Urinary Tract Infection: Antibiotics in Adults

  Adapted from:

Urinary Tract Infections in Adults
This guide was developed with the collaboration of the professional corporations (CMQ, OPQ), the federations (FMOQ, FMSQ) and Québec associations of pharmacists and physicians

Tranexamic Acid Nebuliser

Dosing	Children <25kg	250 mg/dose
	Adult	250-500 mg/dose
Concentration	500 mg/5 mL
Frequency	3-4 times daily
Administration	Jet nebulizer with a flow rate of 5 L of oxygen per minute
Average Duration of Nebulization	15 min

Reference: 

1.  http://journal.publications.chestnet.org/article.aspx?articleid=2487107
2. http://www.resmedjournal.com/article/S0954-6111(09)00056-0/abstract
3. http://www.annsaudimed.net/index.php/vol35/vol35iss3/803.html

Urinary Alkalinization : Indication & Protocol

• Urine alkalinization is a treatment regimen that increases poison elimination by the administration of intravenous sodium bicarbonate to produce urine with a pH 7.5.
• Urine alkalinization is also indicated in various intoxications such as with salicylates and phenobarbital, as well as during methotrexate treatment and exposure to uranyl compounds, in which the toxic substance is more soluble in relatively alkaline urine.
• It may be used for renal protection in cases of rhabdomyolysis, crush injuries, and tumor lysis syndrome , although this indication is becoming secondary to good hydration over the last years, excluding the first hours after injury.

Indication	Protocol	Reference
Urinary alkalinization	Oral : 14mEq (4g) , then 12-24mEq evert 4 hours ; dose shoyld be itrated up to desired urine pH; doses up to 16g/day  (200mEq) in patient less 60 years and g/day in >60 years	Lexicomp
	Parenteral: 50 to 150 mEq sodium bicarbonate diluted in 1 L of D5W to be intravenously infused at a rate of 1 to 1.5 L/hour. Oral: 325 to 2000 mg orally 1 to 4 times a day. One gram provides 11.9 mEq (mmoL) each of sodium and bicarbonate. If the increase in urinary pH is inadequate, increasing the sodium bicarbonate in solution to 100 to 150 mEq/L may result in further alkalinization of the urine.	Drug.com
Elimination of poisons  (herbicides, chlorproparmide, salicylate, diflunisal, fluoride, methotrexate, barbiturates, sulphonamides)	IV bolus 1-2mEq/kg of 8.4% sodium bicarbonate, followed by continuous infusion of sodium bicarbonate. Continuous infusion is mixed by placing 150mEq of sodium bicarbonate into 1L of 5% dextrose	Uptodate
Methotrexate elimination	IV D5W with 100 to 150 mEq of sodium bicarbonate per liter, administered by continuous infusion at 125 to 150 mL/hour Alternative 50 mL of D5W containing sodium bicarbonate 1 mEq/kg can be infused IV over 30 minutes every four or six hours. Oral sodium bicarbonate can also be given starting with two x 650 mg tablets, and increased up to five tablets every two to four hours.	Uptodate

Possible Complications

• Severe alkalemia – shift of blood pH towards alkalinity
• Hypokalemia
• Hypocalcemia
• Coronary / cerebral vasoconstriction

Reference :

1.  Lexicomp
2.  Uptodate
3. https://www.eapcct.org/publicfile.php?folder=congress&file=PS_UrineAlkalinization.pdf
4.  Efficacy of urine alkalinization by oral administration of sodium bicarbonate: a prospective open-label trial.  Retrieved from http://www.sciencedirect.com

Antituberculosis & Joint Pain

	Arthalgia Type 1	Arthalgia Type 2 (Gouty Arthritis)
Possible Causative Agent	pyrazinamide>>ethambutol> isoniazid	pyrazinamide>>ethambutol
Clinical Presentation	Pain and tenderness of joints: fingers, shoulders, knees, etc. (usually mild)	Symptoms : pain, tenderness and swelling of joints (fingers, shoulders, knees, etc) Symptoms are usually severe  Signs: elevated serum uric acid concentrations
Management	TB medications do not require discontinuation Symptomatic relief:  NSAIDS	TB medications usually do not require discontinuation If acute swelling is present examined for urate crystals to confirm the diagnosis of acute gouty arthritis. Symptomatic relief:  NSAIDS or colchicine (as alternative to NSAIDS) If recurrent episodes occur, may consider using prophylactic colchicine

Proposed Mechanism

• A metabolite of pyrizinamide, pyrinazoic acid, inhibits the renal tubular secretion of uric acid and ethambutol reduces its renal clearance.

