor ceftaroline inhibits or induces the clearance of drugs that are metabolized by the cytochrome P450 isoenzymes

Answer 73

- hypersensitivity reactions - Clostridium difficile-associated diarrhea - development of drug-resistant bacteria

Answer 74

- known serious hypersensitivity to ceftaroline or other members of the cephalosporin class - anaphylaxis and anaphylactoid reactions (resemble generalized anaphylaxis but not IgE-mediated)

Answer 75

- production of beta-lactamase enzymes - modification of target PBPs - impaired penetration of drug to target PBPs - shortage of autolytic enzyme - presence of an efflux pump - passage of the cephalosporins through Porin

Answer 76

- imipenem - meropenem - doripenem - ertapenem

Answer 77

- meropenem, imipenem/cilastatin, doripenem, and ertapenem are parenteral synthetic beta-lactams - derived from thienamycin, an antibiotic produced from Streptomyces cattleya - have beta-lactam ring, like penicillins and cephalosporins, but also have a methylene moiety in the ring

Answer 78

ESBL organisms and the SPICE A organisms (Serratia, Pseudomonas/Providencia, Indole-positive Proteus, Citrobacter, Enterobacter, and Acinetobacter) - possess the broadest spectrum of activity of all antimicrobials - active against gram-positive and gram negative organisms – broad spectrum - resistant to most beta-lactamases

Answer 79

similar to other beta-lactams

Answer 80

- all administered IV - half life = 1 hr (except ertapenem = 4 hrs; once daily) - bactericidal against: B. fragilis, Enterobacteriaceae, Pseudomonas, and gram-positive organisms - bacteriostatic against: Listeria and E. faecalis

Answer 81

- meropenem - imipenem

Answer 82

only meropenem is rapidly metabolized by kidneys

Answer 83

excreted by kidneys

Answer 84

- nausea, vomiting, diarrhea, seizures, eosinophilia, and neutropenia - cause seizures in patients with renal dysfunction

Answer 85

- distributes to most tissues including the CNS - inactivated by the renal enzyme dehydropeptidase which lowers imipenem concentration and renders it ineffective - co-administered with cilastatin – cilastatin inhibits dehydropeptidase → increases drug concentration

Answer 86

- another thienamycin derivative - has a 1-beta-methyl substitution in its side chain - this accounts for its differences in pharmacologic properties from imipenem - co-administration with a DHP-I inhibitor is NOT required

Answer 87

- broad spectrum carbapenem antibiotic - structural analog of imipenem - unlike imipenem, doripenem is resistant to cleavage by renal dehydropeptidase I - co-administration with cilastatin is NOT required

Answer 88

- similar to imipenem - IV administration – dose adjustment is required in patients with renal insufficiency, generally safe and well tolerated, lower adverse event rate than imipenem - excretion – excreted unchanged into the urine by glomerular filtration and tubular secretion

Answer 89

- even at higher doses, it still has a low risk of seizures and its gastrointestinal effects are not dose-dependent = as a result, meropenem doses can be elevated to improve efficacy and potentially reduce the emergence of resistant organisms - its safety at higher doses and lower CNS toxicity permit it to be used to treat bacterial meningitis

Answer 90

- mechanisms by which P. aeruginosa resistance to meropenem is acquired are similar to those for imipenem - unlike imipenem, resistance to meropenem requires two independent mutations: mutation that reduces porin channels, and mutation that up-regulates efflux mechanisms (one of these mutations alone only reduces sensitivity to meropenem and does not confer resistance)

Answer 91

- doripenem derives its bactericidal action from inhibition of PBPs and blocking cell wall synthesis - doripenem binds to several high MW PBPs including (PBPs 1, 2, 3 & 4) - binding intensity of doripenem is species specific – ie. PBP3 in P.aeruginosa, PBPs 1, 2 and 4 in S.aureus, and PBP2 in E.coli - results in defective cell walls, cell lysis and bacterial death

Answer 92

- unique member of the carbapenem group - was and remains the least prescribed of the carbapenems - pharmacologic properties and spectrum of activity are different from imipenem and meropenem - belongs to its own separate class within the carbapenem group

