Chap 34: Antiplatelet agents, drugs used in bleeding disorders

Introduction
- PLT regulated by 3 categories of substances

• agents outside plt, act on plt membrane receptors - catecholamines, collagen, thrombin, prostacyclin
• agents generated inside plt, act the same - ADP, prostaglandin D2, E2, serotonin
• agents generated inside plt, act inside plt - prostaglandin endoperoxides, Tx A2, cAMP/GMP

- hence the groups of antiplatelet agents

• PG synthesis inhibitor - aspirin
• ADP-induced plt aggregation inhibitor - clopidogrel, ticlopidine
• glycoprotein IIb/IIIa receptor blockers - abciximab, tirofiban, eptifibatide

ASPIRIN
- Tx A2 - arachidonate product --> plt change shape, degranulate, aggregate
- aspirin --> cyclooxygenase inhibitor irreversibly --> reduce tx A2
- other NSAIDs + salicylates --> do the same but action is reversible hence not used as antiplt


CLOPIDOGREL + TICLOPIDINE
- irreversibly block ADP receptors on plt
- use

• PTI with stent - prevent re-thrombosis
• prevention of vascular events - TIA, completed strokes, unstable angina

- SE

• GIT - nausea, dyspepsia, diarrhoea - 20% pt
• hemorrhage - 5%
• neutropenia - 1% (very serious) - regular monitoring WCC in first 3 months

- clopidogrel has fewer SE than ticlopidine - rarely assoc with neutropenia
- clopidogrel - dose dependent efx - hence need loading dose 300mg (80% plt inhibition) - 75mg maintenance - takes 7-10 days to reach antiplt efx hence the same time to wean off


Aspirin + clopidogrel resistance
- no objective studies
- varies from 5%-75% where thrombosis happens despite rx


GLYCOPROTEIN IIb/IIIa RECEPTOR BLOCKERS
- used in acute coronary syndromes
- IIb/IIIa complex acts as receptors for fibrinogen, vitronectin, fibronectin, and vWF --> as final common pathway of plt aggregation
- average plt has 50,000 copies of receptors --> ppl lacking these receptors = Glanzmann's thrombasthenia --> bleeding tendency

- abciximab - monoclonal antibody - used in PTI and ACS
- eptifibatide
- tirofiban - smaller molecule than eptifibatide - inhibit ligand binding to IIb/IIIa receptor


OTHER ANTIPLTs
- dipyridamole

• vasodilator
• inhibit adenoside uptake + cGMP phosphodiesterase activity
• by itself - no beneficial efx - need to combine with aspirin to prevent cerebrovascular ischaemia

- cilostazol - newer phosphodiesterase inhibitor --> promotes vasodilation + (-) plt aggregn


DRUGS USED IN BLEEDING DISORDERS
Vitamin K
- fat soluble, found in leafy green veges
- human get it from veges + gut bactera
- confers biologic activity on factor 2,7,9,10 by modifying them
- 2 forms - K1 and K2 - K1 found in food, K2 found in human tissue + synthesised by bacteria
- requires bile salt for absoprtion
- onset 6 hrs, compete by 24 hrs
- best given IV + po, not sc (erratic)
- given to all newborn to prevent hemorrhagic disease of newborn (common in premature infants)

Plasma fractions
- spontaneous bleeding occurs when factor activity <5-10% of normal
- commonest: hemophilia A and B (christmas disease, IX deficiency)
- preparation

• prepared from large pools of plasma
• viral transmission elimited/reduced by pasteurisation
• but not prion disease
• now uses recombinant technology

- clinical usage

• if hemorrhage to joint --> infuse factor VIII/IX to maintain 30-50% of normal concentration for 24 hrs
• soft tissue hematoma = minimum of 100% factor activity for 7 days
• hematuria = 10% activity for 3 days
• surgery/major trauma = 100% activity for 10 days
• has loading + maintenance dose
• desmopressin acetate - increases VIII activity with mild hemophilia /vWB disease --> can use in minor surgery like tooth extraction - given intranasal

- cryoprecipitate

• plasma protein fraction from whole blood
• treat deficiencies/qualitative abnorm of fibrinogen
• eg DIC/liver disease
• hemophilia A and vWB disease if desporessin not indicated and other stuff not available --> last resort as cryoprecipitate not treated to reduce risk of viral transmission

Fibrinolytic inhibitor
- aminocaproic acid (EACA) - competitively inhibit plasminogen activation - po and rapidly cleared
- tranaxemic acid

• analog of EACA
• 15mg/kg loading, then 30mg/kg QID
• uses - adjunct therapy for hemophilia, bleeding from fibrinolytic therapy, prophylaxis for intracranial aneurysm, postop bleed (GI, prostatectomy, bladder hemorrhage, drug induced cystitis)
• SE: intravascular thrombosis

-

Chap 34: Fibrinolytic drugs

Introduction
- rapidly lyse thrombin by catalysing plasminogen --> plasmin
- plasmin itself cannot be used due to inhibiting enzymes

Pharmacology
- streptokinase

• made by streotpcocci - converts inactive plasminogen to plasmin

- urokinase

• human enzyme synthesized by kidney

- anistreplase

• anisoylated plasminogen streptokinase activator complex
• complex of purified human plaminogen + bacterial streptokinase
• allows rapid IV injection, allows greater clot selectivity

- tissue plasminogen activators

• preferentially activates plasminogen THAT IS BOUND TO FIBRIN
• in theory - only lyses formed thrombus - avoids systemic activation
• alteplase - recombinant DNA technology --> human tPA
• reteplase - same as alteplase with several amino acids deleted - less expensive to produce but less fibrin-specific than t-PA
• tenecteplase - mutant form of t-PA with longer T1/2

Thrombolytic drugs for AMI
- 20% reduction in mortality for pt with AMI
- PCI (intervention) = PTCA +- stent - better but if not available = thrombolysis
- pt selection is critical

• dx of AMI - clinical + ECG
• pt with STEMI and new onset BBB has best outcomes
• earlier the better, within 6 hrs onset of AMI

Other indication and dosage
- PE with hemodynamic instability
- severe DVT - SVC syndrome, ascending thrombophlebitis of iliofemoral vein - severe edema
- intraarterial PVD
- AMI:

• streptokinase: loading dose 250K units, then 100K U/hr for 24-72 hrs; beware antistreptococcal antibodies - fever, allergic reaction

- acute ischaemic stroke

• <3hrs>
• ensure not hemorrhagic infarct - better outcome
• check dosage as higher dosage 1.5million units --> increased bleeding risk

- d

Chap 34: warfarin + the coumarin anticoagulants

Chemistry + Pharmacokinetics

- formed from spoiled sweet clover silage --> hemorrhagic disease in cattle

- researchers found toxic agent = bishydroxycourarin

- synthesised derivative = warfarin (Wisconsin Alumni Research Foundation, arin from coumarin)