• The resulting hyperuricaemia can give rise to arthralgias and very rarely an arthritis.

Reference; 

1. http://rheumatology.oxfordjournals.org/content/45/9/1173.full
2.  http://www.uphs.upenn.edu/TBPA/treatment/managingsideeffects.pdf

Antihypertensive & Erectile Dysfunction

• Experimental and clinical have strongly indicated that older antihypertensive drugs exert detrimental effects on erectile function while newer agents exert either neutral or even beneficial effects.

• Accumulating data indicate that antihypertensive drug therapy is associated with erectile dysfunction, that antihypertensive drugs have divergent effects on erectile function which is either

           a)   Detrimental (diuretics, beta-blockers, centrally acting agents)

               b)   Neutral (calcium antagonists, ACE inhibitors)

               c)   Potentially beneficial (angiotensin receptor blockers, nebivolol)

• Older antihypertensive drugs (diuretics and beta-blockers) are not ideal candidates for these patients due to their detrimental effects on erectile function, and should be used only if they are absolutely indicated.

•  In case more than one class is indicated for an individual patient, the choice of an ARB should be considered.

• Switching from a drug with negative to a drug with positive effects on erectile function seems to be beneficial in hypertensive patients with erectile dysfunction.

Choice of ARB in Erectile Dysfunction

Losartan	Based on study, treatment with losartan improved erectile function, sexual satisfaction and frequency of sexual activity in hypertensive patients. Losartan alone or in combination with tadalafil significantly improved ED in diabetic patients, those with mild to moderate ED profiting the most from its use
Irbesartan	In mice, irbesartan was shown to improve penile endothelial function by reduction of vascular and cavernosal oxidative stress
Valsartan	In large prospective studies, the use of valsartan increased the rate of sexual intercourses per week and caused a reduction in ED, with improved orgasmic function, intercourse and overall sexual satisfaction in hypertensive men. In comparative studies, long-term use of valsartan was also shown to significantly improve sexual activity in comparison with the β-blockers carvedilol and atenolol, with the latter also reducing serum testosterone levels

1. Doumas M, Boutari C, Viigimaa M. (2016) Arterial Hypertension & Erectile Dysfucntion : An Under-Recognised Duo. European Society of Cardiology. Retrieved from https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-14/arterial-hypertension-and-erectile-dysfunction-an-under-recognized-duo
2. Dézsi, C. A. (2016). The Different Therapeutic Choices with ARBs. Which One to Give? When? Why? American Journal of Cardiovascular Drugs, 16(4), 255–266. http://doi.org/10.1007/s40256-016-0165-4

Bridging Therapy : Rationale

Bridging Theraphy & Rationale

• Bridge therapy  refers to temporary use of intravenous unfractionated heparin or LMWH for a patient on long-term anticoagulation.

• Bridging with low-molecular-weight heparin or other agents is based on balancing the risk of thromboembolism with the risk of bleeding.

• In many cases, warfarin is initiated in hospitals due to presence of active clot. In this situation, warfarin is usually started in conjunction with heparin. This is because: 

1.   The anticoagulant effect of warfarin does not occur for approximately 2-3 days.

2.   Initial period of the treatment with warfarin may be associated with a procoagulant state; heparin provides some protection from the risk related to this.

What is Procoagulant State?

• The anticoagulant effect of warfarin results from the inhibition of the cyclic interconversion of vitamin K in the liver.

• Warfarin, similar in structure to vitamin K, interferes with the cyclic restoration of reduced levels of vitamin K. Hence, warfarin indirectly reduces the synthesis of these clotting factors.

• Warfarin also has simultaneous procoagulant effect, caused by blocking protein C and S.

• Since protein C and S are anticoagulants, a rapid depletion of these proteins leads to a transient hypercoagulable state in first one to two days of warfarin therapy.

