Anti-infectives lecture Flashcards

Question

Quinine and related agents - Cautions

Answer 1

* reduce dose in liver or renal disease | * Glucose6-phosphate deficiency

Answer 2

* avoid in pregnancy- chloroquine can cause fetal ototoxicity * quinine preferred in pregnancy – more experience

Answer 3

• Chloroquine : Risk of retinopathy with probencid • Quinine: inhibits renal tubular secretion of digoxin; potentiates anti- coaggulant effect of warfarin; prolongs QT- avoid with other drugs that do the same

Answer 4

Pyrimethamine | Proguanil

Answer 5

Mechanism • Selective inhibition of dihydrofolate reductase in the parasite; should only be given in combination with the sulphonamide sulfadoxine PK • Well absorbed from the gut and undergoes extensive hepatic metabolism • The half-life is long, about 2-6 hours ADR • Photosensitive rashes, insomnia, megaloblastic anaemia due to inhibition of human folate metabolism (with high doses).

Answer 6

Mechanism • Its active metabolite, cycloguanil, inhibits folate production by inhibiting dihydrofolate reductase in both pre-erythrocytic and erythrocytic parasites PK • Well absorbed from the gut, metabolized by liver to produce cycloguanil, a potent active derivation • The half-life of proguanil is long, about 12-24 hours ADR • Mouth ulcers, epigastric discomfort, diarrhoea

Answer 7

• Derived from the Chinese herb qing hao; also known as sweet wormwood (Artemisia annua) • used for over 2000 years as a chinese herbal remedy, artemesinin and its derivatives (artemether) are some of the most potent anti-malarial drugs available • very rapid acting • Artemisinin now largely given way to the more potent dihydroartemisinin and its derivatives • artemether, artemotil, and artesunate • all converted back in vivo to dihydroartemisinin Mechanism • Inhibition of a parasite Ca2+-dependent ATPase • Exact mode of action unclear • Short half-life makes it unsuitable for chemoprophylaxis and risks resistance

Answer 8

CoArtem • artemethere plus lumefantrine (Riamet®) • first fixed dose combination of an artemisinin derivative with a second unrelated antimalarial compound • highly potent anti-malarial drug • beneficial against resistant strains Lumefantrine • an aryl amino-alcohol • acts over a longer period to eliminate residual parasites • active against all the human malaria parasites, including multi drug–resistant P. falciparum • Different mode of action, reduces risk of resistance developing • blood schizonticidal activity • exact mechanism unknown; suggested that it inhibits the formation of βhematin by forming a complex with hemin and inhibits nucleic acid and protein synthesis

Answer 9

Oral absorption is good (bioavailability > 60%) with peak concentrations usually achieved within 4 hours PK • Well absorbed from the gut • Rapidly hydrolysed to an active metabolite that has a short half-life of 2- 3h ADR • Abdominal pain, nausea, anorexia, diarrhoea, dizziness, headache, sleep disturbance, fatigue • Interactions

Answer 10

more variable oral bioavailability dependent on the excipients in the oral formulation

Answer 11

• Principles of malaria prophylaxis • Awareness about the risk of malaria, bites of mosquitoes should be avoided • Chemoprophylaxia and compliance • Diagnosis of febrile illness • Chemoprophylaxis • chloroquine plus proguanil • start 2-20 days before travel, continue for the duration of stay and for 1-4 weeks after return • ADR • common side effects at therapeutic dosage, not a guarantee against malaria • Standby treatment • Mefloquine, Quinine • Malaria is easily treatable early, delay in treatment can lead to serious/ fatal consequences • Chemoprophylaxis is NOT recommended for residents of endemic area

Answer 12

* cell wall synthesis, cell membrane function * DNA replication/repair, transcription, translation * antimetabolites

Answer 13

* RNA or DNA polymerase inhibitors * Reverse transcriptase inhibitors (retroviruses) * targets specific to particular virus

Answer 14

* Cell membrane | * DNA synthesis

Answer 15

1. Natural Penicillins, (penicillinG and penicillinV) 2. Penicillinase-resistant penicillins, (cloxacillin, dicloxacillin, nafcillin) 3. Aminopenicillins, (ampicillin, amoxicillin, bacampicillin) 4. Extended-spectrum penicillins, (mezlocillin, piperacillin, ticarcillin)