- initially used as rodenticides

- pharmacokinatics

• 100% oral bioavailability
• T1/2 36 hrs = hence take 2-3 days to establish the levels
• 99% albumin bound

- MOA

• block g-carboxylation of glutamine residue in factor 2,7,9,10, protein C, S --> inactive
• also oxidises Vit K
• Vit K needs to be reduced to be active - warfarin blocks activity of Vit K
• mutational change to Vit K epoxide reductase = genetic resistance to warfarin in human, especially rats
• 8-12 hr delay in warfarin action
• T1/2 of factor 2,7,9, 10 are 60, 6,24,40
• larger initial dose of warfarin to 0.75mg/kg hasten anticoagulant efx, above that effect is independent

- toxicity

• crosses placenta --> hemorrhagic disease of fetus, birth defect
• reduced protein C activity --> thrombosis --> cutaneous necrosis in skin, breast, fatty tissue, intestine, extremities

- warfarin resistance

• progression/recurrence of thrombotic event with therapeutic INR
• cancer pt most at risk, typically GIT ca --> can change to LMWH
• can have INR target raised

- drug interactions

• most drugs do
• but NOT ethanol, phenothiazines, benzos, paracetamol, opioids, indocid, most abs except (flagyl different)

- reversal

• may need longer FFP/factor VIIa due to long T1/2

-

Chap 43: Direct thrombin inhibitors

Introduction
- binds to active site of thrombin - rather than through antithrombin like heparin
- hirudin

• leech saliva
• available as recombinant form as lepirudin
• used by surgeons to prevent microvascular thrombosis - reattaching digits
• lepirudin used in pt with HITS
• monitored using APTT

- bivalirudin

• rapid onset + offset
• short T1/2 - used in PTCA

- argatroban - like above, used in pt with HITS
- ximelagatran - oral agent, no monitoring needed

Chap 43: Drugs in coagulation II - anticoagulants - Indirect thrombin inhibitors

INDIRECT THROMBIN INHIBITORS
- binding of antithrombin --> enhances inactivation of Xa --> reduced thrombin formation
- UFH, LMWH, synthetic fondaparinux

Heparin
- heterogenous mixture of sulfated mucopolysaccharides
- binds to endothelium + plasma proteins
- binds to antithrombin --> accelerate 1000x inactivation of clotting factors, esp IIa, IXa, Xa
- UFH - composed of high molecular weight heparin (HMWH) + LMWH

• HMWH - inhibit all 3 factors as above --> marked anticoagulants
• LMWH - inhibit activated factor X - less efx on thrombin
• but trials show that LMWH are as effective as UFH --> hence used

- HITS

• systemic hypercoagulable state
• 1-4% of ppl treated with UFH minimum 7 days
• surgical pt - high risk
• thrombosis - venous and arterial (not so common)
• suspect when - PLT dropping, having new thrombus despite heparin
• Rx with direct thrombin inhibitor/fondaparinux

- monitoring

• UFH - aPTT
• LMWH - no need as weight beight measurement, unlike UFH - but levels can be determined by anti-Xa units

- reversal of heparin action - protamine

• protamine sulfate (basic peptide) - binds to heparin --> stable complex --> no anticoagulant activity
• 1mg protamine sulfate to 100 unit of heparin
• LMWH - partial neutralisation - limited studies 1mg protamine to 1mg enoxaparin
• protamine does NOT reverse fandaparinux

Chap 34: Drugs used in coagulation I - basic principles

BLOOD COAGULATION CASCADE
Intruduction
- end products - fibrin formation
- central role - thrombin
- thrombin

• cleaves peptides from fibrinogen to convert it into fibrin clot
• activates upstream clotting factors - more thrombin formation, activates factor XIII that stabilises clot
• platelet activator
• activates protein C pathway - enhances anticoagulation efx --> no thrombosis causing downstream ischaemia

Initiation of clotting - the tissue factor-VIIa complex
- main initiator = factor VIIa (TF)
- tissue factor

• transmembrane protein
• expressed outside vasculature, intravascularly not active
• exposure to damaged endothelium/blood = binding of factor VIIa + TF = complex --> activation of factor X, IX

- coagulation happens in activated cell surfaces mediated by Ca2+ --> EDTA is a chelator, used in test tubes
- antithrombin (AT) - endogenous anticoagulant --> inactivates IIa, IXa, Xa, XIa, XIIa

- Prot C & S - endogenous anticoagulant --> inactivates Va, VIIIa

- factor V leiden = mutation of factor V = resists inactivation by protein C + S --> thrombophilic

Fibrinolysis

- fibrin digestion by plasmin

- injury --> endothelium releases t-PA --> activates plasminogen to plasmin --> remodels thrombus and limits extension

- t-PA, urokinase, streptokinase - activates fibrinolytic system

- aminocaproic acid - inhibits fibrinolysis

- heparin + oral anticoagulants --> do not affect this pathway

Chap 55: Cancer chemotherapy

CELL CYCLE KINETICS
Introduction
- tumor stem cells

• subpopulation within tumor cells
• has ability to proliferate repeatedly --> hence metastasis
• chemotherapy agents aimed at targeting tumor stem cells
• by definition non-TSC is sterile (they are irreversibly differentiated) ie not target of ctx

- cell cycle specific (CCS) drugs

• effective against proliferating cells - G1 - hematological malig
• solid tumors with predominantly rapidly dividing/in growth faction

- cell cycle non-specific (CCNS) drugs

• many binds to DNA or damage microtubule good for both proliferating and non-proliferating cells - G1 and G0 (resting stage)
• but G1 stage cells would be more sensitive

Resistance to cytotoxics
- primary resistance

• no response on 1st exposure
• due to genomic instability
• brain ca, RCC, melanoma

- acquired resistance

• mutation in chemosensitive tumor cells
• expression of normal gene - MDR1 gene
• expression of abnormal gene - multidrug resistance protein 1 (MRP1) gene

POLYFUNCTIONAL ALKYLATING AGENTS
- bisamines, cyclophosphamide, mechlorethamine, melphalan, chlorambucil
- MOA

• transfer alkyl groups to varius cellular components --> likely DNA --> cell death (N7 position of guanine in DNA)
• cells most susceptible to alkylation at G1

- Resistance

• increased cell ability to repair DNA lesion, reduced permeability, increase gluthathione (inactivates alkylating agent)
• resistance to 1 alkylating agent = all generally

- SE

• direct vesicant efx - at site of injection (into peripheral v is ok - diluted immediated)
• systemic toxicity - affects fast growing tissues (bone marrow, GIT, reporudctive system)
• emetogenic - mediated by 5HT - use 5HT antagonist (ondansetron)

Related drugs acting as alkylating agents
- procarbazine

• oral agent
• use: Hodgkin's, NHL, brain tumors
• leukemogenic, teratogenic, mutagenic --> increased risk of 2ary cancer

