Antimicrobials Flashcards

Question

Cephalosporins SEs

Answer 1

• Allergic reactions (cross-sensitivity with penicillins can occur) However, minor penicillin allergic patients often treated successfully with a cephalosporin • Pain at infection site (IM), thrombophlebitis (IV) • Superinfections (eg, C.difficile) * Cefamandole, cefoperazone & cefotetan contain methyl-thiotetrazole group, all can cause: * hypoprothrombinemia (Vit. K1 admin can prevent) & * disulfiram-like reactions (avoid alcohol)

Answer 2

* Imipenem, Meropenem. Synthetic B-lactam antibiotics * Resist hydrolysis by most B-lactamases * Very broad spectrum of activity * Active against penicillinase-producing Gram-positive & negative organisms; aerobes & anaerobes; P.aeruginosa * Not active against carbapenemase producing organisms eg, carbapenem-resistant enterobacteriaceae, carbapenem-resistant klebsiella * Not active against MRSA Drugs of choice for • enterobacter infections • extended-spectrum B-lactamase producing Gram-negatives

Answer 3

PK • IV • Imipenem forms potentially nephrotoxic metabolite. Combining with enzyme inhibitor Cilastatin prevents metabolism thus prevents toxicity & increases availability. • Meropenem is not metabolized by same enzyme (no need for Cilastatin) SEs • GI distress (nausea, vomiting, diarrhea) • High levels of imipenem can provoke seizures • Allergic reactions (partial cross-reactivity with penicillins)

Answer 4

* Aztreonam * Aerobic Gram-negative rods ONLY (including pseudomonas) * No activity against Gram-positive bacteria or anaerobes * Resistant to action of B-lactamases • UTI’s, lower respiratory tract infections, septicemia, skin/structure infections, intraabdominal infections, gynecological infections caused by susceptible Gram- negative bacteria

Answer 5

* Mainly IV or IM * Can be given by inhalation in CF patients * Penetrates CSF when inflamed * Excreted primarily via urine SE • Relatively nontoxic • Little cross-hypersensitivity with other

Answer 6

* Active against Gram-positive bacteria only * Virtually all Gram-negative organisms are intrinsically resistant * Effective against multi-drug resistant organisms (eg, MRSA, enterococci, PRSP) * Binds to the D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide * Inhibits bacterial cell wall synthesis & peptidoglycan polymerization RESISTANCE • Plasmid-mediated changes in drug permeability • Modification of the D-Ala-D-Ala binding site (D-Ala replaced by D-lactate)

Answer 7

* Treatment of serious infections caused by B-lactam resistant Gram +ve organisms eg, MRSA * Treatment of Gram +ve infections in patients severely allergic to B-lactams * In combination with an aminoglycoside for empirical treatment of infective endocarditis * In combination with an aminoglycoside for treatment of enterococcal endocarditis or PRSP * Given orally for the treatment of staphylococcal enterocolitis or antibiotic-associated pseudomembranous colitis (C.difficile)

Answer 8

* Poor oral absorption * Requires slow IV infusion (60-90 min) * Penetrates CSF when inflamed * 90-100% excreted via kidneys SE • Mostly minor eg, fever, chills, phlebitis at infusion site • ‘Red man’ or ‘red neck’ syndrome (infusion-related flushing over face and upper torso) • Ototoxicity (drug accumulation) • Nephrotoxicity (drug accumulation)

Answer 9

* Effective against resistant Gram-positive organisms (eg, MRSA (ORSA), enterococci, VRE & VRSA) * Recommended for treatment of severe infections caused by MRSA or VRE * Treatment of complicated skin/structure infections caused by susceptible S.aureus * Inactive against Gram-negative bacteria * Not effective in treatment of pneumonia * Novel mechanism of action -> useful against multi-drug resistant bacteria * Binds to cell membrane via calcium-dependent insertion of lipid tail * Results in depolarization of cell membrane with K+ efflux -> cell death

