Cloxacillin : Serum Level

Recommended Plasma Concentration

• According to the European Committee on Antimicrobial Susceptibility Testing (EUCAST), the MIC threshold to determine the strain sensitivity is 2 mg/L for cloxacillin.
• Until now, the optimal plasma concentration target in order to achieve the best cure rate remains undefined, but as oxa- and cloxacillin are time-dependent antibiotics, a time of 100% above the minimum inhibitory concentration (MIC) was considered to be optimal for efficacy.
• Considering that oxa- and cloxacillin are highly bound to albumin and that their unbound fraction—the available fraction for antibiotic efficacy—in healthy patients is known to be 10%,
• Previous study indicated that a dosing regimen of 1 g dicloxacillin every 6 hours should be effective for S. aureus infections with a mean MIC value of 0.125 µg·mL⁻¹ (achieving 67%T > MIC) (higher bioavailability compared to cloxacillin, 48.8% versus 36.9%)

Population: severe infections treated in ICU

• Defined a target range of total antibiotic concentration of 20–50 mg/L to reach the 100% T > MIC
• At a Median Daily Dosing of 105.5mg/kg [75; 150] produced a median plasma concentration of 134.3mg/L  [65.3; 201].
• Using a percentage of 10% to estimate the unbound fraction of oxa- or cloxacillin, all patients would have had a trough unbound fraction concentration superior or equal to the maximum MIC for oxa- or cloxacillin sensitivity, i.e. 2 mg/L

1. https://annalsofintensivecare.springeropen.com/articles/10.1186/s13613-017-0255-8

Oral Cloxacillin

• At a dose of 2g, average calculated dose based on serum concentration was 649mg (32.9%).
• Oral dose of 500mg cloxacillin produced a peak serum level of 8mcg/ml in adults
• After an oral dose of 500 mg, a peak plasma concentration of 7 to 14 μg per mL is attained in fasting subjects in 1 to 2 hours.
• After an oral dose of 500mg cloxacillin, a peak serum level of about 8 micrograms/mL is reached in about 1 hour.

1. PHARMACOKINETICS OF FLUCLOXACILLIN AND CLOXACILLIN IN HEALTHY SUBJECTS AND PATIENTS ON CHRONIC INTERMITTENT HAEMODIALYSIS. Br. J. clin. Pharmac. (1975), 2, 111-121
2. Infectious Diseases of the Female Genital Tract. By Richard L. Sweet, Ronald S. Gibbs
3. Cloxigen Product Information Leaflet

Intramuscular

• serum level after i.m. cloxacillin is approximately twice that obtained when the same dose is given orally to fasting adults

Concentration in Synovial tissue

• After a 30 min i.v. infusion of 1 g cloxacillin, the concentrations of this antibiotic were measured in plasma and synovial tissue samples from 11 patients undergoing total hip replacement.
• The concentration of free drug in synovial tissue was estimated to be 77% of the total tissue concentration.
• The maximum tissue drug concentration after an i.v. bolus dose is predicted to occur at about 37 min.
• it can be predicted that after an i.v. bolus injection of 1 g cloxacillin the maximum synovial tissue concentration will be reached at 37 min after administration. At this time the estimated free drug concentrations in plasma and tissue should be 0.9 mg/l.

1. Diffusion of cloxacillin into synovial tissue. Br. J. clin. Pharmac. (1992), 34, 275-277

Hyponatremia : ACEi vs CCB

Symptoms

• presented with signs and symptoms of hyponatremia (eg, nausea, malaise, headache, lethargy, seizures, coma, respiratory depression) 
• decreased serum sodium levels (101-109 mEq/L)

ACE Inhibitors

• Frequency is unreported
• ACE inhibitors alone can precipitate hyponatremia without co-administration of thiazide diuretics
• hyponatremia induced by ACE inhibitors appears to be dilutional and is accompanied by features of SIADH
• discontinuing the ACE inhibitor leads to resolution of the hyponatremia
• Patients may show hypokalaemia if thiazide or loop diuretics are used concomitantly with ACE inhibitors
•  

Mechanism & Risk

• It is postulated that ACE inhibitors at low doses cannot block the conversion of angiotensin I to angiotensin II in the brain. Increased circulating angiotensin I is converted to angiotensin II in the brain causing thirst stimulation and consequently SIADH.
• risk for hyponatremia may be greater in patients on concomitant diuretic therapy or who have congestive heart failure.