- dacarbazine

• melanoma, HD, soft tissue sarcome

- altretamine
- cisplatin

• inorganic metal complex - discovered serendipitously that Pl inhibit division and induce filamentous growth of E coli
• exact mechanism unknown but likely alkylating agent
• solid tumors - small cell/NSCLC/oesophageal/gastric/H+Neck/GU - testicular, ovarian, bladder
• + bleomycin/etoposide --> cure nonseminomatous testicular ca
• nephrotoxic --> needs hydration

- carboplatin

• 2nd generation platinum analogue --> same spectrum of solid tumors
• toxicity --> myelosuppression, significantly less renal toxicity + GI toxicity than cisplatin
• don't need IV hydration --> widely replaced cisplatin

- oxaliplatin

• 3rd generation platinum
• MOA same
• used for tumors resistant to carbo + cis
• FOLFOX (5-FU, leucovorin) - advanced colorectal ca
• neurotoxic --> dose-limiting, peripheral sensory neuropathy (reversible)

ANTIMETABOLITES
- tumors has some quantitative differences in metabolism from norm cells
- inhibit nucleotide and nucleic acid synthesis
- methotrexate

• antifolate - binds to dihydrofolate reductase --> DNA inhibition
• toxicity - not metabolised, hence toxicity = dose administered
• efx of MTX reversed by leucovorin (5-formyltetrahydrofolate)

- premetrexed

• antifolate like MTX
• + cisplatin for mesothelioma/single agent in NSCLC
• myelosuppression, skin rash, mucositis, diarrhoea, fatigue

PURINE ANTAGONIST
- 6-MP and 6-TG

PYRIMIDINE ANTAGONIST
- 5-FU
- capecitabine
- cytarabine
- gemcitabine

CLINICAL PHARMACOLOGY FOR CHEMOTHERAPY
Introduction
- depends on

• growth fraction
• spontaneous cell death rate
• most cell in G0?
• hypoxic stem cells?
• cell cycle specific?
• hormonal control?
• drug metabolised by liver (cyclophosphamide) or tumor (capecitabine)?

- generally given in 3-4 wk pulse therapy - reason for norm cells to repair itself but not tumor - complete hematologic and immunologic recovery btw courses

The Leukemias
- acute childhood - good px
- acute adult
- chronic myeloid leukemia
- chronic

Breast cancer
- radiotherapy
- chemo
- hormonal - herceptin (trastuzumab) for HER-2 receptor +ve pt

Lung cancer
- NSCLC (majority - 75-80%) vs SCLC
- NSCLC - if advanced - bad px, best rx is avoid smoking + early detection
- SCLC - responds excellently to platinum

Testicular cancer
- platinum based therapy --> contributed much
- PEB - cisplatin, etoposide, bleomycin x3 cycles --> lead to cure

Melanoma
- relatively drug resistant
- dacarbazine, temozolomide, cisplatin most active
- high dose IL-2 has led to cures

Secondary malignancies + cancer chemotherapy
- AML commonest, happens as learly as 2-4 yrs, peaks 5 + 9 yrs
- alkylating agents, procarbazine, etoposide, ionizing radiation --> all leukaemogenic
- others not that much

Chap 53: Antiprotozoal drugs

TREATMENT OF MALARIA
Introduction
- 4 species but falciparum causes nearly all significant cx and deaths
- resistance a major issue with falciparum
- parasite life cycle

• anopheline mosquito --> inoculates sporozoite --> into blood stream --> invade liver cells --> schizonts mature in liver --> merozoites released from liver --> invade RBC --> gametocytes develop in RBC --> taken by mosquite
• it's the RBC infection that causes clinical illness
• falciparum + malariae --> 1 cycle of liver cell invasion --> then liver infection stops in 4wks --> treatment of erythrocytic parasites will cure infection
• vivax + ovale --> dormant hepatic stage (hypnozoite) --> needs to treat RBC and hepatic parasites to achieve cure

- drug classification

• tissue schizonticides - kills developing/dormant liver forms
• blood schizonticides - kills RBC parasites
• gametocides - kills sexual stage and prevent transmission to mosquitoes

- chemoprophylaxis and treatment

Chroloquine
- for rx and chemoprophylaxis, drug of choice for sensitive falciparum and other species
- MOA

• blood schizonticide + gametocytes (for v,o,m not f), not active for liver
• unclear MOA
• resistance - very common in f, increasing in v due to mutation of transporter (to bring drugs into RBC)

- clinical

• Rx: drug of choice in sensitive f and non-f, rapidly terminates fever (in 24-48 hrs) and clears parasite from blood (48-72hrs)
• used in resistant falciparum cos eliminates symptoms quickly - but some has partial genetic immunity
• primaquine is added for v and o to kill liver schizonts
• chemoprophylaxis - preferred agent in sensitive f
• amebic liver abscess - after failing flagyl

- SE

• C/I in psoriasis/porphyria - can precipitate acute attacks
• not used in retinal/visual field abnorm/myopathy
• otherwise - renal, liver, eye (blurring of vision), blood (G6PD def)

Quinine & Quinidine
- 1st line for f malaria esp severe disease cos resistance is uncommon
- derived for cinchona tree in South America (used for intermittent fever)
- quinidine is stereoisomer of quinine
- MOA

• blood schizonticide for all
• gametocidal for v and o (not f)
• NOT liver schizonticide
• overall unknown
• resistance - uncommon only in SEA (esp Thai-Burma border) - but still has partial efx

- clinical uses

• parenteral rx of severe f malaria - IV/IM - should change to po once pt improves
• po rx - use as 1st line in resistant area, if not use chloroquine, need to add on other agent (doxycycline in adults or clindamycin in kids) to shorten duration to 3 days
• babesiosis - 1st line therapy with clindamycin

- SE

• cinchonism - neuro stuff (tinnitus, headache, nausea, dizzy, flush, visual)
• hypersensitivity reaction
• blood - hemolysis, WCC drop, agranulocytosis, thrumbocytopenia
• hypoglycemia - induce insulin
• blackwater fever - marked hemolysis, hemoglobinuria due to quinine - pathogenesis unknown - ?hypersensitivity reaction to drug

Mefloquine
- effective for chloroquine-resistant f malaria
- recommended chemoprophylactic drugs
- blood schizonticidal f and v, not liver/gamet
- resistance uncommon except SEA (Thai burma)
- C/I - epilepsy, psych disorder, arrhythmia, cardiac conduction defects

Primaquine
- liver schizoncidal - only drug to eradicate dormant liver form of vivax, ovale
- gametocidal against 4 human malaria sp
- minimally RBC-cidal but insignificant
- resistance - PNG, SEA, central and south america - resistant vivax - needs repeated therapy for radical cure (eg for 14 days)
- clinical use

• radical cure of acute v and o - add blood agents like chloroquine
• terminal prophylaxis of v and o - prevent relapse
• PCP infection - add clindamycin

- SE

• C/I - granulocytopenia, methb, G6PD def

Antibiotics
- tetracycline + doxy - RBC-cidal, not liver
- clindamycin - slowly active in RBC

