Augmentin and Unasyn Conversions

Aminopenicillins

• some Gram positives (Strep, Enterococcus, Listeria) but NOT MSSA, and limited Gram negative coverage. 
• Notable gram negative holes include Klebsiella, Moraxella, and SPICE A organisms.
• Used for: Upper respiratory infections, sinusitis, otitis media, cellulitis, Listeria infections, UTI’s, early Lyme disease (alternative to Doxycycline), and more.
• Drug of choice for Enterococcal infections if susceptible (E.faecalis generally susceptible, E.faecium usually not).  Used with aminoglycosides for synergy for Enterococcal endocarditis.
• Amoxicillin is the best-absorbed beta lactam (75-90% bioavailability). 
• Little role for oral ampicillin due to inferior absorption vs Amoxicillin

Combined Penicillin / B Lactamase Inhibitors

• addition of beta lactamase inhibitor confers broader spectrum against common beta-lactamase producing organisms (such as MSSA, some gram negatives including H.influenza, Moraxella, and virtually all anaerobes).

Amoxicillin/Clavulanate (Augmentin) – PO

• Spectrum: Relatively broad spectrum with some gram positive (MSSA, Strep), some gram negatives, and anaerobes. 
• Notable holes include NO Pseudomonal activity and other SPICE A organisms.
• Used for:  Sinusitis, respiratory infections, otitis media, some skin/soft tissue infections (including bite wounds), and more. 

Ampicillin/Sulbactam (Unasyn) – IV

• Spectrum: Similar to Amoxicillin/Clavulanate, except has activity vs most Acinetobacter (sulbactam component has activity).
• Still no activity against other SPICE organisms.
• Used for: similar situations as for Amoxicillin/Clavulanate but where IV form is desirable; also, some intraabdominal and GYN infections, aspiration pneumonia and lung abscesses, and more. 
• Caution with Unasyn for polymicrobial intraabdominal infections due to high rate of resistance of E.coli (>50% at some institutions)

Bioavailability

• Oral bioavailability of both oral unasyn and augmentin are very high (about 80%)
• Oral Unasyn is a prodrug (sultamicilin). Peak ampicillin following sultamicillin are approximately twice that of an equal dose of oral ampicilin.

Conversions:

 References:

1. Focus on Converting From Iv to Oral Antibiotics. Omnicare 2016
2. How to Choose Among Myriads of Antibiotics?
3. http://errolozdalga.com/medicine/pages/OtherPages/AntibioticReview.ChanuRhee.html

Adminstration of Nivestim (Filgrastim)

•  Availability: 30MU (300mcg) / 0.5 ml

Storage

• Store and transport refrigerated (2°C – 8°C). Do not freeze.
• Keep the pre-filled syringe in the outer carton in order to protect from light.
• The syringe can be removed from the refrigerator and left at room temperature for a single period of maximum 7 days (but not above 25°C).
• Do not use Nivestim if you notice it is cloudy or there are particles in it

Administration

• Remove the Nivestim syringe from the fridge and allow it to reach room temperature (approximately 25 °C). This will take 15–30 minutes.
• Hold the syringe with the needle pointing upwards.
• Remove the protective cap from the injection needle. The syringe is now ready for use.
• You may notice a small air bubble in the syringe. You do not have to remove the air bubble before injecting. Injecting the solution with an air bubble present is harmless
• Clean the area of skin with an antiseptic wipe
• 
• Pinch a large area of skin, taking care not to touch the area you have cleaned.
• With your other hand, insert the needle at an approximate 45˚ angle
• Pull the plunger back slightly to check if any blood appears in the syringe. If you do see blood inside the syringe, remove the needle and re-insert it in a different site.
• Depress the plunger while grasping the finger flange until the entire dose has been given. The passive needle guard will NOT activate unless the ENTIRE dose has been given

• Remove the needle from your skin, then let go of the plunger and allow the syringe to move up until the entire needle is guarded and locks into place
• Ensure the needle guard covers the needle

•  videa at http://www.medicininstruktioner.se/pfizer/nivestim/

Reference:

• Nivestim Package Information Leaflet

Administration of nebulisation solution

Availability solution for inhalation

• Salbutamol 5mg/ml (10ml)
• Ipratropium bromide 0.25mg/ml
• Budesonide 0.5mg/ml (2ml)

