Tissue Penetration of Oral Bactrim

• Bactrim is rapidly absorbed following oral administration (85%)
• Peak blood levels for the individual components occur 1 to 4 hours after oral administration. The mean serum half-lives of sulfamethoxazole and trimethoprim are 10 and 8 to 10 hours, respectively
• Both sulfamethoxazole and trimethoprim distribute to sputum, vaginal fluid and middle ear fluid
• Average percentage of the dose recovered in urine from 0 to 72 hours after a single oral dose of sulfamethoxazole and trimethoprim is 84.5% for total sulfonamide and 66.8% for free trimethoprim
• trimethoprim also distributes to bronchial secretion
• both pass the placental barrier and are excreted in human milk.

Skin and Tissue Penetration

• Good penetration and are indicated for treatment of several infections
• pharmacokinetic/pharmacodynamic study found that trimethoprim/sulfamethoxazole exhibits good skin/soft tissue penetration in patients with Diabetic foot ulcers as well as bactericidal activity in serum against strains of S. aureus and β-haemolytic streptococci
• Oral options for treatment of gram-negative (osteomyelitis)  infections include fluoroquinolones and trimethoprim-sulfamethoxazole
• Has  excellent oral bioavailability that has been used to treat MSSA and MRSA bone infections, though most of the published experience is with courses of longer than 6 weeks and in device-associated infections. 
• Optimal dosing should be weight based: 5 to 10 mg/kg of trimethoprim/day divided into 2 or 3 doses in individuals with normal renal function

References:

1. http://www.aliem.com/sulfamethoxazole-trimethoprim-ssti-1-2-tablets-bid/
2. http://www.ncbi.nlm.nih.gov/pubmed/23873647
3. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2884905/
4. http://emedicine.medscape.com/article/1348767-treatment

Corticosteroid Dosing Equivalence

• conversion can be calculated using the online calculator at http://www.globalrph.com/corticocalc.htm

Predisolone - Hydrocortisone Equivalence

• prednisolone 5mg = hydrocortisone 20mg in terms of equivalent anti-inflammatory dose 
• hydrocortisone tablets have a high bioavailability, the oral and intravenous (IV) doses of hydrocortisone tend to be the same
• equivalent anti-inflammatory dose reported for these steroids is based on the total daily dose. thus, daily dose of prednisolone should be converted to the daily dose of hydrocortisone and either be divided over three to four doses per day or be given as a continuous 24-hour infusion
• peri-operative dose of hydrocortisone required may be higher than the equivalent prednisolone dose usually taken by the patient

Summary of Activity:

References:

1. http://www.globalrph.com/corticocalc.htm
2. http://www.aacijournal.com/content/9/1/30/table/T3
3. What is the equivalent dose of oral prednisolone to intravenous (IV) hydrocortisone? at www.evidence.nhs.uk

Treatment of Acinetobacter Infections

• Acinetobacter is a gram-negative coccobacillus
• resistance pattern in Malaysia:

First Line Therapy

• broad-spectrum cephalosporin (ceftazidime or cefepime), a combination beta-lactam/beta-lactamase inhibitor (ie, one that includes sulbactam), or a carbapenem (eg, imipenem, meropenem, or doripenem).
• Emergence of resistance during therapy has been observed with ampicillin-sulbactam, cephalosporins, and carbapenems when used as single agents . For this reason, these agents are sometimes used in combination with an antipseudomonal fluoroquinolone or an aminoglycoside. 
• However, there are no clinical data demonstrating that combination therapy either reduces the risk of emergent resistance during therapy or improves clinical outcomes in cases of Acinetobacter infections

Alternative for Resistant Agent

• Polymyxins (polymyxin B and colistin [polymyxin E]) are the most commonly used agents for Acinetobacter isolates resistant to first-line agents
• Colistinhas been used with some success for the treatment of Acinetobacter pneumonia, bacteremia, and meningitis
• In a meta-analysis of four studies (244 patients) evaluating treatment of ventilator-associated pneumonia due mainly to Acinetobacter baumannii but also Pseudomonas aeruginosa, clinical improvement rates, 28-day mortality, and ICU lengths of stay with intravenous colistin were similar to those observed with a comparator agent (carbapenem or high-dose ampicillin-sulbactam)

