Anti-infectives lecture Flashcards
Block addition of amino acids
Cycloserine
The penicillins may be
bactericidal (destroy bacteria) or bacteriostatic (slow or stop multiplication of bacteria)
Mycobacterium tuberculosis
- Physiology and Structure
- Weakly gram-positive, strongly acid-fast, aerobic bacilli; Lipid-rich cell wall
- Resistant to disinfectants, detergents, common antibiotics and traditional stains
• Diseases
• Primarily infection is pulmonary; dissemination to any body site occurs most
commonly in immunocompromised patients and untreated patients
- Epidemiology
- Worldwide; one third population is infected with this organism
- Sixteen million existing cases of disease and 8 million new cases each year
• Treatment, Prevention and Control
• Multiple-drug regimens + prolonged treatment required to prevent
development of drug-resistant strains;
• Immunoprophylaxis with BCG in endemic countries;
• Control of disease through active surveillance, prophylaxis and therapeutic
intervention, and careful case monitoring.
Anti-mycobacterial Drugs - 1st line
- Isoniazid (INH)
- Rifampicin
- Ethambutol
- Pyrazinamide
Anti-mycobacterial Drugs - 2nd line
- Capreomycin
- Streptomycin
- Cycloserine
Latent tuberculosis infection
• Patient is infected with mycobacterium tuberculosis but symptom free;
immune system stimulation due to m. tuberculosis antigens
• Patient at risk of developing active disease in the future
• Treatment dependant on age, HIV status and liver function
• Patients <65yrs: 3 months of isoniazid (with pyridoxine) and rifampicin, or 6
months of isoniazid (with pyridoxine)
• Patients <35yrs where liver toxicity is a concern: 3 months of isoniazid (with
pyridoxine) and rifampicin; 6 months of isoniazid (with pyridoxine) if
interactions with rifamycins are a concern, e.g. in HIV or transplant patients
• For adults between the ages of 35 and 65 years, offer drug treatments only if
hepatotoxicity is not a concern
Active tuberculosis infection
• active TB, no CNS involvement, or active peripheral lymph node TB:
isoniazid (with pyridoxine), rifampicin, pyrazinamide and ethambutol for 2
months, then isoniazid (with pyridoxine) and rifampicin for a further 4 months.
• Active CNS TB: isoniazid (with pyridoxine), rifampicin, pyrazinamide and
ethambutol for 2 months, then isoniazid (with pyridoxine) and rifampicin for a
further 10 months.
• active spinal TB: CT or MRI scan for patients with neurological signs or
symptoms for CNS involvement. Manage direct spinal cord involvement (for
example, a spinal cord tuberculoma) as TB of the CNS.
• Disseminated TB (including miliary TB): Test for neurological signs or
symptoms for CNS involvement. If CNS involvement, treat as for CNS TB
• In all cases, modify the treatment regimen according to drug susceptibility
testing
Isoniazid - mechanism
• Prodrug; activated by bacterial enzymes, exerts inhibitory activity on
synthesis of mycolic acids – unique to cell wall of myobacteria
• Bacteriostatic at low conc, & Bacteriocidal at high conc
Isoniazid - PK
• Readily absorbed from GIT; diffuse into all body fluids (e.g. CSF) and
tissues
• Metabolized in liver by acetylation
• usually renal excretion
Isoniazid - ADR
- Peripheral and optic neuritis
- Allergic reaction
- Hepatitis
- Gastric upset
- Haemolytic anaemia
- Enzyme inhibitor
- CNS toxicity
Rifampicin - mechanism
• Inhibits subunit of bacterial DNA-dependent RNA polymerase, inhibiting
transcription;
• Bacteriocidal
Rifampicin - PK
- Well absorbed orally;
- Adequate CSF conc;
- Excreted mainly through liver to bile
Rifampicin - ADR
- Harmless red-orange colour to urine, sweat, tears, contact lenses;
- Rashes;
- Thrombocytopenia;
- Nephritis;
- Cholestatic jaundice, hepatitis;
- Flu-like syndrome;
- Induce cytochrome p-450
Indication of 2nd line treatment
- Resistance to the drugs of 1st line;
- Failure of clinical response;
- Increase of risky effects;
- Patient is not tolerating the first line drugs
Capreomycin
• It is an important injectable agent for treatment of drug- resistant tuberculosis
• nephrotoxic and ototoxic
• should not be given at the same time as streptomycin or other
drugs that may cause deafness
• 2nd line anti-mycobacteria drug
Malaria
• transmitted by the female anopheles mosquito
Malaria life cycle
- Infected mosquito transmits parasite, in the form of
sporozoites, into the bloodstream - Pre-erythrocytic or hepatic phase. Sporozoites
mature into schizonts which rupture to release
merozoites (3). Duration of this phase depends on
the species.In P. vivax and P. ovale, the schizont
may also differentiate into hypnozoites, dormant
forms of the parasite which may remain in the liver
for several months or years and cause relapse in
the human host.