Answer 10

* IV only * Can accumulate in renal insufficiency SE • Constipation, nausea, headache, insomnia • Elevated creatine phosphokinases (recommended to discontinue coadmin. of statins)

Answer 11

* Unique mechanisms -> no cross resistance * Interferes in late stage cell wall synthesis * Effective against Gram-positive organisms * Marked nephrotoxicity

Answer 12

* Inhibits cytoplasmic enzyme enolpyruvate transferase in early stage of cell wall synthesis * Active against Gram-positive and negative organisms * Oral * Used for treatment of uncomplicated lower UTI’s

Answer 13

* Tetracyclines * Glycylcyclines * Aminoglycosides * Macrolides * Chloramphenicol * Clindamycin * Streptogramins * Linezolid * Mupirocin * Bind to and interfere with ribosomes * Bacterial ribosome (70S) differs from mammalian (80S) but closely resembles mammalian mitochondrial ribosome * Mostly bacteriostatic

Answer 14

* Doxycycline, Minocycline, Tetracycline * Broad-spectrum * Bacteriostatic * Activity against many aerobic and anaerobic Gram- positive & Gram-negative organisms * Entry via passive diffusion & energy-dependent transport unique to bacterial inner cytoplasmic membrane * Susceptible cells concentrate drug intracellularly * Bind reversibly to 30S subunit of ribosome, preventing binding of aminoacyl tRNA

Answer 15

• Widespread resistance (usually plasmid mediated) * 3 main mechanisms: * Impaired influx or increased efflux by active protein pump * Production of proteins that interfere with binding to ribosome * Enzymatic inactivation

Answer 16

• Most common use = severe acne & rosacea • Used in empiric therapy of community-acquired pneumonia (outpatients) • Can be used for infections of respiratory tract, sinuses, middle ear, urinary tract, & intestines • Syphilis (patients allergic to penicillin) ``` Drugs of choice for: • Chlamydia • Mycoplasma pneumoniae • Lyme disease • Cholera • Anthrax prophylaxis • Rickettsia (Rocky Mountain Spotted Fever, typhus) ``` Used in combination for: • H.pylori eradication • Malaria prophylaxis and treatment • Treatment of plague, tularemia, brucellosis

Answer 17

* Variable oral absorption (decreased by divalent & trivalent cations) * Doxycycline (lipid soluble) = preferred for parenteral admin. and good choice for STD’s and prostatitis * Minocycline = reaches high concentrations in all secretions (useful for eradication of meningococcal carrier state) * Concentrate in liver, kidney, spleen & skin * Excreted primarily in urine except doxycycline (primarily via bile) * TERATOGENIC – all cross placenta & are excreted into breast milk (FDA category D) SE • Gastric effects / superinfections (nausea, vomiting, diarrhea) • Discoloration & hypoplasia of teeth, stunting of growth (generally avoided in pregnancy & not given in children under 8y) • Fatal hepatotoxicity (in pregnancy, with high doses, patients with hepatic insufficiency) • Exacerbation of existing renal dysfunction • Photosensitization • Dizziness, vertigo (esp. doxycycline & minocycline)

Answer 18

* Tigecycline * Structurally similar to tetracyclines * Treatment of complicated skin, soft tissue and intra- abdominal infections Antibacterial spectrum • Broad-spectrum against multidrug-resistant Gram- positive, some Gram-negative & anaerobic organisms RESISTANCE • Little resistance • Not subject to same resistant mechanisms as tetracyclines (exceptions = efflux pumps of Proteus & Pseudomonas species)

Answer 19

PK • IV only • Excellent tissue & intracellular penetration • Primarily biliary/fecal elimination ``` SE • Well tolerated • AE similar to tetracyclines Contraindications • Pregnancy & children <8y ``` * Increased risk of mortality has been observed with tigecycline compared with other antibiotics when used to treat serious infections * FDA recommends considering the use of alternative antimicrobials when treating patients with serious infections