 Combination therapy

• Combination antimicrobial therapy is used to increase the likelihood of adequate empiric antibiotic coverage before drug susceptibility testing results are known, to decrease the risk of emergent resistance, and to improve outcomes in multidrug or extensively drug-resistant infections
• but there are no definitive clinical data to support its use for these purposes. 
• Combination therapy (colistin plus Rifampicin) did not decrease the 30 day mortality rate (43.3 versus 42.9 percent with colistin alone) or the infection-related death rate (21.5 versus 26.6 percent) despite increasing the likelihood of microbiological cure (60.6 versus 44.8 percent)
• Other combinations that have favorable effects on multi- and extensively-drug resistant isolates in vitro or in small case series include a carbapenem with colistin and tigecycline with colistin
• However, some recommends that the use of a single agent is not adequate, particularly since resistance can develop during therapy leaving no therapeutic alternatives.

Summary of Treatment

 NAG 2014

ICU Antibiotic Guideline 2012

 References:

1. www.uptodate.com
2. NAG 2014
3. Malaysian ICU Antibiotic Guideline 2012

Combination of Ticlopidine and Clopidogrel

• both agents are from the same group- thienopyridine, with a similar structure and mechanism
• the use of combination is not supported by any guidelines
• moreover, Ticlopidine is a strong CYP2C19 inhibitor. This leads to decreased serum concentrations of active metabolites of Clopidogrel. (interaction: major/fairly reliable)

Recommendation:

• The combination of aspirin and clopidogrel might be considered for initiation within 24 hours of a minor ischemic stroke or TIA and for continuation for 90 days (Class IIb; Level of Evidence B)
• For patients with a history of ischemic stroke or TIA, AF, and CAD, the usefulness of adding antiplatelet therapy to Vitamin K Antagonist therapy is uncertain for purposes of reducing the risk of ischemic cardiovascular and cerebrovascular events (Class IIb; Level of Evidence C). 
• Unstable angina and coronary artery stenting represent special circumstances in which management may warrant DAPT/VKA therapy.

References:

1. Lexicomp
2. AHA/ASA Guideline: Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack

Dosing of polymyxin B in Haemodialysis

Availability: Colomycin/ Colistimethate sodium 1-2 million IU
Dose Conversion

• 1 mg colistin BASE activity (CBA) = 2.4 mg colistimethate sodium 
• 1 mg colistin BASE activity (CBA) = 30,000 IU 
• 1 mg colistimethate sodium (CMS) = 12,500 IU

Dosing Considerations:

• Best practices for colistin dosing are unclear
• Dosing of colistin in hemodialysis patients has varied in published reports
• manufacturer does not provide dosing recommendations for hemodialysis patients or for peritoneal dialysis patients
• intermittent hemodialysis removed a significant quantity of colistin and colistimethate

Dosing Recommendations: 
1. http://www.asp.mednet.ucla.edu/files/view/guidebook/Colistin_Dosing

• High-dose CBA (optimizes the concentration-dependent bactericidal activity). 
• loading dose is included to ensure that therapeutic concentrations are rapidly achieved. 
• In the absence of a loading dose, it may take 48 hours before colistin concentrations exceed the bacterial minimum inhibitory concentration

OR

2. http://www.nebraskamed.com/careers/education-programs/asp/restrictions/colistin

• Maintenance dose and dosing interval should be based on the renal dosing protocol
• A load of 2.5 mg/kg IV q12h x2doses should be given to all patients with a creatinine clearance (CrCl) of <= 40 ml/min (the loading doses are not renally adjusted)
• Subsequent maintenances doses should begin 24 hours after the first loading dose
• In pediatric patients use 1.5 mg/kg/day divided q12h