3 Asexual phase (Erythrocytic schizogony)
Merozoites invade erythrocytes, grow and
mature into trophozoites which appear as ring
forms. The trophozoites develop into schizonts.
Infected cells rupture, releasing numerous
merozoites to infect other cells and causing
fever, chills, rigours and other symptoms of
malaria infection.
4 - 7. Sexual phase
Some merozoites differentiate into male and female gametocytes, which are taken up by mosquitos
during a blood meal. These fuse to form an ookinette in the gut lumen, which invades the stomach
wall to form the oocyst. This in turn develops and releases sporozoites which migrate to the salivary
gland of the mosquito.
Clinical presentation - Malaria
- Malaria – infectious disease caused by Plasmodium protozoa
- Transmitted by mosquito bites
- Initially multiply in liver – this stage largely asymptomatic
- 1-12 weeks after bite, release and multiply in host erythrocytes,
- parasite metabolizes haemoglobin, releasing toxic haem
- cell lysis
Symptoms (malarial paroxysm):
• Initially headache & lack of energy, muscle aches, chills
• fever – up to 40°C
• diarrhoea & vomiting, loss of appetite
Main therapeutic options for the treatment of uncomplicated
falciparum malaria in adults
• oral quinine plus doxycycline (or quinine plus clindamycin in certain
circumstances)
• Artemisinin combination therapy (ACT)
• Atovaquone plus proguanil (Malarone®)
• Mefloquine is effective however not recommended due to side effects and high
rate of non-compliance
Quinine
- derived from cinchona bark
- quinine, chloroquine, quinimax, amodiaquine, mefloquine, halofantrine
- chloroquine is the most widely used
Quinine and related agents - Mech of action
• Quinine/chloroquine etc., pyrimethamine, sulfadoxine, sulfones, tetracyclines all
blood schizonticidal agents
• To prevent toxicity, Haem is polymerized to haemozoin by the parasite
• Chloroquine and quinine inhibit haem polymerase, resulting in haem toxicity in
the parasite
Quinine and related agents - - PK
- good Foral
- t1/2 ~ 45 days due binding to tissue
- metabolized by liver and renal excretion
Quinine and related agents - ADR
- Chloroquine : nausea, vomiting diarrhoea, hot flush, rash
* Quinine: Cinchonism: tinnitus, deafness, headache, nausea, visual effects
Quinine and related agents - Cautions
- reduce dose in liver or renal disease
* Glucose6-phosphate deficiency
Quinine and related agents - CI
- avoid in pregnancy- chloroquine can cause fetal ototoxicity
- quinine preferred in pregnancy – more experience
Quinine and related agents -
Interactions
• 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
Anti-malarial drugs:
Pyrimethamine
Proguanil
Pyrimethamine - Mechanism, PK, ADR
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).
