S. Aureus: Ceftriaxone VS Cloxacillin

Claims on Cloxacillin being more effective

• In in-vitro studies, Ceftriaxone alone was less effective than cloxacillin for the treatment of experimental MSSA endocarditis.
• A study claimed susceptibilities to oxacillin and ceftriaxone in S. aureus; 60% of MSSA bloodstream isolates were reported to be resistant to ceftriaxone.
• The publication was subsequently retracted because the testing method used. In addition, the authors' findings were not consistent with an independent study using a standard broth microdilution method
• Furthermore several studies have showed that lower effectiveness of ceftriaxone is due to use of lower doses

Comparison in terms of MIC

• routine susceptibility testing for S. aureus is performed only for oxacillin, and the results are extrapolated to other beta-lactams, including ceftriaxone
• study have shown ceftriaxone susceptibility may be reasonably inferred based on the testing using oxacillin, as recommended by the 2014 CLSI guidelines
• Using the oxacillin test result, the very major false susceptible error was <0.1% (oxacillin-susceptible/ceftriaxoneresistant) and minor errors were only 4.3% (oxacillin-susceptible/ceftriaxoneintermediate), both of which are well within CLSI’s acceptable limits.
• based on osteoarticular infections, 2 g/day is appropriate but 1 g/day may give inadequate drug levels; thus, a higher risk for failure given ceftriaxone minimum inhibitory concentration (MIC) values against MSSA is 4 µg/mL
• A recent retrospective controlled study with a large number of MSSA PJIs, not cited by the guidelines, suggests that ceftriaxone 2 g/day and oxacillin 2 g every 6 hours have similar cure rates
• we propose using ceftriaxone for serious MSSA infections only when the oxacillin MIC is ≤0.5 µg/mL and with a minimum dosing of 2 g/day.
• Although an oxacillin MIC of 1 or 2 µg/mL does not necessarily exclude ceftriaxone use, a dosage of 2 g every 12 hours would be preferred to ensure adequate drug levels and corresponding PK/PD target attainment

Prosthetic joint infection and osteoarticular infections

• The antimicrobial agents of choice for MSSA are typically oxacillin, nafcillin, and cefazolin
• Ceftriaxone is comparable to cloxacillin in terms of skin and tissue penetrations
• Current US Food and Drug Administration (FDA)–recommended ceftriaxone dosage for MSSA is 2–4 g/day
• In this comparison of ceftriaxone versus oxacillin for MSSA osteoarticular infections, there was no difference in treatment success at 3–6 and >6 months following the completion of intravenous antibiotics. Patients receiving oxacillin were more likely to have it discontinued due to toxicity

Recommendations:

• As Ceftriaxone 2g/day is shown to be comparable to oxacillin 2g/QID for MSSA, there is no justification in using combination of both agent.
• For areas with higher oxacillin MIC, a dose of 2 g every 12 hours would be preferred to ensure adequate drug level
• However, as empirical/initial therapy without any other complications, cloxacillin is still the preferred first line choice.

Reference:

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC127055/
2. Elevated Staphylococcus Ceftriaxone MICs are an Etest Artifact. Clin Infect Dis 2015; 60 (1): 162-163
3. http://aac.asm.org/content/59/2/1370.full
4. Outcomes of Ceftriaxone Use in Methicillin SusceptibleStaphylococcus aureus (MSSA) Bloodstream Infections. https://idsa.confex.com/idsa/2010/webprogram/Paper2970.html
5. A retrospective comparison of ceftriaxone versus oxacillin for osteoarticular infections due to methicillin-susceptible Staphylococcus aureus. http://www.ncbi.nlm.nih.gov/pubmed/22144536
6. Treatment of MethicillinSusceptible Staphylococcus aureus Osteoarticular and Prosthetic Joint Infections: Using the Oxacillin Minimum Inhibitory Concentration to Guide Appropriate Ceftriaxone Use. http://cid.oxfordjournals.org/content/57/1/161.2.full.pdf+html
7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3275755/
8. http://emedicine.medscape.com/article/2018345-overview
9. https://www.hopkinsguides.com/hopkins/view/Johns_Hopkins_ABX_Guide/540518/all/Staphylococcus_aureus
10. NAG 2014
11. HUSM Antibiotic Guideline 2014