Artemisinin & derivative
- active component of herbal medicine of China - antipyretic for 2000 yrs 青蒿素
- analogues - artesunate (water soluble), artemether (lipid soluble)
- rapid blood schizonticidal - not liver
- resistance is not an issue
- important in MDR falciparum malaria - only drug against quinine-resistant strains
- short T1/2 hence not used in chemoprophylaxis
- expensive and widely avaible
- clinical use

• needs combination to treat highly resistant f malaria - with mefloquine

TREATMENT OF AMOEBIASIS
- Entamoeba histolytica
- spectrum of disease - asymptomatic intestinal infection/colitis/dysentry/liver abscess
- treatment options

• metronidazole & tinidazole
• iodoquinol
• diloxanide furoate
• paromomycin sulfate
• emetine & dehydroemetine

- d

Chap 47: Antimycobacterials

INTRODUCTION
- mycobacteria intrinsically resistant to most abx

• grow slowly - abx act on dividing cells
• can be dormant - completely resistant or killed very slowly
• lipid rich cell wall - impermeable to many agents
• intracellular pathogen - organism residing in macrophages are difficult to be entered
• development of resistance is notorious

- combination >2 drugs needed + long term treatment


ANTUBERCULOUS DRUGS
Introduction
- 1st line agents - RIPES
- I+R - 2 most active drugs - 9 months of both will cure 95-98% of cases
- addition of pyrazinamide to above for 1st 2 mths --> reduce duration to 6 mths
- ethambutol and streptomycin

• does not reduce duration of rx
• for coverage of resistant bugs while culture pending

- prevalance of resistance

• INH resistance in US 10%
• both INH and R resistance (MDR) 3%

Isoniazid (INH)
- most active drug
- less effective for atypicals
- penetrates into macrophages --> extracellular and intracellular microbes
- MOA

• inhibit mycolic acid synthesis - components of mycobacterial cell wall - cell death

- resistance

• drug resistance happens in 1 x 10*6
• TB lesions has 1 x 10*8 bacilli - resistant mutants are readily selected
• adding rifampicin - resistance 1 x 10*6 x 10*6 - much higher

- pharmacokinetics

• po - well absorbed
• penetrates all tissue including CNS
• metabolised by liver, renally excreted
• don't need to adjust dose in renal pt

- SE

1. hepatitis - commonest, up 3-4x normal - dont need to stop drugs, if clinically symptoms occur (loss of appetite, n/v, jaundice, RUQ pain - stop drugs promptly (causes liver cell necrosis)
2. peripheral neuropathy - due to relative pyridoxine deficiency (INH promotes pyridoxine excretion) - hence higher risk for alcoholic/malnutrition/DM/AIDS/uremia
3. immunologic - rash, fever, SLE
4. blood disorders - pyridoxine def anemia, tinnitus, GI discomfort

Rifampicin
- semisynthetic abx of rifamycin, produced by Streptomyces mediterranei
- g+ve/-ve, enteric bacteria, mycobacteria (bactericidal), chlamydia
- readily penetrates tissues, phagocytes --> enters abscess and lung cavities
- MOA

• binds to B-subunit of RNA polymerase --> (-) RNA synthesis
• resistance - point mutation - reduction in binding to polymerase

- clinical uses

1. mycobacteria infection
2. others - meningococcal carriage, Hib in kids, + fusidic acid = against staph carriage

- SE

1. orange tinge to bodily fluid
2. hepatitis
3. allergic type - rash, fever, thrombocytopenia

Ethambutol
- synthetic agent
- inhibits mycobacterial arabinosyl transferases --> needed for polymerization of arabinoglycan (component of cell wall)
- resistance - due to mutation unable to bind to transferases
- SE - retrobulbar neuritis - loss of visual acuity, red-green color blindness --> C/I in children too young to allow visual assessment

Pyrazinamide
- exact mechanism unknown
- use - important as 1st line agent to reduce rx time 6mths - as 'sterilizing' agent
- SE - liver toxicity, hyperuricemia (may provoke gout)

Streptomycin
- aminoglycoside - see chapter 45
- penetrate into cells poorly - mainly against extracellular tubercle bacilli

ALTERNATIVE 2ND LINE AGENTS
Introduction
- considered only

1. resistance to 1st line
2. failure of lcinical response
3. serious drug reactions
4. expert guidance to deal with the SE of the agents listed

- examples

• Ethionamide - related to INH - blocks mycolic acid
• Capreomycin - peptide protein synthesis inhibitor
• Cycloserine - inhibit cell wall synthesis
• Aminosalicylic acid (PAS) - anti-folate exclusively against TB
• Kanamycin & amikacin
• Fluoroquinolone
• Linezolid
• Rifabutin
• Rifapentine

DRUGS FOR ATYPICAL MYCOBACTERIA
- 10% of clinical practice in US - not M tuberculosis or M tuberculosis complex

• M avium complex - M avium, M intracellulare

- characteristics of atypical mycobacteria

• special lab characteristic
• present in environment
• not communicable btw person
• less susceptible to normal antiTB drugs

- usually need atypicals - tetracycline, macrolide, sulfonamides
- M kansasii - INH, R, ethambutol
- M avium

• common - important in AIDS
• combination agents - azythro/clarithro + ethambutol +- ciprofloxacin

DRUGS USED IN LEPROSY
- M leprae
- dapsone + other sulfones

• closely related to sulfonamides - same MOA
• resistance issue - used in combination with 3 agents - dapsone, rifam, clofazimine
• NB: dapsone can be used for PCP
• SE: hemolysis (common, esp in thos with G6PD deficiency), metHb, erythema nodosum (can be rx with steroids/thalidomide)

- rifampicin - usually in combination
- clofazimine

• phenazine dye - alternative to dapsone
• MOA unknown - DNA binding
• SE: skin discoloration - red brown to nearly black

Chap 44: Bacterial protein synthesis inhibitors - tetracyclines, chloramphenicol

Tetracycline, macrolide, clindamycin, chloramphenicol, streptogramin - all inhibit protein synthesis

TETRACYCLINE
General
- bacteriostatic
- g+ve and g-ve
- anaerobes, rickettsia, chlamydia, mycoplasma, protozoa
- most tetracyclines has similar antibacterial activity --> resistant ones can use doxy
- differences in clinical efficacy are minor - only differences are due to pharmacokinetics
- MOA

• partly passive diffusion; partly active transport into cell
• binds reversibly to 30S subunit of bacterial ribosome
• inhibit protein synthesis

- resistance

1. reduced influx/increased efflux of drug by active transport protein pump
2. ribosomal protection
3. enzymatic inactivation

Pharmacokinetics
- differences in excretion

• minocycline excreted in tears - eradicate carrier state of meningococcal infection

- excreted mainly in bile and urine --> enterohepatic circulation may contribute to maintenance of serum concentration level
- classified by serum T1/2

• short acting - chlortetracycline, tetracycline, oxytetracycline
• intermediate - demeclocycline, methacycline
• long acting - doxy, minocycline

