Sunday, March 16, 2008

Antibiotics - internet search - general guide



* Antibiotics may need dosage adjustment in patients with renal impairment.
* Calculate creatinine clearance and % of normal dose to be used
by the following formula:
(140-age) (weight in kg)
for men, (x0.85 for women)
(72)(serum creatinine)

* Note: Some abx do not need adjustement for patients with renal
insufficiency (e.g., amphotericin B, azithromycin, ceftriaxone,
chloramphenicol, clindamycin, doxycycline, nafcillin, pyrimethamine,


1. a) Natural penicillins:
Pen G and V indicated against streptococci, anaerobes (above
the diaphragm), syphilis, Listeria monocytogenes (high dose), dog and
cat bites (Pasteurella multocida ). Does not cover S. aureus.

b) Penicillinase-Resistant Penicillins (PRSP):
Methicillin / nafcillin / oxacillin / dicloxacillin are
indicated against penicillinase producing aureus (MSSA not MRSA) for
endocarditis, osteo.

2. Aminopenicillins:
* Ampicillin / Amoxicillin: G(+) coverage similar to above,
covers many G(-) in GI tract (Salmonella, Shigella, E. coli,
Proteus), N. meningitidis, 70% of H. influenza, Listeria, Nocardia.

* Amoxicillin + clavulanate = Augmentin. Covers most G(+)
except MRSA, and many G (-). Anaerobe coverage similar to group III.
Given PO.

* Ampicillin + sulbactam = Unasyn. Coverage to G(+) similar
to above and G(-) all except Serratia, Enterobacter, Pseudomonas,
Legionella. Anaerobe coverage as group III. Indication: GYN, GI and

3. Antipseudomonal penicillins:
* CarboxyPCN (carbenicillin and ticarcillin) and ureidoPCN
(mezlocillin =Mezlin(R) and piperacillin = Pipracil(R)) cover most
streptococci, and most G(-) with variable coverage for Klebsiella, M.
catarrhalis, Serratia, Legionella. No coverage for Staphylococcus
(except Timentin(R) and Zosyn(R)). Good anaerobic coverage (B.
fragilis, C. difficile ). Main indication is Pseudomonas aeuroginosa.

* Ticarcillin + clavulanate = Timentin(R). Covers G(+)
similar to Augmentin(R) and all G(-) except Legionella. Anaerobic
coverage like group III (B. fragilis, C. difficile).
* Piperacillin + tazobactam = Zosyn(R). Similar to
Timentin(R). Note that for serious Pseudomonas infections an
aminoglycoside should be added for synergism.


* The cross reactivity with PCN (5-10%) is a concern especially
if pt had anaphylaxis. In that case cephalosporins should be
completely avoided.
* Cephalosporins do not cover Listeria or Enterococcus.


* Cephalexin (Keflex), Cefazolin (Ancef). They cover all
streptococci, S. aureus (not MRSA) and S. epidermis. Among G (-) they
cover N. gonorrhea, M. catarrhalis, H. influenza , E. coli,
Klebsiella. Main indications are surgical prophylaxis and Strep. /
Staph. (not MRSA)


* can be further subdivided into "good for H. influenza"
-cefamandole (Mandol), cefuroxime (Ceftin, Zinacef) and "good for
anaerobes" -cefoxitin (Mefoxin), cefotetan (Cefotan). Similar G(+)
coverage as 1ST generation and better G(-) coverage including N.
meningitis (not the drug of choice for meningitis), Salmonella /
Shigella / Proteus and +/- Yersenia. Cefoxitin and cefotetan will
cover anaerobes below the diaphragm including B. fragilis and
Clostridium (not difficile) and are an excellent choice for GI
surgical procedures.

* Cefamandole & cefotetan interfere with vit. K and may produce
coagulopathy. Also rare disulfiram-like reactions have been
documented. Main indications are GI (colorectal surgery and
appendectomy), and Ob-Gyn procedures.