Proguanil - Mechanism, PK, ADR
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
Artemesinin
• 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
Artemesinin combination therapy
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
Artemesinin
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
Dihydroartemisinin
more variable oral bioavailability dependent on the excipients in the oral
formulation
Prophylaxis
• 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
Anti bacterial agents (antibiotics)
- cell wall synthesis, cell membrane function
- DNA replication/repair, transcription, translation
- antimetabolites
Anti-viral agents
- RNA or DNA polymerase inhibitors
- Reverse transcriptase inhibitors (retroviruses)
- targets specific to particular virus
Anti Fungal agents
- Cell membrane
* DNA synthesis
There are four groups of penicillins
- Natural Penicillins, (penicillinG and penicillinV)
- Penicillinase-resistant penicillins, (cloxacillin, dicloxacillin, nafcillin)
- Aminopenicillins, (ampicillin, amoxicillin, bacampicillin)
- Extended-spectrum penicillins, (mezlocillin, piperacillin, ticarcillin)
penicillin mechanism
– Inhibit cell wall synthesis –inhibit transpeptidase that polymerizes murein
glycopeptides
penicillin PK
- widely distributed in body fluids
- rapid elimination
There are four groups of cephalosporins
- First-generation: [e.g., Cefazolin (Cefamezin ®) or (Totacef ®)].
- Second-generation: [e.g., Cefuroxime (Zinacef ®)].
- Third-generation: [e.g., Cefotaxime (Claforan ®) & Ceftazidime
(Fortum ®) & Ceftriaxone (Rocephin ®)]. - Fourth-generation: [e.g., Cefepime (Maxipime ®) & Cefditoren (Spectracef ®)]
cephalosporins mechanism
– Inhibit cell wall synthesis – similar to that of penicillins
– More resistant to hydrolysis by b-lactamases
cephalosporins PK
- widely distributed after absorption
- ceforoxime, Ceftriazone, cefotaxime cross BBB
- mostly renal excretion; 40% ceftriazone eliminated in bile
cephalosporins ADR
– Hypersensitivity
– Some cross sensitivity seen in ~10% penicillin-sensitive individuals
Vancomycin
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
Vancomycin PK
•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.
Vancomycin ADR
•The most serious toxicities caused by vancomycin are ototoxicity and nephrotoxicity
Vancomycin CI
• 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
Anti-folates (1): class II reaction
• Bacteria synthesize own folates (human cells have folate transporters)
Anti-folates (2)
• Drugs
– 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)
Anti-folates - cautions, ADR, interactions
• 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
Inhibitors of
bacterial transcription
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
Inhibitors of translation
• Inhibit bacterial ribosome • also may inhibit eurkaryotic ribosome → ADR • bacteriostatic (except aminoglycosides)
Tetracyclines
• 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
Aminoglycosides
• 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
Chloramphenicol
• 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
Macrolides
• 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
DNA synthesis: Class III reaction
• 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
Quinolone antibiotics: “-floxacins”
• 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
Miscellaneous and Less common
Antibacterial Agents
• 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
Drugs used in Leprosy: Dapsone
• 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.
Antibiotics -general comments (1)
Effects of antibiotics
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
Antibiotics -general comments (2)
Spectrum of activity
• 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
Superinfections
• 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.
Antibiotics -general comments (3) Drug resistance (i) – genetic determinants
• 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
The “Super Bug” Issue
• 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
Types of virus
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)
–
Types of virus
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)
Fusion/Entry Inhibitors
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
Inhibitors of uncoating
• 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
Guanine nucleoside analogs
• 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
Nucleoside analogs used to treat HIV
• 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
Non-nucleoside inhibitors of reverse
transcriptase to treat HIV
• 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
HIV protease inhibitors
• 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
Inhibition of virus release
• 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”
Types of fungal infections - Mycoses
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
Fungal cell membrane
• 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
Allylamine and benzylamines
• 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
Azole anti-fungals: Imidazoles and triazoles
• 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)
Polyene antifungals
• 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
Echinocandins
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
Flucytosine
- 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.
Protozoa
• 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
Plasmodium (malarial parasites)
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
AMOEBIASIS
Clinical Features • Asymptomatic Colonization • Dysentery/Amebic Colitis • Extraintestinal Amoebiasis (e.g. liver abscesses)
Amoebicidal drugs
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.
Helminthic Infections
• 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
Anhelminthic drugs
• 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)
Prevent modification
Vancomycin
Prevent polymerisation
B-Lactams (penicillins, cephlasporins, etc)
Prevent dephosphorylation
Bacitracin