Clinical uses
- drug of choice in atypical infections - mycoplasma, chlamydia, rickettsia, spirochetes
- H. pylori - in combination with other regimens
- Vibrio - cholera
- combined with aminoglycosides --> to treat plague, tularemia, brucellosis
- protozoal infection - E. histolytica, Plasmodium falciparum

SE
- GIT - N/V/D
- Bony structures and teeth - binds to Ca in newly formed bone and teeth - enamel dysplasia + retardation in bone growth - hence never give in <8 yo
- Liver
- Nephrotoxic - renal tubular acidosis, renal injury
- Photosensitization
- Vestibular reaction - dizziness, vertigo, n/v

CHLORAMPHENICOL
- binds to 50S ribosomal subunit - inhibit protein synthesis
- bacteriostatic
- active against rickettsia, NOT chlamydia, also g+ve, g-ve aerobic and anaerobic

Clinical use
- rarely used due to resistance, other alternatives, toxicity
- serious rickettsial infection - typhus, rocky mountain spotted fever
- alternative to B-lactams for meningococcal meningitis for pt with serious allergy
- eye infections - cos of its broad spectrum, penetration of ocular tissue + aqueous humor (*ineffective for chlamydial infection)

SE
- BM suppresion - reversible, dose-related - aplastic anemia (idiosyncratic, irreversible)
- newborn infants lack effective glucoronic acid conjugation mechanism --> accummulate drugs in serum --> grey baby syndrome (vomit, flaccid, hypotherm, gray, shock, collapse)
- GIT - N/V/D

Chap 49: Antivirals

INTRODUCTION
- needs to block viral entry/exit from host cell
- or active inside host cell
- hence toxicity relates to intefering host cell function

- viral infection --> replication peaks at/before manisfestation of clinical symptoms
- hence the reason for early initiation of therapy OR prevention of infection (chemoprophylaxis for influenzae A using amantidine)

- stages of viral replication

1. adsorption --> enter host cell
2. uncoating of viral neucleic acid
3. systhesis of early regulatory proteins --> nucleic acid polymerases
4. systhesis of RNA/DNA
5. systhesis of late, structural proteins
6. assembly of viral particles
7. release from cell

AGENTS FOR HSV and VZV
- acyclovir, famvir, valacyclovir
- acyclovir the earliest hence most studied

Acyclovir
- acyclic guanosine derivative
- requires 3 phosphorylation steps for activation --> eventually inhibit viral DNA polymerase
- clinical uses

• primary genital herpes - shortens duration by 5 days
• recurrent genital herpes - shortens by 1-2 days
• VZV - needs higher dosage

- SE

• generally well tolerated
• minor GIT SE: N/V
• neurotoxic - tremor, deliriumm seizure

Valacyclovir
- L-valyl ester of acyclovir
- rapidly converted to acyclovir after po
- serum levels 3-5x higher than with aciclovir

Famcyclovir
Penciclovir
Trifulridine

Agents against CMV
Ganciclovir
- affinity against CMV 100x more than aciclovir
- active against CMV, HSV, VZV, EBV, HHV-8

Valganciclovir
- converted into ganciclovir
- for treatment of CMV retinitis for pt with AIDS

Cidofovir
Foscarnet
Fomivirsen

Chap 48: Antifungal agent

Introduction
- human fungal infection increasing
- advances in surgery, cancer treatment, ICU, AIDS
- divided into

1. Systemic drugs (oral/parenteral) for systemic infections
2. Oral drugs for mucocutaneous infection
3. Topical drugs for mucocutaneous infection

SYSTEMIC ANTIFUNGALS FOR SYSTEMIC INFECTIONS
Amphotericin B
- produced Streptomyces nodosus --> both A + B --> only B in use
- polyene macrolide
- poorly absorbed orally unless intestinal infection
- no effect with renal/liver/dialysis pt
- MOA

• difference in lipid composition of fungal and mammalian cell membranes
• human: cholesterol; fungi: ergosterol
• amp B binds to ergosterol only --> creates pores in cell membrane --> leakage of intracellular ions and molecules --> cell death

- Resistance

• ergosterol binding is impaired by decreasing membrane concentration of ergosterol/mutation by modification of sterol molecule

- SE

• infusion related toxicity: very common - fever, chills, m spasm, vomiting, headache, hypoTN - slow down infusion rate/reduce daily dose or use pre-meds (PCM, antiH1, steroids)
• slower toxicity: renal damage happens in all pt with clinically significant dose of drug, abnorm LFT

- Clinical uses

• broadest spectrum antifungal - drug of choice of all life-threatening mycotic infection
• against all clinically significant yeasts - Candida, Cryptococcus neoformans
• endemic mycoses - H capsulatum, Blastomyces dermatitidis, Coccidiodes immitis
• pathogenic moulds - Aspergillus fumigatus, mocor

Liposomal amphotericin B
- due to SE --> this aim to bind more selectively to fungal ergosterol by being morel lipid soluble
AZOLES
General
- synthetic compounds
- depending on number of N atoms in zole ring - divided into

1. imidazole: ketoconazole, miconazole, clotrimazole
2. triazole: itraconazole, fluconazole, voriconazole

MOA
- inhibit fungal c-P450 enzyme --> inhibit ergosterol systhesis
- more selective to fungal one than human c-P450 --> causes SE

Clinical uses
- Candida, C. neoformans, endemic mycosis, dermatophytes
- Itraconazole + voriconazole --> aspergillus

SE
- nontoxic
- minor GI upset, liver abnormalities, hepatitis

Ketoconazole
- 1st oral azole
- hepatitis - less selective to c-P450 than other azoles

Itraconazole
- oral and IV form
- needs gastric acid for better drug absorption --> take it with coke!
- used in dermatophytoses and onychomycosis
- azole of choice in dimorphic fungi histoplasma, blastomyces, sporothrix

Fluconazole
- high water solubility --> hence better oral absorption
- better GI and hepatic tolerance --> widest therapeutic index
- for mucocutaneous candidiasis
- no activity against aspergillus + filamentous fungi

Voriconazole
- similar to itraconazole in activity
- less toxic than amphotericin B --> drug of choice in invasive aspergillosis

ECHINOCANDINS (capsofungin)
- newest class --> inhibit fungal cell wall synthesis
- IV form - extremely well tolerated in GIT and hepatitis
- indicated for salvage therapy with invasive aspergillosis that failed to response with amphotericin B

- Horvath - advantage of capsofungin over amphotericin

• very narrow spectrum
• has best coverage for candida and aspergillus but nothing else
• not as nephrotoxic as amphotericin
• ampho has broader coverage but nephrotoxic is a problem
  

ORAL ANTIFUNGALS FOR MUCOCUTANEOUS INFECTION
Griseofulvin
- from penicillium
- very insoluble fungostatic --> only use in dermatophytoses
- exact MOA unknown --> deposited in newly forming skin --> binds to keratin --> protect skin from new infection
- hence to be given 2-6 wks for hair/skin infection to replacement of infected keratin
- nail infection --> longer