* Ceftriaxone
(Rocephin) & ceftazidime (Fortaz) are the two most commonly
used IV preparations. G(+) coverage is similar to 1ST and 2ND
generation. Ceftriaxone is indicated for the treatment of meningitis
since it has activity against H. influenza (resistant to PCN),
* N. gonorrhea and N. meningitidis and has good CSF penetration.
Ceftriaxone 125mg IM x1 dose is also used for the treatment of

* Ceftazidime is indicated against Pseudomonas. Anaerobic
coverage varies from one drug to the other. G(-) are generally
covered well except for atypicals (e.g. Legionella). Cefixime
(Suprax) and cefpodoxime (Vantin) are the only 3RD generation used PO.
Cefpodoxime has moderate G(+) activity, while that of cefixime is
poor. Both have been approved for the PO treatment of N. gonorrhea.
Older 3RD generation include cefotaxime (Claforan), similar to
ceftriaxone, and cefoperazone (Cefobid), similar to ceftazidime.


* include Cefepime (Maxipine) which is similar to 3rd generation
but with better G(-) coverage (P. aeruginosa, Enterobacter, Serratia,
C. freundii) and better G(+) coverage (S. aureus ).


o Most common is imipenam + cilastatin (Primaxin), a wide
spectrum abx which covers most G (+) except MRSA and most G (-) except
Legionella and some strains of Pseudomonas (maltophilia, cepacia ).
It also covers all anaerobes and has activity against Listeria and
Nocardia. It is generally given with cilastatin to inhibit renal
breakdown. Seizures are reported particularly in patients with
history of seizures or renal failure. Main indication is multidrug
resistant bacteria and should not be a first choice.


* Covers all G(+) including MRSA, C. difficile, Diphtheria,
Enterococcus. Indications: alternative to PCN / Cephalosporin in the
allergic patient, C. difficile (oral preparation) and MRSA. Red-man
syndrome is seen following rapid administration and is believed to be
histamine mediated. Vancomycin has good CSF penetration and is used
as a secondary drug in meningitis to cover resistant Streptococcus.
Because of emerging patterns in drug resistance, Vancomycin should be
reserved for specific situations and not be used as a first line


* Gentamycin, tobramycin
and amikacin are the most common. Be aware that all
aminoglycosides have the potential to cause nephrotoxicity and
* They cover many G(-) including Pseudomonas aeruginosa (but not
cepacia or maltophilia) and they do not cover Neisseria (gonorrhea or

* They also do not cover anaerobes, Legionella or atypicals. The
G(+) coverage is poor, but they will cover S. aureus (MSSA only) and
Listeria monocytogenes.

* As volume of distribution increases (CHF, ascites, third
spacing) the dosage of the drug must be increased. There is no CSF
penetration. Peaks and troughs should be measured, although other
dosing alternatives are now being used, such as once-daily 7 mg/kg/day
of gentamycin.

* Main indication is for G(-) sepsis, endocarditis (in combination
with PCN), and for synergism against P. aeruginosa infections.
Spectinomycin is still used in PCN allergic patients as a 2 gm IM x 1
dose for the treatment of gonococcal infections.


* Tetracycline, doxycycline, minocycline
- indication today is limited to Rickettsiae, Chlamydia,
Nocardia, Lyme's disease (early), and patients allergic to PCN that
requires treatment for syphilis and P. multocida. Minocycline is more
effective against staph and used for the treatment of acne.
* These drugs should be taken on empty stomach since milk, Fe,
Ca and antacids interfere with absorption. Photosensitivity reported.
Not given to pregnant women or children < 10 years old.


* Until the 1990's, erythromycin was the primary representative of
the macrolide class of antibiotics. In 1991, clarithromycin (Biaxin)
and azithromycin (Zithromax(R)) were approved by the FDA, offering and
expanded antimicrobial spectrum, a lower potential for
gastrointestinal effects, and less frequent dosing relative to

* Clarithromycin and azithromycin have similar antimicrobial
profiles, providing enhanced activity against H. influenza as compared
with erythromycin and retaining good efficacy against G+ organisms.
They cover Streptococcus, Staphylococcus (not MRSA), +/- N. gonorrhea,
H. influenza, M. catarrhalis, Legionella, M. pneumonia and Chlamydia.
Cross-resistance is seen among all macrolides, particularly in Gram
positive bacteria. Because azithromycin has the best activity against
Chlamydia trachomatis, it has been approved as a 1 gm PO single dose
for the treatment of nongonococcal urethritis and cervicitis.