Combivent Inhalation solution

• 0.50mg Ipratropium Bromide + 2.5mg Salbutamol (2.5ml)
• As we do not have the combination product, the solution can be made up using 2ml of ipratropium bromide (0.25mg/ml) and 0.5ml salbutamol (5mg/ml) together with 1.5ml NS

Pulmicort Inhalation solution

• 0.5mg Budesonide (2ml)
• Do not dilute the content unless instructed to do so by physician.(If require lower dose)
• Pulmicort may be nebulised in combination with Terbutaline Sulfate inhalation solution, Salbutamol Inhalation Solution, Ipratropium bromide inhalation solution, Cromolyn Sodium Inhalation solution and Normal Saline.
• Medication should NOT be mixed in advance.
• The admixture should be used within 30 minutes.
• Ultrasonic nebuliser is NOT recommended to be used with Pulmicort Respules as it can cause treatment to be ineffective.

References:

1. Pulmicort Respules Product Leaflet

Lymphatic Filariasis :Doxycycline

• Wolbachia endosymbionts of filarial worms had become the target in finding the therapeutic agents.
• Wolbachia bacteria are essential symbionts of the major pathogenic filarial nematode parasites of humans including 
• Wuchereria bancrofti
• Brugia malayi
• Onchocerca volvulus are important both as chemotherapeutic targets and disease-causing organisms.
• The most promising antiwolbachial agent is doxycycline, as its ability to clear infection and also ameliorate filarial pathology has consistently been proven by several investigators

Mechanism of Action

• Doxycycline is a bacteriostatic drug that inhibits protein synthesis in endosymbiotic bacteria referred to as Wolbachia present in filarial nematodes including Wuchereria bancrofti, Brugia malayi and Onchocerca volvulus.
• Doxycycline could be the missing link in our effort to eliminate filariasis as it depletes Wolbachia, kills adult worms, depletes baby worms and improves the condition of individuals with chronic stages of both onchocerciasis and lymphatic filariasis.

Effectiveness

• The macrofilaricidal activity of the 6 and 4-week regimens were comparable (92 and 83%, respectively), whereas there was no macrofilaricidal activity in the 3-week group.
• Wolbachia loads were only reduced by 80%, in contrast to the other regimens in which a more than 90% reduction of Wolbachia copy numbers were monitored by quantitative PCR.
• There seems to be a minimum cumulative dose of doxycycline required for a more than 90% Wolbachia reduction, which subsequently leads to a macrofilaricidal effect in lymphatic filariasis

Challenges

• Doxycycline is contraindicated in those with allergy or sensitivity to the drug, pregnant and lactating women and children below 8 years because of its deleterious effects on bone and tooth development
• The gold standard for doxycycline treatment in filariasis is a daily dose of 200 mg for 6 weeks. 
• This relatively long duration of treatment creates further logistical challenges as the treatment must constantly be monitored for adverse effects. Such long antibiotic regimes are likely to increase the pace of the development of resistance.

Reference:

The Case for Doxycycline in Our Battle against Filariasis. Kenneth Bentum, Sept 2015

Management of Filariasis

• Onchocerciasis (River blindness)
• Lymphatic filariasis (Elephantiasis)
• Loiasis (Loa loa infection)

All are caused by parasitic filarial nematode worms that are transmitted between humans by blood-sucking insects.

• Onchocerciasis is caused by Onchocerca volvulus, transmitted by the bite of an infected female blackfly
• Lymphatic filariasis is caused by Wuchereria bancrofti (90% of cases), Brugia malayi (most of the remainder) and Brugia timori, and is transmitted by various mosquito species
• Loa loa worms are transmitted by the bites of Mango flies or by Deer flies (Chrysops spp.).

Lymphatic filariasis

• Lymphatic filariasis is caused by three thread-like parasitic worms, called filariae. The species Wuchereria bancrofti is the most prevalent worldwide, Brugia malayi is found mostly in eastern Asia, and B. timori is confined to East Timor and adjacent islands.
• Filarial parasites in their adult stage live in the lymphatic system.
• The worms have an estimated active reproductive span of 4–6 years, producing millions of small immature larvae, microfilariae, which circulate in the peripheral blood.

