Paroxysmal Nocturnal Hemoglobinuria : Thromboembolism

• the ideal treatment is to replace the defective hematopoietic stem cell with a normal equivalent by stem cell transplantation
• however, this is not realistic for many patients, because stem cell transplantation requires a histocompatible donor and is associated with significant morbidity and mortality.
• tendency toward thrombosis in patients with PNH is multifactorial in etiology, involving the absence of GPI-anchored complement inhibitors on the surfaces of circulating platelets, the high levels of intravascular free plasma hemoglobin with the consequent scavenging of NO, fibrinolytic defects, and the pro-inflammatory effects of C5a.
• The relative importance of each factor is not yet known but the integration between the 2 major host protection systems, coagulation and innate immunity, is obvious.

Management
Evidence for Use

• Primary prophylaxis of thromboembolism for patients with PNH has been advocated. 
• This can be prevented using inhibitors of the cyclooxygenase system, such as aspirin, ibuprofen, and sulfinpyrazone.
• Thrombolytic agents used in the acute stage of thrombosis should be followed by full anticoagulation with warfarin or heparin (preferably LMWH).
• Patients with documented thrombosis should receive lifelong secondary prophylaxis. Most authors suggest a target international normalised ratio of 2.0 to 2.5.
• Whether this approach is safe and effective in all patients with PNH remains controversial, however.
• Unfortunately, some patients will continue to develop blot clots despite aggressive anti-coagulation agents.

Evidences against Use

• In addition, thrombocytopenia is a relative contraindication to anticoagulation and this complication is not uncommon in patients with PNH.
• In addition, there are still clear cases of thromboses occurring while patients are therapeutically anticoagulated, which is less surprising when the proposed mechanisms are considered.
• After a thrombotic event, it appears that anticoagulation alone as secondary prevention is not sufficient
• There are no studies of antiplatelet drugs, such as aspirin or clopidogrel, in PNH, but again, mechanistically, it is clear that they are unlikely to be of benefit and again there is a true risk of hemorrhage.

Recommendations

• the pros and cons of prophylactic anticoagulation needs discussion with the patient

Alternatives
Eculizumab

• Because thrombosis is the leading cause of death, the impact of eculizumab on thrombosis largely explains the improved survival seen with eculizumab therapy.
• in the past, patients with thrombosis were maintained on anticoagulation for the remainder of their life. 
• This is still recommended, although it is not clear that this is necessary in patients receiving eculizumab. 
• Eculizumab seems to markedly reduce the incidence of thrombosis in PNH

Others

• Enoxaparin, dalteparin, heparin and warfarin had also be used
• Sometimes, heparin can exacerbate the thrombotic problem, possibly by activating complement.
• Prophylactic anticoagulation with warfarin or heparin derivatives has been used with variable success

Warfarin

• Not an alternative to eculizumab, but there is evidence that it reduces thrombosis risk
• The risks with warfarin anticoagulation in several studies is deemed too high as the studies were not reflective of the PNH population whom are generally younger

References:

1. http://emedicine.medscape.com/article/207468-treatment
2. http://www.hopkinsmedicine.org/kimmel_cancer_center/types_cancer/paroxysmal_nocturnal_hemoglobinuria_pnh.html
3. http://www.bloodjournal.org/content/121/25/4985?sso-checked=true
4. http://bestpractice.bmj.com
5. Technology Assessment Report no. 209. Preliminary Assessment Analysis on Eculizumab for PNH, May 2013. 
6. Eculizumab for treating patients with paroxysmal nocturnal hemoglobinuria. Cochrane Database of Systematic Reviews, 2014

Tramadol : Cardiovascular Side Effects

Hypotension

• There have been several reported cases of patient who are receiving Tramadol and develop hypotension. 
• Several references did mention the development of hypotension as side effect of administration of tramadol but it categories as rarely occurrence.
• Overdose of Tramadol also may cause patient to develop hypotension such as in underweight patient or error in administration. This factor need to be rule out first.

Insert leaflet of Tramal Injection

• Uncommon effects include disorders of cardiovascular regulation (e.g. palpitation, tachycardia, postural hypotension up to cardiovascular collapse), further, retching and gastrointestinal irritation, or dermal reactions (e.g. pruritus, rash or urticaria).

Insert Leaflet of ULTRAM

Drugs.com

Insert Leaflet Trama Injection

Intra-abdominal infection: Antibiotics

• Abdominal infections are usually polymicrobial and result in an intra-abdominal abscess or secondary peritonitis, which may be generalized or localized (phlegmon).
• predominant bacteria involved in such infections are coliforms (mainly Escherichia coli, Klebsiella spp, Proteus spp, and Enterobacter spp) streptococci, enterococci, and anaerobic bacteria
• dominant isolates in most series are Bacteroides fragilis and E. coli

Choice of antibiotics

• although clindamycin and cefotetan were previously considered acceptable options for intra-abdominal infections involving anaerobes, these drugs are no longer recommended due to escalating rates of resistance in the B. fragilis group.
• As detailed in those guidelines, ampicillin-sulbactam is also not recommended due to high rates of resistance among community-acquired E. coli
• Single-drug regimens that have expanded activity against gram-negative aerobic and anaerobic bacilli include meropenem, imipenem-cilastatin, doripenem, and piperacillin-tazobactam. Combination regimens include ceftazidime or cefepime in combination with metronidazole.
• Cephalosporin-based regimens lack anti-enterococcal activity, so ampicillin or vancomycin can be added to these regimens for enterococcal coverage until culture results are available.
• For those known to be colonized with ampicillin-resistant, vancomycin-resistant Enterococcus (VRE), a VRE-active agent, such as linezolid or daptomycin, should be included
• comparable in vitro efficacy of cefoperazone-sulbactam and piperacillin-tazobactam