Answer 16

– Inhibit cell wall synthesis –inhibit transpeptidase that polymerizes murein glycopeptides

Answer 17

- widely distributed in body fluids | - rapid elimination

Answer 18

1. First-generation: [e.g., Cefazolin (Cefamezin ®) or (Totacef ®)]. 2. Second-generation: [e.g., Cefuroxime (Zinacef ®)]. 3. Third-generation: [e.g., Cefotaxime (Claforan ®) & Ceftazidime (Fortum ®) & Ceftriaxone (Rocephin ®)]. 4. Fourth-generation: [e.g., Cefepime (Maxipime ®) & Cefditoren (Spectracef ®)]

Answer 19

– Inhibit cell wall synthesis – similar to that of penicillins – More resistant to hydrolysis by b-lactamases

Answer 20

- widely distributed after absorption - ceforoxime, Ceftriazone, cefotaxime cross BBB - mostly renal excretion; 40% ceftriazone eliminated in bile

Answer 21

– Hypersensitivity | – Some cross sensitivity seen in ~10% penicillin-sensitive individuals

Answer 22

Vancomycin (Vancocin) is a complex and unusual tricyclic glycopeptide antibiotic. It is the only drug in its class; Vancomycin is bactericidal because it inhibits cell wall synthesis by altering the cell’s permeability. Vancomycin also inhibits the synthesis of RNA. As such, resistance to vancomycin has been limited to strains of group D streptococci. Vancomycin is exceptionally effective for treating gram-positive infections in penicillin-allergic patients & for penicillin- and methicillin-resistant staphylococcal infections; Vancomycin is used in treating bacterial septicemia, endocarditis, bone and joint infections, and pseudomembranous colitis caused by C. difficile - Vancomycin is ineffective for treating gram-negative infections

Answer 23

•After intravenous administration, plasma concentrations reach a peak approximately 1 hour after infusion •Vancomycin is not used in treating meningitis because of poor penetration into CSF.

Answer 24

•The most serious toxicities caused by vancomycin are ototoxicity and nephrotoxicity

Answer 25

• for patients with hypersensitivity and for pregnant patients. •Although it is excreted into breast milk, vancomycin is not contraindicated for breast-feeding women. Breast-feeding neonates and infants, however, should be monitored for vancomycin serum concentration to avoid potential toxicities

Answer 26

• Bacteria synthesize own folates (human cells have folate transporters)

Answer 27

– Sulfonamides (sulfamethoxazole; sulfadiazine) » resistance is common » now mostly used in combinations –synergy » co-trimoxazole – sulfamethoxazole combination with trimethoprim – severe skin rashes – restricted to treating pneumonia & toxoplasmosis – trimethoprim - selectively inhibits bacterial DHFR. Bacteriostatic » trimethoprim excreted unchanged in urine » Most commonly used for uncomplicated urinary tract infections – methotrexate - inhibits mammalian and bacterial DHFR (see oncology lectures) – Pyrimethamine – selectively inhibits parasitic DHFR (malaria)

Answer 28

• Cautions – avoid in renal insufficiency – ensure fluid intake sufficient (crystalluria) – avoid in pregnancy (folate!) & folate deficiency • ADR – rash, crystalluria – bone marrow suppression (easy bruising, sore throat) – seek immediate medical attention • Interactions – effect of warfarin increased

Answer 29

RNA polymerase forms complex with DNA Elongation of nascent RNA molecule Bacterial RNA polymerase is sufficiently distinct from eukaryotic RNA polymerase that selective inhibitors exist. • Rifampicin block RNA elongation 1st line drug for anti-mycobacterium rapid emergence of resistance – generally used in combination