Onset of Anticoagulant Effect of Warfarin

• An anticoagulation effect generally occurs within 24 hours after warfarin administration. However the full anticoagulant effect of warfarin does not occur until two to three days of drug administration

• Anticoagulant effects of warfarin are delayed for several days after dosing changes and therapy initiation. This is because of the variable half-lives of previously formed circulating clotting factors.

• During the first few days of warfarin therapy, prolongation of the PT/INR mainly reflects depression of factor VII, which has the shortest half-life (four to six hours); however, other vitamin K-dependent factors (eg, factors II [prothrombin], IX, and X) have longer half-lives and are not fully depleted for two to three days.

• Thus, for patients with a very high thromboembolic risk, it may be necessary to overlap ("bridge") warfarin with another anticoagulant such as unfractionated or low molecular weight heparin during initiation of warfarin therapy.

Reference: 

1. http://www.aafp.org/afp/2013/0415/p556.html
2. http://www.bpac.org.nz/resources/campaign/inr/inr_poem.asp?page=3
3. https://www.drugs.com/pro/warfarin.html

SC Humalog Mix 50 Dosing & Dose Adjustment

Dosing Strategy

Patient	Dose	Frequency	Ref
Insulin naïve patient	5 units	BD (Breakfast & Dinner)	Product brochure
	Titration : every 3-4 days based on premeal BG to acheieve BG <6.1mmol/L
Converting from low mix twice daily	1/3 units from current dose	TDS ( Breakfast, Lunch & Dinner)
Converting from low mix three times daily (Twice daily Humalog Mix 50 & Once Daily Humalog Mix 25)	1/3 Humalog Mix50 (Breatkfast & Lunch) 1/3 Humalog Mix25 (Dinner)
For any diabetic population	5 to 10 units once or twice daily (prebreakfast and/or presupper). Titrate : 1 unit everyday until blood glucose reached target level		Diabetec.ca
Type 1 /Type 2 patient	Type 1 : 0.3-1U/kg/day in divided doses Type 2 : 0.5-1.5U/kg/day		Tarascon Pharmacopoeia 2014

Dose Adjustment 

Average glucose before meal (mmol/L)	Change in insulin dose	Ref
<4.4	-2	Product brochure
4.4-6.1	0
6.1-7.7	+2
7.7-11.1	+4

References: 

1. Product Brochure
2. http://guidelines.diabetes.ca/Browse/Appendices/Appendix
3. Eli Lilly Spokesperson 
4. http://guidelines.diabetes.ca/CDACPG_resources/Insulin_Prescription_May_5_2014.pdf

Methotrexate - PPI Interaction

FDA	Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitor (PPI) therapy. Concomitant use of some PPIs with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities.  Delayed methotrexate elimination was observed when high-dose methotrexate was co-administered with PPIs, but was not observed when methotrexate was co-administered with ranitidine.  No formal drug interaction studies of methotrexate with ranitidine have been conducted.
Lexicomp	Severity :Moderate  (clinical significance pf the interaction may be lower with typically lower methotrexate dose ) Mechanism :MTX is actively secreted in distal renal tubule with hydrogen ions produced via hydrogen/potassium ATPase pump, PPI by inhibiting renal elimication of hydrogen ion may inhibit MTX elimination. Management: Monitor increased MTX toxicity (mucositis, myalgias, etc)
BC Cancer Agency Cancer Drug Manual	Management of concomitant use Monitor for methotrexate toxicity for high-dose methotrexate - consider discontinuing PPI one day prior to methotrexate consider an H2 antagonist (e.g., ranitidine) instead of PPI
Bezabeh et al, 2012	The majority of the reported cases occurred with the administration of high-dose methotrexate. Although the product label describes high-dose therapy as 12 g/m2 as a 4-hour infusion, doses ≥500 mg/m2 are frequently cited as “high dose” in the literature, and the majority of the above case reports and series were reported from patients receiving doses of 300 mg/m2 to 12 g/m2. It appears the risk is greatest in the high-dose setting; however, there were also cases of patients taking a PPI and experiencing toxicity at doses as low as 15 mg of methotrexate per week. Clinicians should consider substituting H2 blockers for PPIs when acid suppression is clinically indicated during methotrexate therapy.