Terbinafine
- systhetic allylamine
- keratophilic medication like griseo; but unlike griseo: fungicidal
- inhibit fungal enzyme (squalene epoxidase) --> accummulate sterol squalene (toxic to fungi)
- cure rate up to 90% for onychomycosis for 12wks duration --> better than itroconazole/griseo

TOPICAL ANTIFUNGALS
Nystatin
- polyene macroline (like amphotericin B)
- too toxic for parenteral admin --> only orals
- active against candida ==> for suppression of local candidal infection

Topical Azoles
- clotrimazole, miconazole
- shampoo form of ketoconazole for seborrheic dermatitis, pityriasis versicolor

Topical allylamines (terbinafine)
- tinea cruris and corporis

Chap 51: Clinical use of antimicrobial agents

Empirical therapy
- presumptive therapy
- justification: early intervation = better outcome

Approach to empirical therapy
- get clinical dx
- specimen for lab exam
- formulate microbiologic dx
- is empirical therapy necessary?
- start treatment
- monitoring of treatment

Choice of antimicrobial agents
- host factor

• PMHx - liver, renal, AIDS
• drug allergy
• age
• pregnancy status

- pharmacologic factor

• pharmacokinetics
• delivery of drugs to site of action
• SE
• drug interaction

ABX OF KNOWN INFECTIOUS AGENTS
Interpretation of culture results
Reasons for -ve results

1. wrong sample - give abx first, contaminated
2. wrong request - bacterial vs viral culture
3. non-cultivable organism/slow growing stuff - H. capsulatum, bartonella
4. non knowing special needs of culture medium

Susceptibility testing
- measures MIC - minimum drug concentration to INHIBIT organism growth
- or MBC - minimal bacteriocidal concentration
- usually MIC is measured
- only in severe cases where MBC is measured - meningitis, endocarditis, neutropaenic sepsis

Specialised assay methods
- B lactamase assay
- synergy studies

Monitoring therapeutic response - duration of therapy
- 2 methods

1. microbiology - cultures/specimens should become sterile
2. clinically - symptoms, inflammatory markers, radiology

- duration depends on pathogen, site of infection, host factor

• generally determined empirically
• serious infection: 7-10 days after pt is afebrile
• recurrent infections: longer

Clinical failures
- check culture
- check host
- check abx

Bacteriostatic vs bacteriostatic activity
- generally, cell wall agents are bactericidal

• aminoglycosides
• B-lactams abx
• isoniazid
• metronidazole
• pyrazinamide
• quinolones
• rifampicin
• vancomycin

- protein synthesis inhibitors are bacteriostatic

• chloramphenicol
• clindamycin
• ehtambutol
• macrolides
• nitrofurantoin
• oxazolidinones
• sulfonamides
• tetracyclines
• trimethoprim

- which to choose?

• immunocompetent - doesnt matter it's the same
• immunocompromised - bactericidal
• severe infection like meningitis/endocarditis/neutropaenic - bactericidal

- bactericidal agents divided into 2 groups

• concentration dependent killing - aminoglycosides, quinolones
• time dependent killing - B-lactams, vancomycin; bactericidal activity continues as long as serum concentration > MBC

Postantibiotic effect
- persistant suppression of bac growth after limited exposure
- reason:

1. reversible non-lethal damage to cell structures --> needs time to recover
2. drug still at binding site within periplasmic space
3. then need to synthesize new enzymes before growth will resume

Route of administration
- many have similar pharmacokinetic properties po vs iv

• tetracycline
• trimethoprim-sulfamethoxazole
• quinolones
• chloramphenicol
• metronidazole
• clindamycin
• rifampicin
• fluconazole

- IV are for:

1. critically ill pt
2. bacterial meningitis/endocarditis
3. cannot swallow
4. abx that are poorly absorbed orally

Management of antimicrobial drug toxicity
- usually able to switch
- some no alternatives - eg neurosyphilis has anaphylaxis to penicillin - needs desensatisation
- penicillin + cephalosporin <10%>

- penicillin + imipenem cross reaction - >50%



ANTIMICROBIAL DRUG COMBINATION
Rationale
- seriously ill
- polymicrobial infections - intra-abdominal abscess
- reduce resistance (eg TB)
- reduce dose-related toxicity with single agent
- enhanced inhibition/killing



Synergism and antagonism
- 2 drugs together - MIC/MBC using 1/4th of the dosage compared to using single agent
- see text how to calculate synergism and antagonism

• FIC (fractional inhibition concentration) index <=0.5 = synergism
• FIC index >=4 = antagonism

- 3 mechanisms of synergism

1. Blockade of multiple steps in metabolic sequences - eg in bactrim as folic acid p/way - against PCP
2. Inhibit enzymatic inactivation - amoxyl-clavulanic acid, timentin, tazocin
3. Enhancement of antimicrobials uptake - cell wall agents (penicillin) increases aminoglycoside uptake by bacteria - eg Staph, enterococci, Pseudomonas, strep

- 2 mechanisms of antagonism

1. Inhibition of cidal agents by static agents - cell wall agents need dividing cells to act upon - if stopping cell division = cannot work; eg: tetracycline + chloramphenicol inhibit cell wall agents
2. Induction of enzymatic inactivation - g-ve (enterobacter, pseudomonas, serratia, citrobacter) if given imipenem, cefoxitin, ampicillin - can induce B-lactamase secretion --> hence B-lactams will lose activity

Antimicrobial prophylaxis
Surgical vs non surgical

• Surgical - needs to cover common pathogen - typically cefazolin/cefalothin
• Non-surgical - for suspected exposure or immunocompromised - depends on situation

National Research Council Wound classification
- clean

• infection rate <2%
• elective
• primarily closed procedure - respiratory, gastrointestinal, biliary, genitourinary, or
  oropharyngeal tract not entered
• no acute inflammation and no break in technique

- clean contaminated

• infection rate 10%
• emergency of an otherwise elective as above
• minimal spillage/minimal break

- contaminated

• Infection rate 20%
• Acute nonpurulent inflammation
• major technique break or major spill from hollow organ
• penetrating trauma <>
• chronic open wounds to be grafted or covered

- dirty

• Infection rate 40%
• Purulence or abscess present
• preoperative perforation of respiratory, gastrointestinal, biliary, or oropharyngeal tract
• penetrating trauma > 4 hrs old

Chap 50: Misc antimicrobial agents

METRONIDAZOLE
- antiprotozoal + antibacterial (anerobes) - bacteroides, clostridium
- well absorbed po - use as 1st line
- crosses BBB
- iv/pr/po
- metabolised by liver
- clinical uses

• anerobes - intra-abdominal infection
• vaginosis - can use topically
• clostridium
• brain abscess

- adverse

• GI - N/V/D
• peripheral neuropathy with prolonged use (never discharge someone on long term flagyl) - irreversible