Answer 20

* Amikacin, Gentamicin, Tobramycin, Streptomycin, Neomycin * Bactericidal * Associated with serious toxicities * Largely replaced by safer antibiotics * Most active against aerobic Gram-negative bacteria * Anaerobes lack O2-dependent transport * Used mostly in combination * Empiric therapy of serious infections eg, septicemia, nocosomial respiratory tract infections, complicated UTI’s, endocarditis etc * Once organism is identified aminoglycosides are normally discontinued in favor of less toxic drugs Drugs of choice for: • Empiric therapy of infective endocarditis in combination with either a penicillin or (more commonly) vancomycin • Streptomycin is the drug of choice for Plague (Y.Pestis) * Passively diffuse across membranes of Gram-negative organisms * Actively transported (O2-dependent) across cytoplasmic membrane * Bind to 30S ribosomal subunit prior to ribosome formation leading to: * misreading of mRNA, & * inhibition of translocation

Answer 21

3 principal mechanisms: • Plasmid-associated synthesis of enzymes that modify and inactivate drug • Decreased accumulation of drug • Receptor protein on 30S ribosomal subunit may be deleted or altered due to mutation

Answer 22

• Used as adjunct in treatment for hepatic encephalopathy ``` Alternative treatment options for hepatic encephalopathy: • Lactulose • Oral vancomycin • Oral metronidazole • Rifaximin ```

Answer 23

Other Effects • Prebiotic (suppression of urase producing organisms) • Osmotically active laxative Adverse Effects • Osmotic diarrhea • Flatulence • Abdominal cramping

Answer 24

* Parenteral admin. only (except neomycin - topical) * Once-daily admin. * Well distributed (excluding CSF, bronchial secretions) * High levels in renal cortex & inner ear * 99% excreted in urine (reduce dose in renal insufficiency) SE Both time- and concentration-dependent • Ototoxicity • Nephrotoxicity • Neuromuscular blockade (myasthenia gravis = contraindicated) • Pregnancy (contraindicated unless benefits outweigh risks – FDA Category D)

Answer 25

* Erythromycin, Clarithromycin, Azithromycin, Telithromycin * Mainly used to treat Gram-positive infections * Bacteriostatic (bactericidal at high conc.) * Most active against Gram-positive bacteria (some activity against Gram-negatives) * Spectrum is slightly wider than that of penicillins * Azithromycin, clarithromycin & telithromycin have broader spectrum than erythromycin * Used in empiric therapy of community-acquired pneumonia (outpatient & in combination with B-lactam for inpatients) * Treatment of upper respiratory tract & soft-tissue infections (eg, Staph, H.influenzae, S.pneumoniae, enterococci) * Erythromycin = DOC for whooping cough (B.pertussis) * Common substitute for patients with penicillin allergy * Reversibly bind to 50S subunit inhibiting translocation * Binding site is identical or close to that for clindamycin & chloramphenicol

Answer 26

3 main mechanisms (usually plasmid encoded): • Reduced membrane permeability or active efflux • Production of esterase that hydrolyze drugs (by enterobacteriaceae) • Modification of ribosomal binding site (by chromosomal mutation or by a methylase) • Complete cross-resistance between erythromycin, azithromycin, & clarithromycin • Partial cross-resistance with clindamycin & streptogramins

Answer 27

* Clarithromycin, azithromycin, telithromycin = improved oral absorption, longer t1/2, increased bioavailability compared to erythromycin * Azithromycin & telithromycin = greater tissue penetration compared to other macrolides * Erythromycin, clarithromycin & telithromycin = CYP P450 inhibition (NOT azithromycin) SE • GI irritation • Hepatic abnormalities (erythromycin & azithromycin) • QT prolongation • Severe reactions are rare (anaphylaxis, colitis) CI • Statins (due to macrolides inhibiting CYP P450) • Telithromycin – fatal hepatotoxicity, exacerbations of myasthenia gravis, & visual disturbances -> don’t use for minor illnesses