When to initiate Iron Supplementation in PreTerm Infants

• There are wide variations in the dose, initiation and duration of supplementation and iron compounds used for enteral supplementation
• Iron supplementation is not recommended nor is it necessary during the transition period soon after birth 
• an exogenous source of 2–4 mg/kg d⁻¹ iron is recommended during the period of stable growth, beginning at 4–8 weeks and continuing until 12–15 months of age. Whereas these recommendations provide useful guidelines for iron therapy in preterm infants, they may not be universally applicable as discussed below

TIME of INITIATION:

• ranged from 14 days to 10 weeks among the neonatal units. The current recommendation is to begin supplementation from 4–8 wks of age, irrespective of gestational age or birth weight
• However, beginning supplementation earlier may be prudent for the more immature preterm infants, many of who may be in negative iron balance by one month of age 
• supplementing 2–5 mg/kg d⁻¹ of iron from 2 weeks of age reduces the need for erythrocyte transfusions and the risk of iron deficiency between 2 and 6 months of age
• Early iron supplementation was tolerated well and was not associated with morbidities

HARMS of EARLIER INITIATION

• On the other hand, the risk of iron-induced hemolysis in preterm infants with vitamin E deficiency is maximal during the first 6 weeks of life
• Serum iron and ferritin concentrations remain elevated during the first 4–6 wk of life even without supplementation. There is a potential for iron excess with higher doses of supplementation since enteral iron absorption appears to be poorly regulated during the first month of life in ELBW infants
• Furthermore, supplemental iron is better incorporated into red cells when it is administered after the onset of erythropoiesis. These studies would support delaying iron supplementation until 4–6 wk.

RECOMMENDATIONS:

• based on Malaysian Paeds Protocol, recommend to initiate at about 4 weeks of life at 2-3mg/kg/day.
• However, further changes can be carried out based on other needs and factors such as ferritin level, maturity, early negative iron balance etc.

References:

1. Iron Therapy for Pre Term Infants. Raghavendra et al Clin Perinatol. 2009 Mar; 36(1): 27–42.
2. Neonatal Medication Protocol (based on Neofax 2012) http://kemh.health.wa.gov.au/services/nccu/guidelines/drug_protocols/FerrousSulphate.pdf\
3. Frank Shann
4. Malaysian Paediatric Protocol (3^rd Edition)

Recommendations for missed oral contraceptives

• Oral contraceptives are usually started on the first or fifth day of your menstrual period or on the first Sunday after or on which bleeding begins. You need to use another method of birth control during the first 7 to 9 days that you take your oral contraceptive and the doctor will help you choose a method.
• If you vomit or have diarrhea while you are taking an oral contraceptive, you should use a backup method
• For missed doses, refer to the chart below:

references:

1. Missed Hormonal Contraceptives: New Recommendations. – Committee opinion. J Obstet Gynaecol Can. 2008 Nov;30(11) :1050-77.

When to initiate oral Acyclovir in Chicken Pox (varicella zoster)

TIME

• Most studies carried out/ shows benefit of initiating therapy within the first 24 hours after onset of rash
• In adults, treatment from 25 to 72 hours after the onset showed no effect on the course of illness. Reduction in other complications (such as varicella pneumonia was not studied)

RECOMMENDATIONS:

• To initiate within 24hours of symptom
• Should not be used routinely in otherwise healthy children with varicella due to its modest effect (CDC)

BENEFITS within 24 hours:

• fewer lesions
• accelerated healing
•  shorter duration of fever

HIGH RISK group

• Older children (>12 years)
• Secondary household cases (can be more severe)
• History of chronic cutaneous or cardiopulmonary disorders
• Taking inhaled or intermittent oral steroid
• Taking chronic salicylates (higher risk of developing Reye syndrome)

REFERENCES:

1.       www.uptodate.com

Monitoring parameter for Aspirin induced Thrombocytopenia

• Drug-induced thrombocytopenia is a reversible form of thrombocytopenia (ie, platelets <150,000/microL) that should be suspected in a patient who presents with new onset of thrombocytopenia or recurrent episodes of acute thrombocytopenia, without an obvious alternative etiology

• The thrombocytopenia is typically isolated (ie, unaccompanied by anemia, leukopenia, leukocytosis, or coagulation abnormalities) and severe (ie, platelet count <20,000/microL with clinical bleeding) in a patient taking one or several different medications or herbal remedies, foods, beverages, or other substances.