Answer 30

``` • Inhibit bacterial ribosome • also may inhibit eurkaryotic ribosome → ADR • bacteriostatic (except aminoglycosides) ```

Answer 31

• Drugs – Doxycycline, oxytetracycline, lymecycline, minocycline, tetracycline • Mechanisms – Binding reversibly to the 30S ribosomal subunit, block tRNA binding – accumulate in gram positive bacteria – provides selectivity (also inhibits eukaryotic ribosome). – broad spectrum activity – resistance can arise (plasmid) • PK – bind cations (eg Ca2+,Al+ , Mg2+, Fe 2+) that impair absorption – take on empty stomach – after absorption can accumulate in bone and teeth – usually renal excretion – but less so with doxycycline (preferred for patients with renal impairment) • ADR – nausea & vomiting – UV photosensitivity • Cautions – exacerbated diabetes insipidus & myasthenia gravis -avoid – can worsen renal & hepatic insufficiency- avoid • Contraindications – pregnant women/children – deposited in teeth & bones • Drug interactions – antacids impair absorption

Answer 32

• Drugs – gentamicin, tobramycin, neomycin,streptomycin – drug resistance (plasmid) • Mechanism – Binding irreversibly to the 30S ribosomal subunit, inhibiting translation from mRNA to protein and also increase the frequency of misreading of the genetic code – low concentration: abnormal codon: anticodon leads to misreading of the message – high concentrations – translation stalls at AUG – Bactericidal – more activity in Gram-negative than Gram-positive – synergy with b-lactams (facilitates entry) • PK – not absorbed from gut –parenteral (i.v., i.m.) admin. instead » except for neomycin used for GI infections; ADR too significant for systemic use – may accumulate – need to monitor – adjust dose according to plasma conc – almost complete renal clearance • ADR – hypersensitivity – ototoxicity:auditory (tinnitus, deafness)& vestibular (nausea, dizziness) – nephrotoxicity ( damage to renal tubules) • Cautions – monitor plasma levels in patients with renal insufficiency • Drug interactions – Diuretics (furosemide) can potentiate nephrotoxicity

Answer 33

• Mechanism – Inhibition of transpeptidation: binding reversibly to the 50S subunit of the bacterial ribosome, inhibiting peptide bond formation by impairing the translation of mRNA – Bacteriostatic – Broad spectrum • Indications – often used to treat eye infection (topical) • ADR (non-topical admin.) – severe – rarely used systemically – significant GI effects -nausea & vomiting, diarrhoea – Inhibits erythropoiesis – hepatic toxicity

Answer 34

• Drugs – Erythromycin, clarithromycin – Macrolide = large ring lactone • Mechanism – Inhibition of translocation: binding reversibly to the 50S subunit of the bacterial ribosome, causing dissociation tRNA from its tranlocation site, therefore blocking translocation – bacteriostatic – resistance can arise from esterases (plasmid) • Indications – often used to treat respiratory tract infections – similar activity to penicillins – useful in patients with penicillin allergy • PK – oral bioavailability is variable and dependant on salt form (estolate often best) • ADR – nausea & vomiting, diarrhoea – hepatic toxicity • Cautions – prolong QT – avoid in patients with cardiac conduction problems • Interactions – Inhibits p450 so may affect metabolism of other drugs – avoid with other drugs that prolong QT

Answer 35

• Topoisomerase – eukaryotic: relieves tension in DNA (supercoils) that arise during replication – bacteria: allows separation of interlocking rings – (in bacteria, one topoisomerase is called DNA gyrase) Quinolones –inhibit bacterial but not eukaryotic topoisomerase –topoisomerase binds and nicks DNA, allows another strand to pass through, then re-ligates –quinolones promote dissociation of topoisomerase before relegation –resistance is not common

Answer 36

• Drugs – Ciprofloxacin, norfloxacin, Ofloxacin • Indications – broad sepctrum: gram positive & negative infections, less effective for treating staphlococci & cutaneous infections – Resistance is not common • PK – eliminated unchanged in urine – t1/2 1h – 6h • ADR – GI: nausea, vomiting, diarrhoea, abdominal pain – CNS- headache, dizziness, hallucinations, seizures • Cautions – avoid in epilepsy • Interactions – inhibition of P450 increases concentration of theophylline, warfarin, ciclosporin – antacids reduce their absorption

Answer 37

• Metronidazole It is an antiprotozoal agent but is also active against anaerobic bacteria such as Bacteroides, Clostridia spp. and some streptococci • Nitrofurantoin Prodrug activated by bacterial nitrofuran reductase to unstable metabolites inside bacteria causing DNA damage. Primary used to treat urinary tract infections in patients where other antibiotics are not tolerated • Polymyxins Damage to cytoplasmic membrane – Increase permeability by disorganizing the structure or inhibiting the function of bacterial membranes

Answer 38