Empiric antibiotic regimens for low-risk community-acquired intra-abdominal infections

	Dose
Single-agent regimen
Ertapenem	1 g IV once daily
Piperacillin-tazobactam	3.375 g IV every six hours
Ticarcillin-clavulanate	3.1 g IV every four hours
Combination regimen with metronidazole
Cefazolin	1-2 g IV every eight hours
OR
Cefuroxime	1.5 g IV every eight hours
OR
Ceftriaxone	1 g IV once daily
OR
Cefotaxime	1-2 g IV every six hours
OR
Ciprofloxacin	400 mg IV every twelve hours or 500 mg PO every twelve hours
OR
Levofloxacin	750 mg IV or PO once daily
PLUS
Metronidazole	500 mg IV or PO every eight hours

Empiric antibiotic regimens for high-risk community-acquired intra-abdominal infections

	Dose
Single-agent regimen
Imipenem-cilastatin	500 mg IV every six hours
Meropenem	1 g IV every eight hours
Doripenem	500 mg IV every eight hours
Piperacillin-tazobactam	4.5 g IV every six hours
Combination regimen with metronidazole
Cefepime	2 g IV every eight hours
OR
Ceftazidime	2 g IV every eight hours
OR
Ciprofloxacin	400 mg IV every twelve hours
OR
Levofloxacin	750 mg IV once daily
PLUS
Metronidazole	500 mg IV every eight hours

Empiric antibiotic regimens for healthcare-associated intra-abdominal infections

	Dose
Single-agent regimen
Imipenem-cilastatin	500 mg IV every six hours
Meropenem	1 g IV every eight hours
Doripenem	500 mg IV every eight hours
Piperacillin-tazobactam	4.5 g IV every six hours
Combination regimen
Cefepime	2 g IV every eight hours
OR
Ceftazidime	2 g IV every eight hours
PLUS
Metronidazole	500 mg IV every eight hours
PLUS
Ampicillin*	2 g IV every six hours
OR
Vancomycin*	15-20 mg/kg IV every eight to twelve hours

References:

1. www.uptodate.com
2. Cefobid product leaflet
3. Comparison of in vitro activities of ceftazidime, piperacillin-tazobactam, and cefoperazone-sulbactam, and the implication on empirical therapy in patients with cancer. Indian J Cancer 2009;46:318-22
4. http://www.antimicrobe.org/drugpopup/Cefoperazone.htm
5. Updated Guideline on Diagnosis and Treatment of Intra-abdominal Infections. Am Fam Physician. 2010 Sep 15;82(6):694-709. 
6. Diagnosis and Management of Complicated Intra-abdominal Infection in Adults and Children: Guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis. (2010) 50 (2): 133-164. 
7. https://www.ncbi.nlm.nih.gov/pubmed/18570578 
8. Canadian practice guidelines for surgical intra-abdominal infections. Can J Infect Dis Med Microbiol. 2010 Spring; 21(1): 11–37.

Erythromycin: Ethylsuccinate VS Stearate

Drugs	Eryhthromycin Ethylsuccinate 400mg	Erythromycin Stearate 250mg
Equivalence	400mg	250mg
Frequency	Q6-12h	Q6-12h
Drugs.com          URTI/Pharygitis	Mild-moderate:  PO 400-800mg QID Severe:  IV/IVI 1-4g/day QID	Mild-moderate:  PO 250-500mg QID Severe:  IV/IVI 1-4g/day QID
Lexicomp Usual dosage range	PO 400-800 mg BD-QID.  Max 4g/day	PO 250-500mg BD-QID.  Max 4g/day
Sanford Antibiotic Guidelines Usual dosing	PO 400-800 mg BD-QID.  Max 4g/day	PO 250-500mg BD-QID.  Max 4g/day
Product leaflet	PO 400mg QID or 800mg BD Max: 4g/day	PO 1-2g daily in divided doses Severe infections:  4g daily in divided doses Duration of treatment: URTI: 5-10 days

Erythromycin stearate

• Previously healthy with no risk factors for drug-resistant S. pneumoniae
• Erythromycin base (stearate) (250 mg every six hours, 333 mg every eight hours, or 500 mg every 12 hours may double dose for serious infections
• but twice-daily dosing not recommended for total daily dose over 1000 mg

Erythromycin ethyl succinate

• Erythromycin ethyl succinate is available in 400 mg tablets, and two strengths of liquid formulation - 200 mg/5 mL and 400 mg/5 mL.
• The usual adult dose is 400 mg, four times daily. Alternatively, 800 mg, twice daily, may be a more convenient dose regimen for some patients. In severe infections, the dose may be increased up to a maximum of 4 g per day.
• Tablets may be taken with or without food

Pharmacokinetics

• The time peak serum erythromycin concentrations are reached varies depending on the salt. 
• A single dose of erythromycin ethylsuccinate 400mg reaches approximately 0.8mcg/ml at 1 hour whereas a single dose of erythromycin stearate 250mg reaches approximately 0.8mcg/ml at 3 hours. 
• Several references state that in general, oral administration of 250 mg of erythromycin as the base, estolate, or stearate, or 400 mg of erythromycin as the ethylsuccinate, 4 times daily maintains antibacterial serum concentrations of 0.1-2 mcg/mL

References:

1. Outpatient Treatment of Community-Acquired Pneumonia in Adults. Prescriber's Letter 2013; 29(12):291224
2. http://www.bpac.org.nz/BPJ/2012/may/macrolides.aspx
3. https://nzpharmacy.wordpress.com/2009/02/09/dose-conversions-of-erythromycin-salts/
4. www.lexicomp.com