Reference: 

1. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm284421.htm
2. http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Methotrexate_monograph_1Feb2016.pdf
3. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3336837/
4. Lexicomp

Statin Myopathy & CoQ10

What is CoQ10

• Coenzyme Q10 is an important factor in mitochondrial ATP production.
• It is a potent lipid soluble antioxidant present in cell membranes and carried in the blood by LDL.
•  CoQ10 is biosynthesized in the body and available from dietary sources.
• Individual statins may have distinct effects on the synthesis of coenzyme Q10 (CoQ10).
• It has been speculated that a reduction in ubiquinone in skeletal muscle may contribute to statin-induced muscle injury.
• Different studies derived different conclusions about whether statin treatment decreases levels of ubiquinone in skeletal muscle.

Is CoQ10 Beneficial in Statin Myopathy?

• There’s a lack of evidence on the use of CoQ10 in prevention and improvent of statin accociated muscle event
• Two randomised controlled trials have investigated Co-enzyme Q10 for statin-associated myalgia, but they have conflicting results.
• One trial found that Co-enzyme Q10 (100mg daily for 30 days) improved pain scores for people with statin-associated myalgia more than vitamin E (400 IU daily).
• The other trial involving people who previously had statin-associated myalgia found no difference between Co-enzyme Q10 (200mg daily for 12 weeks) and placebo in myalgia scores or in the number of people who tolerated a higher dose of a statin.
• A 2015 meta-analysis of randomized trials concluded that existing trials do not suggest any significant benefit of CoQ10 for statin myopathy, but that larger trials are needed to confirm this lack of benefit.
• Patients may take coenzyme Q10 to lessen muscle symptoms, although published studies have not generally identified a benefit.

References:

1. Uptodate
2. http://www.fda.gov/ohrms/dockets/dailys/02/May02/052902/02p-0244-cp00001-02-Exhibit_A-vol1.pdf
3.  http://www.nps.org.au/medicines/nutrition/vitamins-and-minerals-oral/companion-products/q10-and-vitamin-d3-with-statins
4. https://www.pharmacist.com/coenzyme-q10-statin-induced-myopathy

Management of Severe Hyponatremia

Hyponatremia Correction : General Principle

• The rate of sodium correction should be 6 to 12 mEq per L in the first 24 hours and 18 mEq per L or less in 48 hours.
• An increase of 4 to 6 mEq per L is usually sufficient to reduce symptoms of acute hyponatremia.
• Chronic hypernatremia should be corrected at a rate of 0.5 mEq per L per hour, with a maximum change of 8 to 10 mEq per L in a 24-hour period.
• Rapid correction of sodium can result in osmotic demyelination (previously called central pontine myelinolysis).
• Overcorrection is common and is typically caused by rapid diuresis secondary to decreasing ADH levels. Every attempt should be made not to overcorrect sodium levels.

Severe Hyponatremia Sodium Correction

• One study of 25 patients with severe symptoms and sodium levels less than 120 mEq per L showed that concurrent treatment with a weight-based dose of 3% saline and 1 to 2 mcg of desmopressin every six to eight hours resulted in a rate of correction of 3 to 7 mEq per L per hour without causing overcorrection.
•  Guidelines from the European Society of Endocrinology recommend infusing one dose of 150 mL of 3% saline over 20 minutes, with sodium monitoring every 20 minutes until symptoms resolve. This regimen may be repeated if the patient remains symptomatic or until the goal sodium target of 5 mEq per L is achieved

Reference: 

1. Diagnosis and Management of Sodium Disorders: Hyponatremia and Hypernatremia, AAFP 2015

H Pylori: Eradication Therapy

 First Line Therapy

• Choose the treatment regimen with the lowest acquisition cost and take into account previous exposure to clarithromycin or metronidazole (it is not necessary to consider previous metronidazole exposure in patients with penicillin allergy).

 First-line seven-day triple or quadruple therapy regimens

 Second Line Therapy

• Second-line therapy should use different antibiotics to first-line therapy.
• Seek advice from a gastroenterologist if eradication of H. pylori is not successful with second-line therapy
• Quadruple Therapy includes addition of bismuth to Tetracycline and Metronidazole Combination therapy

Second-line seven-day triple or quadruple therapy regimens

Adapted from:
http://www.mims.co.uk/combination-regimens-eradication-h-pylori-nice-guideline/gi-tract/article/882106