``` • PK – Well absorbed orally, widely distributed; – Excreted into bile and reabsobed in the intestine; – Excreted in renal as acetylated; – It is well tolerated. • Clinical uses – For leprosy: dapsone and rifampicin; • ADR – Haemolytic anaemia; – Methemoglobinemia; – Gastriointestinal intolerance; – Fever, pruritus, rashes; – Erythema nodosum leprosum. ```

Answer 39

``` Bacteriostatic v bacteriocidal –Bacteriostatic »inhibit proliferation but do not kill »may allow immune system to eliminate infection »infection may re-emerge if treatment stopped too soon –Bacteriocidal » kill bacteria – a drug may be bacteriostatic against some organisms but bacteriocidal against other ```

Answer 40

• Choice of antibiotic – spectrum of anti-bacterial activity (narrow vs broad) » appropriate to organism » may test culture or likely choice based on nature of infection » narrow spectrum preferred if possible – resistance » local patterns? – PK » distribution to affected tissue; topical admin? » poor perfusion may limit response – ADR, drug interactions, cautions, contraindications – consider combination with other antibiotics

Answer 41

• Antibiotics associated diarrhoea – alter gut flora – allow replacement with other organism e.g. C. difficile – leads to diarrhoea – can be fatal in elderly – narrow spectrum antibiotic may be preferred over broad spectrum • Antibiotics can disrupt the normal flora (nonpathogenic microorganisms within the body) causing Superinfection (a secondary infection that occurs during antibiotic treatment); • This new infection is “superimposed” on the original infection. • A superinfection may occur with the use of any antibiotic, especially when these drugs are given for a long time or when repeated courses of therapy are necessary.

Answer 42

• Modification or bypass of target – by mutation or acquisition of extrinsic DNA – Staphylococus. aureus resistance to flucloxacillin » acquires an extra PBP2 to become MRSA – S. aureus resistance to mupirocin » Chromosomal mutations in low-level resistance » Plasmid-borne extra ILTS gene in high-level resistance – Rifampicin resistance in M. tuberculosis » Point mutations in RNA polymerase gene

Answer 43

• MRSA (methicillin-resistant Staphylococcus aureus) • Resistance developed against - Beta-lactam antibiotics - Aminoglycosides (Streptomycin) - Macrolides - Chloramphenicol - Sulphonamides (Sulpamethoxazole + Trimethoprim) - Rifampicin - Fusidic Acid - Quinolones • Vancomycin was the last resort against it but resistance has also developed • Linezolid (oxazolidinone– only drug that defies resistance at moment. Act on bacterial protein synthesis by inhibiting tRNA binding to 70s subunit. Active against gram positive, MRSA, anaerobes e.g. Cl. Difficile, pneumonia, septicaemia, skin and soft tissue infections

Answer 44

heterogeneous » single strand – (+) stranded viruses – immediately translated to protein – negative stranded viruses – virus encodes RNA dependant RNA polymerase to make (+) strand » double strand – RNA dependant polymerase to make mRNA » retroviruses – RNA reverse transcribed to DNA – DNA virus » poxviruses (smallpox); » herpesviruses (chickenpox, shingles, cold sores, glandular fever); » adenoviruses (sore throat, conjunctivitis); » papillomaviruses (warts). – RNA viruses » orthomyxoviruses (influenza); » paramyxovirusse (measles, mumps, respiratory tract infections); » Rubella virus (German measles) » Rhabdovirues (rabies) » Picornaviruses (colds, meningitis, poliomyelitis) » Retroviruses (AIDS, T-cell leukaemia) » Arenaviruses (meningitis, Lassa fever) » Hepadnaviruses (serum hepatitis) » Arboviruses (arthropod-born encephalitis, various febrile illnesses, e,g, yellow fever) –

Answer 45

heterogeneous » single strand – (+) stranded viruses – immediately translated to protein – negative stranded viruses – virus encodes RNA dependant RNA polymerase to make (+) strand » double strand – RNA dependant polymerase to make mRNA » retroviruses – RNA reverse transcribed to DNA – DNA virus » poxviruses (smallpox); » herpesviruses (chickenpox, shingles, cold sores, glandular fever); » adenoviruses (sore throat, conjunctivitis); » papillomaviruses (warts). – RNA viruses » orthomyxoviruses (influenza); » paramyxovirusse (measles, mumps, respiratory tract infections); » Rubella virus (German measles) » Rhabdovirues (rabies) » Picornaviruses (colds, meningitis, poliomyelitis) » Retroviruses (AIDS, T-cell leukaemia) » Arenaviruses (meningitis, Lassa fever) » Hepadnaviruses (serum hepatitis) » Arboviruses (arthropod-born encephalitis, various febrile illnesses, e,g, yellow fever)

Answer 46

 HIV (gp120) binds CD4+ on host T-cells – acts as receptor for viral proteins • Then viral surface glycoprotein, gp41 binds to co-receptor on host cell causing fusion to allow viral nucleic acid to enter host cell • Enfuviratide (T-20, a peptide, admin by s.c. injection) - interacts with gp41 to prevent fusion of viral and cellular membranes  In vitro resistance has already been identified due to mutations in the gp41  Variable response between individuals

Answer 47