Answer 28

* Potent inhibitor of protein synthesis * Broad-spectrum (aerobic & anaerobic Gram-positive & - negative organisms) * Bacteriostatic (usually) * Toxicity limits use to life-threatening infections with no alternatives * Very broad spectrum * Activity against Gram-positive and negative bacteria, including Rickettisae & anaerobes * N.meningitidis, H.influenzae, Salmonella & bacteroides = highly susceptible * Never given systemically for minor infections (due to adverse effects) • Serious infections resistant to less toxic drugs • When chloramphenicols penetrability to site of infection is clinically superior to other drugs • Active against many VRE • Topical treatment of eye infections (mainly outside US) * Enters cells via active transport process * Binds reversibly to 50S ribosomal subunit (site adjacent to site of action of macrolides & clindamycin) * Can inhibit protein synthesis in mitochondrial ribosomes -> bone marrow toxicity RESISTANCE • Presence of factor that codes for chloramphenicol acetyltransferase (inactivates drug) • Changes in membrane permeability

Answer 29

* Oral, IV or topical * Wide distribution (readily enters CSF) * Inhibits hepatic oxidases (3A4 & 2C9) ``` SE • GI distress • Bone marrow depression: • dose-related reversible depression • severe irreversible aplastic anemia • Gray baby syndrome (cyanosis), due to drug accumulation ```

Answer 30

* MOA = same as macrolides (binds to 50S subunit) * Mainly bacteriostatic * Primarily used against Gram-positive anaerobic bacteria (including bacteroides) * Anaerobic infections (eg, bacteroides infections, abscesses, abdominal infections) * Skin and soft tissue infections (streptococci and staphylococci, and some MRSA) * In combination with primaquine as an alternative in PCP * In combination with pyrimethamine as an alternative in toxoplasmosis of brain * Prophylaxis of endocarditis in valvular patients allergic to penicillin ``` RESISTANCE Due to: • mutation of ribosomal receptor site • modification of the receptor • enzymatic inactivation of drug • Most Gram-negative aerobes & enterococci are intrinsically resistant • Cross-resistant with macrolides ```

Answer 31

* Oral or IV * Good penetration (including abscesses and bones) SE • GI irritation (~ 20% people experience diarrhea) • Potentially fatal pseudomembranous colitis (superinfection of C.difficile) • Skin rashes (~10 %) • Neutropenia & impaired liver function

Answer 32

* Quinupristin, Dalfopristin * Given as a combination (act synergistically to have bactericidal action) * Long postantibiotic effect * Gram-positive cocci * Multi-drug resistant bacteria (streptococci, PRSP, MRSA, E.faecium) * Restricted to treatment of infections caused by drug- resistant Staphylococci or VRE Mechanism of action • Bind to separate sites on 50S bacterial ribosome • Resistance is uncommon

Answer 33

* IV only * Penetrates macrophages & polymorphonucleocytes * Inhibitors of CYP 3A4 SE • Infusion related (venous irritation, arthralgia & myalgia) • GI effects • CNS effects (headache, pain)

Answer 34

* Bacteriostatic (cidal against streptococci & Clostridium perfringens) * Most Gram-positive organisms (staphylococci, streptococci, enterococci, Corynebacterium, Listeria monocytogenes) * Moderate activity against mycobacterium tuberculosis * Treatment of multi-drug resistant infections Mechanism of action • Inhibits formation of 70S initiation complex • Binds to unique site on 23S ribosomal RNA of 50S subunit RESISTANCE • Decreased binding to target site • No cross-resistance with other drug classes

Answer 35

* Oral (100% bioavailable) & IV * Widely distributed (including CSF) * Weak reversible inhibitor of MAO SE • Well tolerated for short admin. (GI, nausea, diarrhea, headaches, rash) Long-term admin. can cause: • Reversible myelosuppression • Optic & peripheral neuropathy, & lactic acidosis CI • Reversible, nonselective inhibitor of MAO -> potential to interact with adrenergic and serotonergic drugs

Answer 36

• Narrow spectrum macrocyclic antibiotic • Activity against Gram-positive aerobes and anaerobes especially Clostridia • No activity against Gram-negative bacteria • Treatment of C.difficile colitis (in adults) • Inhibits bacterial protein synthesis by binding to RNA polymerase PK • When administered orally, systemic absorption is negligible but fecal concentrations are high SE • Main effects appear to be gastrointestinal disorders • The safety and effectiveness of fidaxomicin in patients < 18 years of age have not been established.