•  acetaminophen and naproxen, for which drug-dependent, platelet-reactive antibodies have only been identified for drug metabolites and not for the intact drug

The clinical course and outcome has been described in several publications:

• The median time for daily exposure to a drug before thrombocytopenia occurs is six days (range 1 to 10).

• Median recovery after discontinuation of the suspected drug occurred in five to seven days, similar to the median recovery rate of eight days reported from a Danish registry.

• Twenty-three of 266 patients (9 percent) with definite or probable evidence for drug-induced thrombocytopenia had major hemorrhage, including two patients (0.8 percent) who died of bleeding. This mortality rate from bleeding was lower than the value of 3.6 percent reported from a Danish registry

Recommendation: 

No recommendation for routine monitoring parameter as the recovery is fast. Suggest following up patient if platelet counts are decreasing trend upon treatment initiation (platelet turn around takes an estimated 8-10 days). If values falls further can consider stopping therapy and monitor for increase after 1 week. If platelet count increases, the drug can be suspected to be the culprit and avoided

references:
1. www.uptodate.com
2. http://www.clevelandclinicmeded.com

Use of Anticonvulsant Prophylaxis for Cerebral Haemorrhage

Risk of Seizure

• The reported risk of seizures in patients with acute spontaneous ICH ranges from 4.2 to 29 percent. Seizures are more common in lobar as compared to deep hemorrhage.
• The frequency depends in part on the extent of monitoring, as seizures associated with ICH are often nonconvulsive
• If a seizure occurs, appropriate intravenous antiepileptic drug (AED) treatment should be administered to prevent recurrent seizures. The choice of the initial antiepileptic agent depends upon individual circumstances and contraindications. Current guidelines suggest the use of intravenous phenytoin in this setting¹
• Initiate fosphenytoin or other anticonvulsant definitely for seizure activity or lobar hemorrhage, and optionally in other patients. Levetiracetam has shown efficacy in children for prophylaxis of early posthemorrhagic seizures. Additional data suggest that levetiracetam is more effective than phenytoin for seizure prophylaxis without suppression of cognitive abilities in patients with ICH²

Prophylaxis prior to Seizure

• While some experts suggest a brief period of AED prophylaxis soon after ICH onset as a potential means of reducing the risk for early seizures in patients with lobar hemorrhages, 2010 guidelines recommend against prophylactic use of AEDs. This strategy has not been tested prospectively in clinical trials
• It was associated with poorer outcomes (a concern that has also been raised for subarachnoid hemorrhage patients), these were nonrandomized, observational studies, and sample size did not allow for examination of a differential effect from different AED
• The 2010 AHA/ASA guidelines do not offer recommendations on prophylactic anticonvulsants, but suggest that continuous EEG monitoring is probably indicated in patients with intracranial hemorrhage whose mental status is depressed out of proportion to the degree of brain injury
• Prophylactic anticonvulsant therapy has been recommended in patients with lobar hemorrhages to reduce the risk of early seizures. One large, single-center study showed that prophylactic antiepileptic drugs significantly reduced the number of clinical seizures in these patients
• In addition, AHA/ASA guidelines from 2012 suggest that prophylactic anticonvulsants may be considered for patients with aneurysmal subarachnoid hemorrhage. In such cases, however, anticonvulsant use should generally be limited to the immediate post-hemorrhagic period. Routine long-term use is not recommended, but it may be considered in patients with a prior seizure history, intracerebral hematoma, intractable hypertension, or infarction or aneurysm at the middle cerebral artery

References:

1. www.uptodate.com
2. Medscape http://emedicine.medscape.com/article/1916662-treatment#aw2aab6b6b2 
3. Seizure Prophylaxis in Patients with Traumatic Brain Injury. Department of Surgical Education, Orlando Regional Medical Center (2012)
4. The prophylactic use of an antiepileptic drug in intracerebral hemorrhage. Clin Neurol Neurosurg (2011), doi:10.1016/j.clineuro.2011.07.008

Choice of Antibiotics for Necrotising Fasciitis

Emperical Therapy

• Empiric antibiotics should be started immediately. Initial antimicrobial therapy should be broad-based, to cover aerobic gram-positive and gram-negative organisms and anaerobes. 
• A foul smell in the lesion strongly suggests the presence of anaerobic organisms. 
• The maximum doses of the antibiotics should be used, with consideration of the patient's weight and liver and renal status
• Clindamycin is often added due to  for its antitoxin effects against toxin-elaborating strains of streptococci and staphylococci

Duration

• no specific duration based on clinical trials
• based on available recommendations, to use based on clinical response, no requirement for surgical debridements and fever free for at least 48-72 hours.

Acceptable regimens include administration of:

• A carbapenem or beta-lactam-beta-lactamase inhibitor, plus
• Clindamycin (dosed at 600 to 900 mg intravenously every eight hours in adults or 40 mg/kg per day divided every eight hours in neonates and children) for its antitoxin effects against toxin-elaborating strains of streptococci and staphylococci), plus
• An agent with activity against methicillin-resistant S. aureus (MRSA; such as vancomycin, daptomycin, or linezolid) (table 3). In neonates and children, vancomycin (15 mg/kg/dose every six to eight hours) is the usual empiric antibiotic for MRSA; the six-hour dosing interval is employed for sicker children

Organism Specific Treatment

Management of Skin and Soft Tissue Infections: 2014 Update IDSA

NAG 2014

Malaysian ICU Antibiotic Guideline 2012

references:
1. www.uptodate.com
2. http://emedicine.medscape.com/article/2012058-overview
3. Practice Guidelines on the Management of Soft Tissue and Skin Infection 2014 (IDSA)

Oral Corticosteroid for Acute Gouty Arthritis

• When selecting corticosteroids as the initial therapy, the TFP (Task Force Panel) recommended to first consider the number of joints with active arthritis. For involvement of 1 or 2 joints, the TFP recommended the use of oral corticosteroids (evidence B); the TFP additionally recommended the option of intraarticular corticosteroids for acute gout of 1 or 2 large joints (evidence B)
• For intraarticular corticosteroid therapy in acute gouty arthritis, it was recommended that dosing be based on the size of the involved joint(s), and that this modality could be used in combination (Table 1) with oral corticosteroids, NSAIDs, or colchicine (evidence B)
• Where intraarticular joint injection is impractical , the TFP recommended oral corticosteroids, prednisone, or prednisolone at a starting dosage of at least 0.5 mg/kg per day for 5–10 days, followed by discontinuation (evidence A) (28,43), or alternately, 2–5 days at the full dose, followed by tapering for 7–10 days, and then discontinuation (evidence C)
• no particular maximum doses indicated- depended on the nature and severity.

references:

1. www.uptodate.com

2. 2012 ACR Managemnet of Gout Part 2

Hepatotoxicity Associated with Anti-Epileptic

Virtually all of the major antiepileptic drugs (AEDs) can cause hepatotoxicity, although fatal hepatic reactions are rare. The mechanisms, incidences, and risk profiles for such reactions differ from drug to drug

PHENYTOIN

• most common causes of clinically apparent drug induced liver disease and acute liver failure.
• The typical case arises after 2 to 8 weeks of therapy with initial onset of fever, rash, facial edema and lymphadenopathy, followed in a few days by jaundice and dark urine
• In most cases due to hypersensitivity reaction

CARBAMAZEPINE

• Carbamazepine hepatotoxicity occurs in the setting of anticonvulsant hypersensitivity syndrome in about half of cases with onset of fever, followed by rash, facial edema, lymphadenopathy, elevations in white count and eosinophilia or atypical lymphocytosis, 1 to 8 weeks after starting therapy
• In most cases due to hypersensitivity reaction