``` • Drugs – amantadine – Rimantadine • Mechanism – only effective for influenza A (not B, C) – viruses endocytosed to endosome – influx of H+ through viral M2 ion channel leads to dissolution of matrix proteins prior to replication – amantadine inhibits M2 ion channel • ADR – confusion, depression, insomnia – not a popular drug ```

Answer 48

• Indications – herpes – shingles – cmv • Mechanism – inhibit viral polymerases – phosphorylated to triphosphate in cell – herpes encodes an efficient thymidine kinase that also phosphorylates other bases including guanosine – compete with endogenous nucleotide triphosphates – if incorporated, cause chain termination • Guanine derivatives - herpes – Acyclovir » Valaciclovir (acyclovir prodrug) – Penciclovir » Famciclovir (penciclovir prodrug) – Ganciclovir (effective against CMV, others are’nt) » Valganciclovir (ganciclovir prodrug) • PK – acyclovir p.o., iv. or topical – the prodrugs have better oral bioavailability • Cautions – Aciclovir » renal excretion (glomerular filtration and tubular secretion); ensure adequate hydration or crystallizes in renal tubule; reduce dose in renal impairment. – low neutrophil or platelet count (see below) • ADR – aciclovir » can cause local inflammation when give iv, topically » headache, diahorrea,nausea when given p.o. – ganciclovir » more ADR than others-30% patients have drug withdrawn » myelosuppression (esp. neutropenia, which may be countered with G-CSF) » 5% patients suffer headache, confusion, hallucinations route dependant • Contraindications – avoid ganciclovir & zidovudine – significant myelosuppression • Interactions – few with topical formuations – gangciclovir – avoid with other drugs causing myelosuppression – avoid with Primaxin® (imipenem + cilastin antibiotics) - risk of convulsion

Answer 49

``` • HIV is a retrovirus • zidovudine (azidothymidine, {AZT}) – phosphorylated by host kinase – substrate for reverse transcriptase – chain termination (azide) – unlike acyclovir no selectivity for infected cells – inhibit mitochondrial DNA polymerases – serious toxicity as a result – mostly in proliferating cells- neutopenia, anaemia • Lamivudine - analogue of cytosine – L not D stereoisomer (sugar) – doesn’t inhibit mitochondrial DNA polymerase – less toxicity • Abacavir - anolgue of guanosine • Didanosine - analogue of deoxyadenosine • Stavudine - analogue of thymidine • Zalcitabine - analogue of cytosine • Emtricitabine - analogue of cytidine ``` • ADR – lactic acidosis can be fatal » nausea, vomiting, abdominal pain, breathing problems, muscle weakness – individual drugs have additional ADR • Caution – avoid or dose reduction if hepatic or renal insufficiency • Drug Interactions – co-trimoxazole with lamivudine – increase concentration of lamivudine – ganciclovir with zidovudine – bone marrow suppression

Answer 50

• Drugs - Efavirenz- - delavirdine - nevirapine • Mechanism – bind RT but prevent it transferring dNTP to DNA – resistance develops – used in combination  Inhibit replication directly by binding non-competitively to reverse transcriptase. Binds to hydrophobic pocket close to (¬10A away), but not contiguous with, the active site. Leads to a conformational change in aspartate residues of the active site which reduces the enzyme’s ability to bind its natural substrate. • Caution – avoid or dose reduction if hepatic insufficiency • ADR – less than with nucleoside analogs • Drug Interactions – p450 substrates » p450 inhibitors increase concentration » p450 inducers reduce concentration

Answer 51

• Viral protease essential for maturation • non-cleaved virus buds from cells but is not infectious – Ritonavir – Saquinavir – Nelfinavir – Idinavir • ADR – metabolic dysfunction – raised cholesterol & triglyerides- statin or fibrate may be necessary – insulin resistance – fat redistribution – base of neck “buffalo hump” • Drug Interactions – inhibit CYP 3A4 –especially ritonavir – may increase metabolism of oral contraceptives – warn patients accordingly – risk of pregnancy

Answer 52