Answer 37

• Antibiotic belonging to monoxycarbolic acid class • Activity against most Gram-positive cocci, including MRSA and most streptococci (but not enterococci) • Only topical/intranasal agent with activity against MRSA • Intranasal: • Eradication of nasal colonization with MRSA in adult patients and healthcare workers • Topically: • Treatment of impetigo or secondary infected traumatic skin lesions due to S.aureus or S.pyogenes • Binds to bacterial isoleucyl transfer-RNA synthetase resulting in the inhibition of protein synthesis SE • Resistance develops if used for long periods of time • Mainly local and dermatologic effects (eg, burning, edema, tenderness, dry skin, pruritus)

Answer 38

* Broad spectrum, bactericidal drugs * Enter bacterium via porins * Inhibit bacterial DNA replication via interference with topoisomerase II (DNA gyrase) & IV * Classified into generations * Lower generations have excellent Gram-negative activity * Higher generations have improved activity against Gram- positives RESISTANCE • Emerged rapidly in 2nd generation (esp. C.jejuni, gonococci, Gram-positive cocci, P.aeruginosa & serratia). • Due to chromosomal mutations that: • encode subunits of DNA gyrase (eg, gonococci resistance) and topo IV • regulate expression of efflux pumps (eg, S.aureus, S.pneumonia, M.tuberculosis) • Cross-resistance between drugs occurs

Answer 39

1st - Nalidixic acid • Moderate Gram -ve activity • Uncomplicated UTI’s 2nd - Ciprofloxacin •Expanded Gram -ve activity • Some activity against Gram +ve and atypical organisms • Synergistic with B-lactams •Travelers diarrhea (E.coli) • P.aeruginosa (CF patients) • Prophylaxis against meningitis (alternative to ceftriaxone & rifampin) 3rd - Levofloxacin • Expanded Gram -ve activity • Improved activity against Gram +ve and atypical organisms • Excellent activity against S.pneumoniae • Prostatitis (E.coli) • STD’s (not syphilis) • Skin infections • Acute sinusitis, bronchitis, TB Community acquired pneumonia 4th - Gemifloxacin, Moxifloxacin • Improved Gram +ve activity and anaerobic activity • Community acquired pneumonia