* More recently, dirithromycin (Dynabac(R)) was added to this
group of antimicrobials. Approved in June 1995, it offers a spectrum
of activity and a safety profile similar to those of erythromycin but
with the advantage of once-daily dosing. Like erythromycin,
dirithromycin has good activity against G+ organisms, but some strains
of H. influenza are resistant. Dirithromycin is also less active than
other macrolides against Legionella species, Chlamydia trachomatis,
and Helicobacter pylori.

* Their main indications are as an alternative to PCN in allergic
patients, non-gonococcal urethritis / cervicitis, URI and pneumonia
secondary to Legionella or Mycoplasma.

* Adverse effects most commonly include gastrointestinal
complaints, particularly nausea, abdominal pain and diarrhea.
Azithromycin and clarithromycin have the lowest incidence of these
effects. Other adverse effects are headache, abnormal LFT's and
(rarely) reversible hearing loss. Clarithromycin can cause a taste
disturbance that may be intolerable for some patients. Achiles
rupture was reported with the latter.
* Drug interactions
are more significant with clarithromycin and erythromycin, as
they both increase serum concentrations of drugs metabolized by the
P-450 system in the liver. They may increase the levels of warfarin,
digoxin, carbamezapine and cause arrhythmias when used with some


* Ciprofloxacin
has good activity against G(-) such as Proteus mirabilis and E.
coli. It is also good for GI pathogens such as Vibrio cholera,
Campylobacter jejuni, Yersinia, Salmonella and Shigella and it is the
drug of choice for traveler's diarrhea. It is the most active
fluoroquinolone against the Pseudomonas species. It is also good
against bacteria that depend on the production of beta lactamase for
survival, thus it covers H. influenza and S. aureus . However, it is
surprisingly weak against streptococci (including S. pyogenes and S.
pneumonia) and it has no activity against anaerobic bacteria,
including B. fragilis. Because of this lack of activity against
anaerobes and weakness against chlamydia and enterococci, it is not a
good choice for the treatment of PID. It has been shown to impair
proper growth of cartilage, and thus cannot be used in children.
* Norfloxacin is similar to ciprofloxacin but it is poorly
absorbed PO. It is concentrated in the GI/GU system and is thus
limited in use for traveler's diarrhea and urine infections.

* Ofloxacin (Floxin) is also very similar to ciprofloxacin, but it
has better activity against Chlamydia and can thus be used to treat
STD's such as Chlamydia (300mg po bid x7days) and gonorrhea (400mg po
single dose) and has been approved as oral monotherapy for treatment
of PID. Like ciprofloxacin it is not very good for streptococci,
staphylococci or enterococci. It can cause hyper or hypoglycemia
particularly in diabetics.

* Levofloxacin (Levaquin) is the pure L-isomer of ofloxacin. It
has better activity against Gram (+) cocci and perhaps less toxicity.
The main advantage is that it is given only once a day (250-500mg po
qd), but it is more expensive than ofloxacin.

* Sparfloxacin (Zagam) is similar to levofloxacin with even better
activity against Gram + cocci (including enterococci), and retaining
good activity against Chlamydia. There is, however, a significant
incidence of drug related phototoxicity (not prevented by the use of
sunscreens), and Torsade de pointes on patients receiving drugs known
to prolong the QT interval.

* Trovafloxacin (Trovan) is active against G(+) bacteria,
including penicillin-susceptible and penicillin-resistant pneumococci;
S. aureus (but not MRSA); anaerobes such as Bacteroides fragilis ;
G(-) bacteria including Pseudomonas aeruginosa; and atypical
organisms including Mycoplasma pneumoniae, Chlamydia trachomatis and
Legionella species. Unfortunately it is used infrequently due to
potential liver toxicity.

* Grepafloxacin has G(+) activity against penicillin-susceptible
and penicillin-resistant pneumococci, covers the atypical bacteria and
is useful for H. influenza and Neisseria gonorrhea.
* Many other quinolones are being de
veloped and promoted. The advantages of the new generation
quinolones are once a day dosing and a wider spectrum of antibacterial


* Metronidazole
(Flagyl) is indicated mainly for anaerobic coverage. It has
good activity against C. difficile (given PO), Trichomonas, Giardia
and B. fragilis. It may cause a disulfiram-like effect when consumed
with ETOH.