``` • Mechanism – Inhibitors of influenza neuraminidase – Viral envelop contains haemagglutinin which allows attachment to sialic acid in host cell membrane – same mechanism prevents virus release! – virus expresses neuraminidase which leaves sialic acid from membrane, allowing release • Inhibitors of neuraminidase – zanamivir – poor Foral, powder inhalation – oseltamivir - good Foral • prophylactic treatment for flu • effective against H5N1 “avian flu” ```

Answer 53

```  Superficial mycoses * Affect skin, hair and nails  Subcutaneous mycoses (tropical) * Affect connective tissue immediately below skin and muscle  Systemic (invasive) mycoses * Involve internal organs * Primary vs. opportunistic  Allergic mycoses *Affect lungs or sinuses * Patients may have chronic asthma, cystic fibrosis or sinusitis ```

Answer 54

``` • Ergosterol in place of cholesterol • 14a sterol demethylase is a fungal P450 enzyme • Inhibition of ergosterol synthesis compromises cell membrane structure and function • Fungistatic • Fungicidal if disrupt function of membranes involved in electron transport ```

Answer 55

• Terbinafine, naftifine, butenafine • Mechanism - Inhibits squalene epoxidase, prevent lanosterol synthesis • PK (Terbinafine) – oral and topical formulation – t1/2 ~300 hours- accumulates in skin, nails, fat – 99% plasma protein bound, – Distribution » concentrates in adipose tissue & epidermis –useful for dermatological infections » also reaches nails after prolonged oral administration – significant first pass metabolism; foral = 40% • ADR – well tolerated • Caution – hepatic insufficiency – can cause liver toxicity – monitor liver function • Drug Interactions – P450 inhibitors and inducers affect plasma concentration

Answer 56

• Imidazoles - ketoconazole, clotrimazole, miconazole • Triazoles - fluconazole, itraconazole, voriconazole – fluconazole first line therapy for systemic infections • Resistance – mutation in demethylase • PK – Ketoconazole- - good oral absorption and wide distribution - inactivated in liver, excreted in bile and urine - liver toxicity (rare but fatal) – fluconazole » Foralhigh concentrations and wide distribution (CSF, urine, saliva, ocular fluids) » Half life ~ 25h; 90% excreted unchanged by kidney; 10% in faeces – itraconazole » variable absorption (pH dependant) and not distributed to CSF, urine, saliva), extensive 1st pass, lipid-soluble, half-life ~36h » IV formulation with b-cyclodextrin formulation overcomes variable absorption – topical application » preferred for non-invasive disease » clotrimazole, miconazole, terconazole » not used systemically - toxic • ADR – unlikely from topical application – systemic » risk of liver toxicity with ketoconazole & itraconazole; fluconazole preferred » rash » nausea & vomiting • Contraindications - iv voriconazole not to be used in renal failure (cyclodextrin accumulates, causes CNS toxicity) – pregnancy – teratogenic – can cause heart failure – avoid in cardiac disease or with negative inotropic agents • Drug interactions – P450 inhibitors – remember that their target is related to p450 • Drugs that increase gastric pH will decrease blood levels of ketoconazole e.g. antacids, omeprazole, H2 blockers (Drug absorption depends on conversion to salt in acid pH)