Calcium Channel Blockers

• In theory, calcium channel antagonists with natriuretic properties could cause hyponatremia.
• A case of amlodipine-associated hyponatremia has been reported.
• calcium channel antagonist– related hyponatremia, if it exists, is extremely rare.

Management

• In mild to moderate cases with a normovolaemic fluid status clinically, ceasing the offending drug and gentle fluid restriction would improve serum sodium levels gradually within a week.
• In an acutely unwell patient due to severe drug induced hyponatraemia, severe fluid restriction or infusion of hypertonic saline may be require
• May consider changing therapy and monitoring patient for improvement

Alternatives

• Diuretics are not recommended as have higher likelihood of causing hyponatremia
• ARBs are also established to cause hyponatremia and no available data on comparison with ACEi
• Beta Blockers- Beta blockade, especially of the Beta 1 receptor at the macula densa, inhibits renin release, & the release of aldosterone. This causes hyponatermia and hyperkalemia

References:

1. http://www.gpnotebook.co.uk/simplepage.cfm?ID=x20120201092040500242
2. https://www.pjms.com.pk/issues/aprjun207/article/casereport3.html
3. Jenny A. Van Amburgh. Can Lisinopril Cause Hyponatremia? - Medscape - Jul 28, 2011
4. American Journal of Kidney Diseases, Vol 52, No 1 (July), 2008: pp 144-153

Comparison: Antiemetics

Selection Rationale

• choice of antiemetic should be guided by the cause
• multiple causes may necessitate antiemetic polypharmacy 
• If a patient is already taking oral antiemetics and still nauseated, they may benefit from a change in route of administration for a few days

Comparison

 References:

1. http://www.aafp.org/afp/2004/0301/p1169.html
2. https://basicmedicalkey.com/nausea-and-vomiting-4/
3. https://www.pharmacytoday.co.nz/events/palliative-care-resource/choosing-the-right-antiemetic-agent.aspx

Interaction : Riamet and Akurit 4

Availability in Hospital Keningau:

• Riamet (Artemether 20mg + Lumenfantrine 120mg)
• Akurit-4 (Rifampicin 150mg, Isoniazid 75mg, Pyrazinamide 400mg & Ethambutol HCl 275mg)

Interaction:

• Oral administration of Rifampicin (600mg) daily, a strong CYP3A4 inducer with Riamet Tablets (6 dose regimen over 3 days) in 6 HIV-1 and Tuberculosis co-infected adults without Malaria resulted in significant decreases in Arthemeter (89%) ,DHA (85%) and Lumenfantrine (68%) when compared to exposure values after Riamet alone.
• Concomitant use of strong inducers such as Rifampicin, Carbamazepine, Phenytoin, St John’s Wart is contraindicated with Riamet.

Alternatives:

• A study was done on the effect of combined therapy (rifampicin and quinine) in patients with acute uncomplicated P.Falciparum Malaria. Interestingly, they observed that the parasite clearance was faster with the combination.
• This could be because of the rifampicin antimalarial effect rather than a drug interaction as rifampicin can take several days to induce CYP3A4 activity that is responsible for quinine metabolism.
• After the second day of rifampicin treatment, quinine pre-dose plasma concentrations decreased progressively throughout the treatment period, leading to a fall in quinine activity that may have been the reason for a malaria recrudescence rate five times higher in this group.
• In those patients who are already on rifampicin for the treatment of TB, quinine doses must be increased.