VALPROATE

• Valproate has been rarely associated with anticonvulsant hypersensitivity syndrome and generally is a safe alternative
•  5% to 10% of persons develop ALT elevations during long term valproate therapy, but these abnormalities are usually asymptomatic and can resolve even with continuation of drug
• Three clinically distinguishable forms of hepatotoxicity (besides simple aminotransferase elevations) can occur with valproate – hyperammonemia, acute hepatocellular injury with jaundice and Reye-like syndrome.
• Young age (<2 years), presence of other neurological conditions and concurrent use of other anticonvulsants appear to be important risk factors for acute liver failure due to valproate

LAMOTRIGNINE

• less than 1% of subjects develop elevations in serum aminotransferase levels
•  typically short, ranging from one to several weeks.  Presenting symptoms are a diffuse maculopapular rash, followed in a few days by high fever, nausea and vomiting.  The rash can develop into a systemic hypersensitivity reaction and multiorgan failure or be associated with jaundice and hepatitis

LEVETIRACETAM

• rare instances of serum enzyme elevations and occasional cases of clinically apparent liver injury
• time to onset of liver injury after starting levetiracetam has ranged from 1week to 5 months and the usual pattern of injury has been hepatocellular
• Immunoallergic features and autoantibodies were rare

CLONAZEPAM, DIAZEPAM

• rarely associated with serum ALT elevations, and clinically apparent liver injury from clonazepam is extremely rare.

PHENOBARBITONE

• Clinically apparent hepatotoxicity from phenobarbital is rare but can be abrupt in onset, severe and even fatal
• typically occurs in the setting of anticonvulsant hypersensitivity syndrome with onset of fever, rash, facial edema, lymphadenopathy, elevations in white count and eosinophilia occurring 1 week to several months after starting therapy

 REFERENCES

1.    http://livertox.nih.gov/AnticonvulsantDrugs.htm
2.    www.uptodate.com
3.    http://onlinelibrary.wiley.com/doi/10.1111/j.1600-0404.2008.01009.x/abstract
4.    http://www.seizure-journal.com/article/S1059-1311(06)00002-1/pdf

Oral Sodium Chloride use in hyponatraemia

AVAILABILITY: 
Sodium Chloride Powder [1 g = 17mmol]
NaCl 3% [1 L = 513 meq]
NaCl 0.9% [1 L = 154 meq]

• In theory, oral sodium chloride might be an option for patients with chronic hyponatremia. However, randomized trials comparing oral with intravenous sodium chloride for the management of hyponatremia have not been performed. 
• Traditionally 1-2 g three times daily has been used when sodium chloride was given orally, but no consistent dosing strategy for oral sodium chloride in patients with hyponatremia is available in the published literature. 
• Gastrointestinal intolerance (e.g., nausea, vomiting, diarrhea) is a potential problem with oral therapy. The response (serum changes) is also unpredictable. 
• Patients with syndrome of inappropriate antidiuretic hormone secretion (SIADH) who have very mild or absent symptoms and a serum sodium above 120 meq/L can be treated with oral salt tablets in addition to fluid restriction. 
• Given hourly, salt tablets can substitute for hypertonic saline in nonurgent situations. 
• Oral salt tablets may also be effective in hypovolemic patients who are treated as outpatients (in combination with reversing the cause of hypovolemia)
• Calculating the dose of oral salt tablets uses the same principles as intravenous isotonic or hypertonic saline: 9 g of oral salt provides a similar quantity of sodium as 1 L of isotonic saline (154 meq) but without any water; 1 g of oral salt is equivalent to 35 mL of 3 percent saline.
• Oral salt tablets should not be given to edematous patients (eg, those with heart failure, cirrhosis)

reference:

1. www.uptodate.com

2. http://www.ashpmedia.org/advantage/hyponatremia/docs/hyponatremia_e-newsletter_3-2012.pdf

3. http://www.ncbi.nlm.nih.gov/pubmed/23816479