* Clindamycin is excellent against anaerobes, including such below
the diaphragm pathogens as B. fragilis. It also covers streptococci
and S. aureus (not MRSA). It is well absorbed orally. It is the most
frequent cause of C. difficile pseudomembranous colitis.


* (Bactrim) has wide spectrum including activity against
streptococci and H. influenza.

* Indicated PO for uncomplicated UTI, COPD/bronchitis, otitis
media and PCP prophylaxis.

* It is indicated IV for active PCP with pO2 < 70 mmHg or if
unable to tolerate PO. It is given as TMP/SMX (TMP 20mg/kg/day
divided into 4 doses). In HIV (+) pt allergic effects are as high as
50%. Drug should also be avoided in G6PD deficiency.

Thursday, January 17, 2008

Chap 22: Sedative/Hypnotics

- sedative = anxiolytics = reduce anxiety + exert calming efx - CNS depressive efx minimal
- hypnotics = CNS depression = produce drowsiness + induce sleep state
- many sedatives - increase dose = hypnotics- drug A = alcohol, barbiturates --> can cause anaesthesia + death
- drug B = BZD, newer hypnotics --> needs higher dose to cause anaesthesia

Chemical classifications of sedative/hypnotics
  • most BZD contain carboxamide group
- barbiturates
  • glutethimide + meprobamate - different structures than barbiturates but similar efx
  • ethanol, chloral hydrate
- zolpidem (imidazopyridine), zaleplon (pyrazolopyrimidine), eszopiclone (cyclopyrrolone), ramelteon (melatonin receptor agonist), buspirone (slow-onset anxiolytic agent)
  • all structurally unrelated to BZD but similar MOA
- antipsychotics, antidepressants, antihistamine

Absorption + distribution
- depends on fat solubility
- all cross placental barrier + CNS system, detectable in breast milk --> CNS depressant efx

Metabolism (Biotransformation)
  • liver clears all BZD
  • phase I (oxidization) and II (conjugation)
  • individual drugs has different biotransformation --> some after phase I are metabolically active hence longer T1/2
- barbiturates
  • hepatic oxidation to form alcohols, acids + ketones
  • usually slow in metabolism hence barbiturates have long T1/2 eg phenobarbital 4-5 days
  • beware of multiple dosing
- newer hypnotics
  • zolpidem reaches peak in 1.6 hrs --> elimination T1/2 1.5-3.5 hrs
- by kidney

Molecular pharmacology of GABA*vA receptor
- binds to molecular components of GABA*vA receptors
- GABA*vA receptors - neuron membranes in CNS
A model of the GABAA receptor-chloride ion channel macromolecular complex (others could be proposed). A heterooligomeric glycoprotein, the complex consists of five or more membrane-spanning subunits. Multiple forms of a, b, and g subunits are arranged in different pentameric combinations so that GABAA receptors exhibit molecular heterogeneity. GABA appears to interact with a or b subunits triggering chloride channel opening with resulting membrane hyperpolarization. Binding of benzodiazepines to g subunits or to an area of the a unit influenced by the g unit facilitates the process of channel opening but does not directly initiate chloride current.

Sunday, January 6, 2008

Chap 42: Bone Mineral Homeostasis

- Ca + PO4 - 2 most important minerals for cell function
- Bone is major storage

  • 98% of total 1-2kg of Ca
  • 85% of 1kg of PO4
- 2 hormones important - PTH and Vit D
Non hormonal agents affecting bone mineral homeostasis
- analog of pyrophosphate
- inhibit formation and dissolution of hydroxyapatite crystals in/out skeletal system
- predilection for bone - effects come from osteoclasts
- <10%> take with empty stomach --> 50% accumulates in bone, 50% renally excreted unchanged
- SE:

  • gastric irritation/esophageal irritation --> glass of H2O, sitting upright 30 mins
  • osteonecrosis of the jaw
  • renal damage
- clinical uses

  • alendronate - seemed to increases bone mineral density over 2 yrs hence used in osteoporosis/# NOF
  • zolendronate - hyperCa 2ary to malignancy
  • pamidronate - same as above but cheaper, less potent

Wednesday, December 19, 2007

Chap 34: Antiplatelet agents, drugs used in bleeding disorders

- 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
- 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

- 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

- 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

- 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

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

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

- 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
  • 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

- 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