Answer 93

- safe and well tolerated - intramuscular or intravenous administration - high protein-binding percentage and long half-life - once daily administration/low risk of seizure - less susceptible to renal insufficiency - IM administration is irritating → drug is formulated with 1% lidocaine

Answer 94

- limited activity against gram-negative, non-fermenting bacteria such a P. aeruginosa, B. cepacia, and Acinetobacter spp - clinically used to treat infections with ESBL-producing pathogens, but ertapenem activity is lower against these bacteria than other carbapenems - use is limited to treating serious community-acquired infections - should not be routinely used empirically to treat nosocomial infections

Answer 95

- signs of an allergic reaction include: hives, difficulty breathing, swelling of face, tongue, or throat - loss of balance or coordination, trouble walking - tremors, twitching, or rigid (very stiff) muscles - seizures (black-out or convulsions) or - diarrhea that is watery or bloody

Answer 96

carbapenems bind to GABA receptors - decreased valproic acid levels and absorption - antibiotics inhibition of intestinal transporters - decrease enterohepatic circulation of valproic acid - decreased gut bacterial beta glucuronidase - increased valproic acid in erythrocytes

Answer 97

- patients who have demonstrated anaphylactic reactions to beta-lactams - probenecid increases the risk of ertapenem's side effects - effectiveness of divalproex sodium or valproic acid may be decreased by ertapenem

Answer 98

- ertapenem has been designed to be effective against gram-negative and gram-positive bacteria – also effective against anaerobic bacteria - not effective against MRSA, ampicillin-resistant enterococci, Pseudomonas aeruginosa, or Acinetobacter species - does NOT cover Pseudomonas, but does still cover ESBL (main advantage is convenient once daily dosing – great outpatient IV drug)

Answer 99

- bacterial specific beta-lactamase - mutation: loss of the outer membrane porin → transport of the drug into the cell is blocked - cross-resistance may occur between the carbapenems - efflux pump more active – not for imipenem, but for meropenem and doripenem

Answer 100

- relatively resistant to beta-lactamases - active against gram negative organisms - inactive against gram positive organisms or anaerobic strains - well tolerated, little or no allergic reactions in patients who are sensitive to penicillins or cephalosporins - may be useful as a replacement for aminoglycoside antibiotic

Answer 101

narrow spectrum - active only against aerobic gram-negative bacteria (Enterobacteriaceae, pseudomonas) - no gram-positive or anaerobic activity - aztreonam IV or IM (no oral admiration) - therapeutic concentrations in CSF if meninges inflamed

Answer 102

- side effects include phlebitis, skin rash, inflammation abnormal liver function - little cross reactivity with penicillin

Answer 103

- derivative of phosphonic acid - isolated from a Streptomyces fradiae strain - broad spectrum antibiotic – effective against both gram-positive and gram-negative bacteria, including ESBL-producer strains - bactericidal

Answer 104

- fosfomycin trometamol is more soluble and stable in the gastric acidic environment. - oral administration – rapidly absorbed and converted to the free acid - bioavailability (37-44%)

Answer 105

- fosfomycin is distributed to the kidneys, bladder wall, prostate, and seminal vesicles - fosfomycin is not protein bound

Answer 106

- fosfomycin is excreted unchanged in urine via glomerular filtration (38%) and feces (18%) - mean half-life elimination is 5.7 hours - CrCl 7-54 mL/min is 50 hours - urinary excretion decreases to 11% in patients with CrCl 7-54 mL/min - urinary concentrations remain >100 mg/L for at least 30-40 h post-dose

Answer 107

mainly chromosomal: - due to mutations that interfere with transport systems required for fosfomycin uptake resulting in reduced intracellular concentrations of the drug - plasmid mediated resistance: - however, these mutations are uncommon

Answer 108

- all ESBL positive E. coli, P. mirabilis - methicillin-resistant S. saprophyticus strains isolated from urine - KPC-producing K. pneumoniae isolates (82%)

Answer 109

- half-life of fosfomycin is increased in patients with chronic severe renal failure, significantly (up to 50 h), with low recovery in urine - in case of creatinine clearance is >10 mL/min: reduce the dose

Answer 110

- well tolerated, very low incidence of side effects - diarrhea and nausea are most common but mild

IID 04: Pharmacology of Beta Lactams Flashcards

(137 cards)