Answer 40

``` Levofloxacin, moxifloxacin & gemifloxacin (excellent activity against S.pneumoniae, H.influenzae & M.catarrhalis) Used in treatment of pneumonia when: • First-line agents have failed • In the presence of comorbidities • Patient is an inpatient ```

Answer 41

* Good oral bioavailability * Well distributed into all tissues and fluids (including bones) * Iron, zinc, calcium (divalent cations) interfere with absorption * Dosage adjustments required in renal dysfunction (except moxifloxacin) SE • GI distress • CNS, rash, photosensitivity • Connective tissue problems (avoid in pregnancy, nursing mother, under 18’s) • QT prolongation (moxifloxacin, gemifloxacin, levofloxacin) • High risk of causing superinfections (C.difficile, C albicans, streptococci)

Answer 42

* Theophylline, NSAIDs & corticosteroids = enhance toxicity of fluoroquinolones * 3rd & 4th generation = raise serum levels of warfarin, caffeine & cyclosporine * Pregnancy & nursing mothers * Children < 18y (unless benefits outweigh risks)

Answer 43

* Sulfamethoxazole, Sulfadiazine, Sulfasalazine * Structural analogs of p-aminobenzoic acid (PABA) * Bacteriostatic against Gram-positive & Gram-negative organisms * Infrequently used as single agents (resistance) * Topical agents (ocular, burn infections) * Oral agents (simple UTI’s) * Sulfasalazine (oral) = ulcerative colitis, enteritis, IBD * Inhibit bacterial folic acid synthesis * Synthetic analogs of PABA (p-amino-benzoic acid) * Competitive inhibitors (& substrate) of dihydropteroate synthase

Answer 44

Plasmid transfers / random mutations that: • Altered dihydropteroate synthase • Decreased cellular permeability • Enhanced PABA production • Decreased intracellular drug accumulation

Answer 45

* Oral or topical * Can accumulate in renal failure * Acetylated in liver. Can precipitate at neutral or acidic pH -> kidney damage SE • GI distress, fever, rashes, photosensitivity are common • Crystalluria (nephrotoxicity) • Hypersensitivity reactions • Hematopoietic disturbances (esp. patients with G6PD deficiency) • Kernicterus (in newborns and infants <2 months)

Answer 46

• Warfarin, phenytoin and methotrexate can lead to increased plasma levels SE • Newborns & infants < 2 months (kernicterus) – drugs compete with bilirubin for binding sites on albumin

Answer 47

* Structurally similar to folic acid * Bacteriostatic against Gram-positive & Gram-negative organisms * UTI’s * Bacterial prostatitis * Bacterial vaginitis * Potent inhibitor of bacterial dihydrofolate reductase * Inhibits purine, pyrimidine & amino acid synthesis PK • Mostly (80-90%) excreted unchanged through kidney • Reaches high concentrations in prostatic & vaginal fluids SE • Antifolate effects (contraindicated in pregnancy) • Skin rash, pruritus

Answer 48

* Combination of trimethoprim & sulfamethoxazole * Bactericidal * Uncomplicated UTI’s (drug of choice) • PCP (drug of choice) * Nocardiosis (drug of choice) * Toxoplasmosis (alternative drug) * Respiratory, ear, sinus infections (H.influenzae, M.catarrhalis) Mechanism of action • Synergistic: inhibition of sequential steps in tetrahydrofolic acid synthesis

Answer 49

* Oral admin. generally (can be given IV) * Well distributed (including CSF) ``` SE • Dermatologic (common) • GI • Hematologic (hemolytic anemia) • AIDS patients = higher incidence • Contraindicated in pregnancy (esp. 1st trimester) ```

Answer 50

• Antimicrobial, amebicide & antiprotozoal • Activity against anaerobic bacteria (including bacteroides & Clostridium) • Bactericidal * Anaerobic conditions are vital for optimal activity * Undergoes reductive bioactivation of its nitro group by ferredoxin * Forms cytotoxic products that interfere with nucleic acid synthesis * C.difficile infections (drug of choice) * Anaerobic or mixed intra-abdominal infections * Vaginitis (trichomonas & bacterial vaginosis, G.vaginalis) • Brain abscesses * H.pylori eradication (in combination)

Answer 51

* Oral, IV, rectal or topical * Wide distribution (including CSF) * Elimination = hepatic metabolism SE • GI irritation, stomatitis, peripheral neuropathy (prolonged use) • Headache, dark coloration of urine • Leukopenia, dizziness, ataxia (rarer) • Opportunistic fungal infections • Disulfiram-like effect (avoid alcohol) • Use generally not advised in 1st trimester

Answer 52

* Urinary antiseptics. Oral agents with antibacterial activity in urine but little or no systemic effect * Use is limited to prophylaxis and treatment of lower UTI’s * Bacteriostatic & bactericidal * Active against many Gram-positive and Gram-negative bacteria * Reduction of nitrofurantoin by bacteria in the urine leads to formation of reactive intermediates that subsequently damage bacterial DNA * Slow emergence of resistance and no cross-resistance

Answer 53

Pharmacokinetics • Rapid elimination (only achieves adequate concentrations in urine) Adverse Effects • Anorexia, nausea & vomiting. •Neuropathies, hemolytic anemia (G6PD deficient patients) CI • Significant renal insufficiency • Pregnancy at term (38-42 weeks) • Infants <1 month (risk of hemolytic anemia)