MUPIROCIN
- produced Pseudomonas fluorescens
- inactived after po --> only topical
- MOA and uses

• g+ve cocci - MSSA and MRSA
• inhibit isoleucyl tRNA synthetase
• can induce resistance
• topical treatment for minor skin infection - impetigo
• intranasal elimination of MRSA
• NOT recommended for long term ulcers/surgical wound due to emergence of resistance

NITROFURANTOIN
- g+ve, g-ve bacteria
- well absorbed - rapidly metabolised and excreted --> no systemic antibacterial action, only in urine - renal impairment can cause systemic toxicity
- clinically - prophylaxis of chronic UTI - keep urine pH <5.5 (enhances activity)
- SE - N/V, G6PD def (neuropathy, hemolytic anemia)

DISINFECTANTS, ANTISEPTICS, STERILANTS
Disinfectants - strong chemicals that inhibit/kill microbes
Antiseptics - disinfectants with low toxicity to host cell - used on mucous membrane, skin
Sterilants - kills vegetative cells and spores

Alcohol
- disinfectant + antiseptic - denatures proteins
- NOT sporicidal hence not sterilant
- ethanol and isopropyl alcohol (isopropanol)
- quick - kills vegetative bacteria, mycobacteria, many fungi, lipophilic viruses
- optimal concentration - 60-90% by volume in water
- disadvantages

• lack residual action - evaporate quickly
• skin drying effect - can add emollient
• damages corneal tissue - tonometer has to be wait till completely evaporated/water rinsed
• flammable

Chlorhexidine
- active for vegetative bac, mycobacteria, moderate against fungi and viruses
- strongly binds to bac membranes --> leakage of small molecules + precipitation of cytoplasmic proteins
- slower action than alcohol --> but has residual activity hence similar to alcohol action if used repeatedly
- most effective - g+ve cocci, inhibit spore germination
- less irritating to skini
- no oral toxicity (poorly gut absorbed) - can cause ototoxicity and neurotoxicity (never used in such surgeries)

Halogens
- Iodine

• most active antiseptic for intact skin
• bactericidal in 1 min; kills spores in 15 mins
• problems: hypersensitivity reaction, stains clothing + dressings

- Iodophors

• complexes of I2
• retain activity as above
• less irritating to skin + producing less toxicity

- Chlorine

• universal disinfectant - oxidizing agent - must be kept in air sealed containers
• inactivated by serum/blood/feces/urine/protein containing stuff --> hence surfaced must be cleaned before using

Chapter 46: Sulfonamides, trimethoprim

SULFONAMIDES
General
- sulfonamides are antifolate drugs
- basic formula --> similar to p-aminobenzoic acid (PABA)
- some microbes require extracellular PABA to form dihydrofolic acid --> form purine and nucleic acid


- mechanism of action - competitively competes with PABA as above
- susceptibility: g+ve, g-ve, nocardia, chlamydia, protozoa, some enteric bacteria (e coli, klebsiella, salmonella, shigella, enterobacter)
- rickettsia NOT inhibited by sulfonamides - stimulated by it

Resistance
- some bac dont have enzymes for folate systhesis - nothing to block
- overproduction of PABA due to mutation
- production of enzyme that has low affinity to sulfonamides

Pharmacokinetics
- po/iv - metabolised by liver --> urinary excretion *reduce dose for renal pt

Clinical uses
- hardly used anymore alone
- needs combination

TRIMETHOPRIM
- inhibits bacterial dihydrofolic acid reductase --> see diagram
- binds 50,000 times more efficiently than same enzyme
- creates synergism with sulfanamides
- combination is bactericidal vs bacteriostatic alone

Resistance - due to plasmid encoded mutation
- reduced cell permeability
- overproduction of dihydrofolate reductase
- mutation of reductase - reduced drug binding

Pharmacokinetics
- po or iv
- absorbed well orally
- 1:5 preparation with sulfamethoxazole - peak concentration in serum 1:20 (due to increased lipid solubility)
- concentrates in prostatic fluid and vaginal fluid (more acidic) --> more antibacterial activity
- renal excretion

Uses
- UTI - prostatitis
- PCP
- GIT - shigellosis, salmonella infection
- respi - strep pneumoniae, haemophilus, M catarrhalis, K pneumoniae
- not mycoplasma

SE
- antifolate --> megaloplastic anemia, bone marrow suppresion
- can give folinic acid for prevention

Chapter 45: Aminoglycosides

General
- active ingredient - hexose ring attaching to amino sugars
- works in synergism with B-lactams + vancomycin
- MOA: irresible protein synthesis inhibitor - exact mechanism unknown

• passive diffusion via porin channel across outer membrane (see B-lactamase cell wall)
• actively transported into cytoplasm
• binds to 30S subunit ribosomal protein
• inhibit protein synthesis

- resistance - NO activity against anaerobes

1. production of transferase enzyme/enzyme that inactivate aminoglycoside
2. impaired entry into cell --> mutation/deletion of porin protein
3. receptor protein on 30S ribosomal subunit deleted/altered

- pharmacokinetics

• poorly absorbed po unless has ulcers
• IM or IV
• cencentration-dependent killing + has postantibiotic effects (several hours) --> hence can be given OD rather than traditional TDS in smaller doses

- aminoglycoside toxicity

• concentration and time dependent
• toxic threshold achieved --> once the concentration achieved --> the time above the threshold becomes critical
• usually look at trough - hence the monitoring of genta at 12hrs post abx
• with OD dosing - unncessary to measure serum level in 3 days

- SE

• ototoxic - neomycin, kanamycin, amikacin
• nephrotoxic - neumycin, tobra, genta
• vestibulotoxic - streptomycin and genta
• likely to be encountered for therapy >5 days
• loop diuretics --> potentiate kidney damage
• don't use with concurrent nephrotoxic abx (vancomycin, amphotericin B)

- water soluble, cannot mix with B-lactams with administration

Spectinomycin
- alternative rx for gonorrhoea allerg to penicillin

Gentamicin
- isolated from Micromonospora purpurea
- g+ve and g-ve - inhibit staph and coliform and g-ve
- synergistic with B-lactams against pseudomonas, proteus, enterobacter, klebsiella, serratia, stenetrophomonas
- resistance

• strep and enterococci - failure of drug to enter cell --> add vanco or penicillin (break down cell wall)
• ribosomal resistance is rare
• mostly from plasmid - encoded aminoglycoside-modifying enzymes --> this type of resistance will be susceptible to amikacin

- clinical use

• IM/IV
• topical - infected burns/wounds/skin lesion
• intrathecal - g-ve meningitis

Tobramycin
- similar to genta in dose, frequency, chemical
- slightly different

• genta covers serratia better
• tobra covers pseudomonas
• E. faecalis susceptible to both
• E. faecium only to genta
• otherwise can interchange

- can be given via neb for Pseudomonas rx

Amikacin
- works with g-ve that are resistant to genta and tobra --> proteus, pseudomonas, enterobacter, serratia
- MDRTB