*Quninie Sulphate 300mg is available in Hospital Keningau

References:

1. Riamet ® Product leaflet
2. Mims Malaysia
3. Sousa, M., Pozniak, A., & Boffito, M. (2008). Pharmacokinetics and pharmacodynamics of drug interactions involving rifampicin, rifabutin and antimalarial drugs. Journal of Antimicrobial Chemotherapy, 62(5), 872-878.

Fish Oil in Liver Disease

• Fish oil is primarily composed of omega-3 fatty acids, which, along with omega-6 fatty acids, make up the essential fatty acids.

TPN associated Liver Disease

• Subjects who received fish-oil–based emulsion experienced
• reversal of cholestasis 4.8 times faster than those who received soybean emulsions
• 6.8 times faster in analysis adjusted for baseline bilirubin concentration, gestational age, and the diagnosis of necrotizing enterocolitis

Oil-induced Fatty Liver

• effects of dietary fish oil on fatty liver differ according to the cause of fatty liver; fish oil prevents sucrose-induced fatty liver but exacerbates safflower oil-induced fatty liver
• The exacerbation of fatty liver may be due, at least in part, to increased expression of liver PPARgamma

Fatty Liver Disease

• results of meta-analysis support the beneficial effect of n-3 PUFA (omega-3 fatty acid supplementation) in optimizing liver fat, liver enzyme levels (GGT), and blood lipid levels (TG, HDL) in patients with NAFLD
• n-3 PUFAs may slow down the progress of NAFLD (nonalcoholic fatty liver disease)
• a recent review by Parker et al., showed a benefit on liver fatness and found no significant benefit on ALT and AST levels

References

1. http://pediatrics.aappublications.org/content/121/3/e678
2. http://onlinelibrary.wiley.com/doi/10.1002/hep.21934/full

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019889/

Meropenam : Duration of Slow Infusion

• Availability: IV Meropenam 500mg and 1g

Administration

• Should be administered by IV infusion over approximately 15 minutes to 30 minutes.
• Doses of 1 gram may also be administered as an IV bolus injection (5 mL to 20 mL) over approximately 3 minutes to 5 minutes

Stability

• Depended on diluent and storage condition
• In Room Temperature: 8h for 0.9% NS, 2-3h for other diluents
• At 2-8 ‘C : 24h for 0.9%NS, 8-14h for other diluents

Half Life:

•  In subjects with normal renal function, the elimination half-life of is approximately 1 hour in adults, 1.5h for children <2 years

Rationale

• Time-dependent agents
• the maintenance of concentrations for about 40% of the dosing interval above the MIC of the pathogen (t > MIC) was found to be the pharmacodynamic target for maximal bactericidal activity in experimental animal models of infection
•  Recent literature supports prolonged/extended infusion times of beta-lactam antibiotics as a way to maximize the time-dependent bactericidal activity and improve the probability of target attainment

Recommendation

• If slow infusion is needed, treatment must always be started with a 1- to 2-g pulse loading dose administered over 30 min in order to promptly achieve therapeutically effective concentrations,
• Continuous infusion should start immediately afterward loading dose
• Reconstitution of the solution every 6 to 8 h (maximum) must be recommended for optimal use

References

1. Medication Administration: Extended-Infusion Meropenem (Merrem®) Protocol
2. http://aac.asm.org/content/56/12/6343.long
3. https://www.drugs.com/pro/meropenem.html
4. https://www.ncbi.nlm.nih.gov/pubmed/25230866

IV Multivitamin and Oral Multivitamin

Availability in Hospital Keningau

• Oral Multivitamin(Flavettes)
• Injection Multivitamin (Parentrovite)