Answer 57

• Mechanism – Bind ergosterol (with higher affinity than for cholesterol) – creates pore in membrane, altering fungal membrane permeability – Fungi with low ergosterol content are resistant • Nystatin – topical application only –not absorbed systemically from skin, vagina or GI tract – too toxic for systemic administration; mostly used for cutaneous infections – ADR: nausea, vomitting, diarrhoea • Amphotericin – Mechanism also involves disburbance in ion channel loss of K+ from cell – can be used systemically for invasive infections if essential – ADR » probably due to binding cholesterol » common after systemic admin » significant toxicity – anaphylaxis, convulsions, nephrotoxicity » test dose and monitor liver and kidney function, electrolytes and blood cell number – Poor Foral – but allows oral admin to treat GI fungal infections! – slow i.v. infusion – Caution - only use systemically in renal insufficiency if no alternative • Less toxic preparations: Liposomal Amp. , Amp. colloidal dispersion , AmpB lipid complex

Answer 58

``` Cyclic lipopeptide - interfere with fungal cell wall synthesis by inhibition of ß-(1,3) Dglucan synthase • Loss of cell wall glucan results in osmotic fragility • Active against Candida species including nonalbicans isolates resistant to fluconazole, Aspergillus spp. •Caspofungin -drug of choice for invasive aspergillosis or candidiasis which is unresponsive to other antifungal drugs ```

Answer 59

* Restricted spectrum of activity. * Acquired Resistance – due to monotherapy [decreased uptake, (permease activity), altered 5-FC metabolism (cytosine deaminase or UMP pyrophosphorylase activity)] * Candidiasis, Cryptococcosis, ?Aspergillosis - treated in combination with amphotericin B or fluconazole.

Answer 60

• Four main groups: Sporozoa, Ameoeba, Flagellates, Ciliates and others • Diverse feeding behaviour, with some being parasitic • Many have extremely complex life cycles, sometimes involving several hosts, reminiscent of the helminths

Answer 61

P. falciparum  The most important species as it is responsible for 50% of all malaria cases worldwide and nearly all morbidity and mortality from severe malaria  Found in the tropics & sub-tropics P. vivax  The malaria parasite with the widest geographical distribution  Seen in tropical and sub-tropical areas but rare in Africa  Estimated to cause 43% of all malaria cases in the world P. ovale  This species is relatively rarely encountered  Primarily seen in tropical Africa, especially, the west coast, but has been reported in South America and Asia P. malariae  Responsible for only 7% of malaria cases  Occurs mainly in sub-tropical climates

Answer 62

``` Clinical Features • Asymptomatic Colonization • Dysentery/Amebic Colitis • Extraintestinal Amoebiasis (e.g. liver abscesses) ```

Answer 63

Metronidazole (a nitroimidazole) • Mechanism – Kills the trophozoites but no effect on the cysts – pro-drug activated by bacterial nitroreductase found in anaerobes – active metabolite reacts with DNA and protein – resistance not common but increasing • Indication – infection with anaerobes, not active against aerobic bacteria • PK – p.o. or p.r. • ADR – rare • Caution – avoid alcohol – has same effect as Antabuse – pregnancy – mechanism of action is to cause mutation! • Interactions – Inhibits p450 –potential to inhibit metabolism of other drugs Amoebicidal drugs Diloxanide • Indication – For asymptomatic infected patients, and often given as a follow-up after the disease has been reversed with metronidazole.

Answer 64

• successful parasites live in, but do not kill their hosts • Unlike protozoa, helminths are large and have complex cellular structure • protozoa multiply within hosts expression of disease depends on host factors • helminths do not multiply within hosts severity of disease depends on parasite burden and immunologic response to parasites • direct destruction of tissue • hypersensitivity reactions • eosinophilia – occurs with helminths, not protozoa – results from tissue migration

Answer 65

• Anthelminthic drugs – Paralysing the parasite (e.g. by preventing muscular contraction); – Damage the worm such that the immune system can eliminate it; – Altering its metabolism (e.g. by affecting microtubule function). Mebendazole • Selectively inhibits nematode tubulin polymerization • Single dose, but second dose after 2 weeks to help prevent re-infection • Need to treat other close contacts to avoid re-infection • Little Foral so few ADR • Caution – pregnancy (some Foral if taken with high fat meal; evidence of teratogenicity in animal studies)

Answer 66

Vancomycin

Answer 67

B-Lactams (penicillins, cephlasporins, etc)

Answer 68

Bacitracin

Anti-infectives lecture Flashcards

(92 cards)