CrCl >40: No adjustment necessary
CrCl 20-40: 75% of total daily dose IV divided q12h
CrCl 10-19: 50% of total daily dose IV divided q12h
CrCl <10, intermittent hemodialysis, or peritoneal dialysis: 50 mg IV q12h. Administered after dialysis on dialysis days

 OR

3. http://www.infectiousdiseases-ucla-affiliated.org/Intranet/FILES/ColistinDosing

Loading dose 

• (LD, All patient categories) LD of CBA (mg) =5.0 x body wt (kg) 
• Use the lower of ideal or actual body wt (kg) 
• Not to exceed 300mg 

Maintenance dose: 

• 1 st dose should be given 24 hours after LD 
• Not on renal replacement therapy: Daily dose of CBA (mg) = 2.5 x (1.5xCrcl+30)
• Dosing interval adjusted based on CrCl (ml/min/1.73m2): 
• CrCl70ml/min/1.73m2 = q8h 

Intermittent hemodialysis: 

• None HD day- Daily dose of CBA = 75mg; given as 37.5 mg q 12h 
• On days when dialysis is given an additional 30% of the daily maintenance dose is given after HD [exm: 1 st dose = 37.5mg. Second dose (12 hours later) = 60 mg ]

CRRT: 

• Daily dose =480mg; give as 160 mg q 8 h.

OR

4. Medscape

•  intravenous dosages of CMS are 2–3 mg/kg after each hemodialysis treatment

Suggestion:

• Based on available guides, do suggest to use a BD dosing to achieve therapeutic level
• (case report:  patient received 2 million units of colistimethate every 12 hours, and received hemodialysis on a daily basis. Patient achieved close to the MIC breakpoint of 2 mg/L)
• As most recommendations are at a lower dosing, would suggest for initiation at 1-1.5 million Unit BD rather than 2 million unit. 

References:

1. http://www.ahcmedia.com/articles/20230-colistin-dosing-in-renally-impaired-patients
2. http://www.asp.mednet.ucla.edu/files/view/guidebook/Colistin_Dosing
3. http://www.nebraskamed.com/careers/education-programs/asp/restrictions/colistin
4. http://www.infectiousdiseases-ucla-affiliated.org/Intranet/FILES/ColistinDosing
5. https://www.medicines.org.uk/EMC/medicine/1590/SPC/Colomycin+Injection/
6. http://www.medscape.com/viewarticle/772588_4
7. http://ac.els-cdn.com/S120197121401666X/1-s2.0-S120197121401666X-main

Treatment Options For Keloids

Types of keloids

Scar type	Characteristics	Maturation
Minor keloid	Focally raised Pruritic Extends beyond burn borders May have genetic component for keloid development Typical site: earlobes	May develop one year after burn Does not regress spontaneously Recurrence generally follows surgical excision
Major keloid	Large (>0.5 cm) Painful Pruritic Extends beyond burn borders over normal tissue Can result even from minor trauma	Does not spontaneously regress  Can continue to progress in size over the years

Available Product In HKGU

Generic name	Brand name
Triamcinolone Acetonide 40mg/ml Inj	Kenacort-A

Minor keloids (<0.5 cm)

• Triamcinolone acetonide 10 to 40 mg/mL 
• Repeated at four-week intervals
• Intralesional corticosteroid injections are painful. For local anesthesia, EMLA cream may be applied under occlusion for 1.5 hours before injection
• Second-line therapies, intralesional 5-FU in combination with intralesional corticosteroids (0.9 mL of 5-fluorouracil 50 mg/mL plus 0.1 mL of Triamcinolone acetonide 40 mg/mL)

Major keloids (>0.5cm)

• Intralesional Triamcinolone acetonide 40 mg/mL 
• Repeated at intervals of three to four weeks for four to six months

REFERENCE :

http://www.aafp.org/afp/2009/0801/p253.html

Indian Journal Of Dermatology, Venereology & Leprology

Uptodate

ACS Management In Patients Who Were Previously On Warfarin

 

REFERENCE :

http://www.wsh.nhs.uk/aboutus /foi/foire questsandresponses/attachments/1490f.pdf