Content	Oral Multivitamin(Flavettes)	Injection Multivitamin (Parentrovite)
Vitamin A	5000iu	-
Vitamin D	400iu	-
Thiamine HCl (B1)	3.5mg	250mg
Riboflavin (B2)	2.5mg	4mg
Pyridoxine (B6)	2.5mg	50mg(BP)
Cyanocobalamin (B12)	0.005mg	-
Ascorbic Acid (C)	50mg	500mg (as sodium salt)
Nicotinamide	25mg	160mg (BP)
Calcium Panthethonate (B5)	4mg	-
Dexpanthenol (B5)	-	5mg
Folic Acid	0.5mg	-
Calcium	25mg	-
Copper	0.75mg	-
Iron	5mg	-
Iodine	0.005mg	-
Manganese	0.5mg	-
Magnesium	0.5mg	-
Phosphorus	20mg	-
Potassium	1mg	-
Zinc	2mg	-
Dextrose	-	1000mg BP

Table 1.0 Content of Oral Multivitamin and Injection Multivitamin

Product Information:

• Tablet Multivitamin 
• indicated for prevention and treatment for vitamin deficiencies.
• Injection Multivitamin 
• indicated for rapid and treatment for severe vitamin deficiencies which can occur in association with alcoholism: Wernicke’s Encephalopathy and Korsakoff’s psychosis;subacute confusional delirious or amnesic states
• specific deficiency syndrome-pellagra, beri beri, aneroxia nervosa;
• parenteral nutrition, severe malnutrition.

Thiamine:

• Thiamine and Vitamin C deficits do pose special risks however, not least since thiamine deficiency is widespread in the population admitted to emergency units.
• Thiamine supplements (to the level of 100–300 mg/day) should be provided during the first 3 days in the ICU in patients with possible thiamine deficiency, and especially when alcohol abuse is suspected.

References:

• Flavettes Product Information
• CCM-Trovite IV Injection
• ESPEN Guidelines on Parenteral Nutrition: Intensive care 2009

Essential Phospholipid:Livolid and Livolin Forte

Availability in Hospital Keningau

• Livovid (Essential Phospholipid)

Content	Livovid (%US RDA)	Livolin Forte (US RDA)*
Essential Phospholipid	500mg	300mg
Vitamin B1	3mg(200)	10mg(666.67)
Vitamin B2	3mg(177)	6mg(352.94)
Vitamin B6	3mg(150)	10mg(500)
Vitamin B12	3mcg(100)	10mcg(500)
Nicotinamide	15mg(75)	30mg(157.89)
Vitamin E	3.3mg(10)	10mg(66.67)

Table 1.0 Content of Livovid and Livolin Forte (*current product)

  
Recommended daily dose:

• The dosage for Livovid is 1 to 2 softgels daily or as directed by physician
• The dosage of Livolin Forte is 1 capsule 3 times daily after meal or as directed by physician

Content:

• The content of Essential Phospholipid in Livovid is higher than Livolin Forte while the content of vitamins are higher in Livolin Forte.
• All the contents are within Tolerable Upper limit except Vitamin B1(Not established),Vitamin B12(Not established) and Nicotinamide (30-35mg/daily).

Nicotinamide:

• High-dose nicotinamide should still, however, be considered as a drug with toxic potential at adult doses in excess of 3 gm/day and unsupervised use should be discouraged.
• Nicotinamide has an off label use for pellagra with 100mg every 6 hours for several days and followed by 50mg every 8-12hours

Vitamin B12:

• Maximum daily intake unlikely to cause adverse health effect thus no upper limit is established.
• For Vitamin B12 deficiency may take up to 1000-2000mmcg daily for 1-2 weeks orally

Vitamin B1:

• Large doses have been seen particularly in the treatment of Wernick Korsakoff Syndrome(10mg-1500mg daily)

References:

• Livovid Product Information
• Livolin Forte Product Information
• http://frantzmd.info/Alternative%20Medicine/Tolerable%20Upper%20Limits.htm
• https://www.consumerlab.com/RDAs/
• https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional
• Lexicomp
• FUKKM