Netilmicin
Neomycin & kanamycin
- paromomycin member of the group
- active g+ve and g-ve but not strep and pseudomonas
- widespread use in bowel prep --> resistance
- limited to topical (joint injection/infected surfaces) or oral use

Chap 43: B-lactam abx + other cell wall inhibitors

General
- active structure: B-lactam ring
- group of families: penicillins, cephalosporin, monobactam, carbapanem - hence cross reaction can occur
- all b-lactams are renally excreted --> reduce in renal impairment

PENICILLINS
- penicillins - g+ve, g-ve cocci, g-ve rods resistant (e. coli)
- antistahy penicillins - nafcillin
- extended spectrum

Mechanism of action
- histology - layers of bacterial cell wall (1st two constitute cell wall)

• outer membrane (only in g-ve, lipid layer)
• peptidoglycan (very thick in g+ve)
• periplasmic space - where b-lactamase work
• cytoplasmic membrane - where b-lactams bine
• - binds to protein PBP (penicillin binding protein) in cytoplasmic membrane in bac cell wall - inhibit cell wall synthesis

- timentin --> can cause bone marrow dysfunction --> neutropaenia/thrombocytopenia (think about used in febrile neutropaenia)
- antipseudomonal penicillins --> home IV on piperacillin not timentin due to stability of solution in the baxter pump

CEPHALOSPORIN
- more stable than penicillin
- not active against enterococci and Listeria
- 4 major groups of increasing g-ve cover
- 1st generation: cephalothin, cephalexin, cefazolin, cephradine, cephapirin
- 2nd: cefamandole, cefoxitin
- 3rd: ceftriaxone, cefotaxime

ID stuff
Ceftazidime vs cefepeme
- antipseudomonal
- similar to timentin but lacks g+ve cover as compared to cefepeme
- hence cefepeme is the abx of choice in neutropaenic pt - to cover g+ve
- but for pseudomonas alone - should use ceftaz but reserve as last agent

MONOBACTAMS
- aztreonam
- g+ve, pseudomonas, serratia cover

B-LACTAMASE INHIBITOR
- clavulanic acid, sulbactam, tazobactams
- resemble B-lactam, but weak antibacterial action
- active against Staphy, H influenzae, N gonorrhoea, salmonella, shigella, E. coli, Klebsiella

CARBAPENEM
- structurally similar to B-lactam abx
- covers everything but NOT

• Enterococcus faecium
• MRSA
• C. difficile (use flagyl)
• Burkholderia cepacia
• Stenotrophomonas maltophilia (use bactrim)

VANCOMYCIN
- glycopeptide
- produced by Streptococcus orientalis
- inhibit cell wall synthesis
- has VRE and vancomycin resistant S. aureus (VRE significance - transmit VR into SA)
- syngergistic with genta and streptomycin against E faecium and E faecalis
- given IV, only orally for C. dificcile enduced enterocolitis (but due to emergency of VRE - metronidazole is used instead)
- SE: phlebitis, 'red man'/'red neck' syndrome - antihistamine release (give phenergan/slow down infusion)

- if someone on vancomycin - no use doing MRSA swab - it will come back -ve --> still needs isolation

TEICOPLANIN
- similar to vanco, but given IM and IV
- allows once daily dosing due to long T1/2 --> hence easier for home IV

Quinolones

QUINOLONES
- nalidixic acid as prototype
- DNA gyrase inhibitor
- DNA gyrase - uncoil DNA to for replication
- nalidixic acid + flurinated group = fluoroquinolone - increases antibacterial spectrum

Antibacterial activity

• g-ve aerobic bacteria and atypical cover (mycoplasma, chlamydia, legionella, mycobacteria)
  
• limited g+ve (covers MSSA, not MRSA)
  
• development of fluoroquinolone aims to cover more g+ve
• cipro, lemo, levo, oflox, peflox = good g-ve, moderate to good against g+ve
• cipro best for P. aeruginosa
• gati, moxi, spar, trova (3rd group) - covers Strep pneumoniae
  

Resistance

• Staph, pseudomonas, serratia
• Cross resistance happens

Pharmacokinetics

• IV = oral administration = hence give oral

Clinical

• UTI - norfloxacin concentrated in urine
• bacterial diarrhoea

SE

• QTc prolongation
• damage growing cartilage --> not recommended <18>
• tendinitis
  

Antibiotics - macrolides, ketolids, streptogramins, clindamycin

MACROLIDES IN GENERAL

• Have similar activity
  
• Major differences in side effects, half lives (frequency of dosage), admin method
• Obtained from streptomyces erythreus
• Binds to 50s ribosomal DNA - bacteriostatic/cidal depending on dosage and susceptibility
  

Erythromycin
- Activity

• G+ve stuff - pneumococci, strep, staph, corynebacterium
• atypicals - chlamydia, mycoplasma, legionella, helicobacter, listeria
• mycobacteria

- Resistance

• Plasmid encoded
• Cross-resistance complete btw all macrolides

- Clinical uses + SE

• Stimulates gut motility - used in post operative gut surgery to promote gastric emptying - only for erythromycin NOT other macrolides
• Due to this SE - we don't use them a lot routinely
• Liver toxic
• Inhibit cP450

Clarithromycin

• increased activity with g+ve (Horvath)
  
• advantage over erythromycin - lower GIT SE, better gut absorption - hence used in eradication of H. pylori

Azithromycin

• Difference from above - penetrates tissue extremely well - [tissue] > [serum] - hence slowly released from tissue = longer T1/2 of 3 days
  
• hence once daily dosing
• 1g = 7 day of doxycycline

KETOLIDES

• semisynthetic macrolide
• 3-keto group added
• eg: telithromycin

CLINDAMYCIN AND LINCOMYCIN
Lincomycin - no longer used due to toxicity
Clindamycin
- like erythromycin in activity - binds 50s ribosomal subunit - reduce toxin production - hence used in necrotising fasciitis (reduces exotoxin produced by Strep)
- covers g+ve (strep, staph, pneumococci) and anaerobes
- doesn't cover: enterococci, g-ve aerobic, clostridium
- bacteriostatic --> hence if someone has staph bacteremia --> treat with fluclox first to kill, then use clindamycin orally --> if not use clindamycin + other agents eg rifampicin (never use this alone)
- has excellent oral bioavailability (one of those to use orally unless mechanical reason, like ciprofloxacin)

- clinical uses

• has the best oral bioavailability for staph (1st clindamycin, 2nd fluclox, 3rd augmentin, last keflex)
• severe anaerobic infection (bacteroides)

- SE

• diarrhoea - major SE leading to disuse
• colitis - usually pseudomembranous

OXAZOLIDINONES
Linezolid
- g+ve: staph, strep, enterococci, listeria, corynebacteria
- binds to 23S ribosomal RNA of 50S subunit - unique to linezolid - hence there's no cross resistance
- problem: hematologic toxic - low PLT most common (3%), neutropaenia
- use: VRE