Diagnosis

• The standard method for diagnosing active infection is the identification of microfilariae in a blood smear by microscopic examination.
• The microfilariae that cause lymphatic filariasis circulate in the blood at night (called nocturnal periodicity). Blood collection should be done at night to coincide with the appearance of the microfilariae, and a thick smear should be made and stained with Giemsa or hematoxylin and eosin.
• For increased sensitivity, concentration techniques can be used.
• Serologic techniques provide an alternative to microscopic detection of microfilariae for the diagnosis of lymphatic filariasis.
• Patients with active filarial infection typically have elevated levels of antifilarial IgG4 in the blood and these can be detected using routine assays.
• Because lymphedema may develop many years after infection, lab tests are most likely to be negative with these patients.

Goal of treatment

• The main goal of treatment of an infected person is to kill the adult worm.

Choice of medications

Diethylcarbamazine citrate (DEC)

• Have both microfilaricidal and active against the adult worm, is the drug of choice for lymphatic filariasis. The late phase of chronic disease is not affected by chemotherapy.

Ivermectin

• Effective against the microfilariae of W. bancrofti, but has no effect on the adult parasite.

Albendazole

• No direct effect on microfilariae but leads to a slow decline in microfilaremia due to macrofilaricidal activity against the adult worms. Albendazole can be used in patients with concomitant loiasis or onchocerciasis.

Treatment

• All people with filariasis who are positive in the immunochromatographic test or have microfilaraemia should receive anti-filarial drug treatment to eliminate microfilariae (and adult worms when diethylcarbamazine is used)

• They can be treated with one of the following regimens:

(i) a single dose of a combination of albendazole (400 mg) with ivermectin (150–200 μg/kg) in areas where onchocerciasis is co-endemic

(ii) a single dose of a combination albendazole (400 mg) plus diethylcarbamazine (6 mg/kg)
or
(iii) diethylcarbamazine 6 mg/kg alone for 12 days in areas where onchocerciasis is non co-endemic

For tropical pulmonary eosinophilia (TPE), a longer DEC treatment course of 14-21 days is generally recommended. DEC is generally well tolerated.

Diethycarbamazine precaution

• DEC is contraindicated in patients who may also have onchocerciasis due to the possibility of severe exacerbations of skin and eye involvement.
• DEC should be used with extreme caution in patients with circulating Loa loa microfilarial levels > 2,500/mm3 due to the potential for life-threatening side effects, including encephalopathy and renal failure. Neither steroids pre-treatment nor slow dose escalation prevents these complications.

References

1. https://www.cdc.gov/parasites/lymphaticfilariasis/health_professionals/dxtx.html

2. https://www.uptodate.com.ezp.imu.edu.my/contents/diagnosis-treatment-and-prevention-of-lymphatic-filariasis

3. World helath Organization Global Programme To Eliminate Lymphatic Filariasis, 2013

Palivizumab: RSV prophylaxis

• Palivizumab, a humanized murine monoclonal immunoglobulin
• Standard dosing is 15 mg/kg administered intramuscularly every 30 days during RSV season for a maximum of five doses
  

Efficacy

• results of randomized controlled trials (RCTs) investigating palivizumab, demonstrating a reduction in hospitalizations of approximately
• 80% in infants with prematurity but without chronic lung disease of prematurity (CLD)
• 40% in infants with CLD
• 45% in children with congenital heart disease (CHD)
• Efficacy was not demonstrated in the CHD subgroup with cyanotic heart disease
• A recent systematic review summarized 20 published observational palivizumab studies and estimates of effectiveness were generally in the range predicted by the RCTs

Cost-Effectiveness

• Reports concerning the cost-effectiveness of palivizumab have varied, owing in large part to disparate estimates of its short- and long-term benefit
• Short-term benefits- there is no evidence that palivizumab prevents mechanical ventilation or death or that breakthrough RSV hospitalizations are less severe than hospitalizations in control
• Long term benefits - one RCT showed that palivizumab administered to infants 33 to 35 weeks’ GA without CLD decreased days with parent-reported wheezing in the first year from 4.5% to 1.8% (P<0.001; number needed to treat = 38) and decreased recurrent wheezing from 21% to 11% (P=0.01)
• Palivizumab prophylaxis has limited effect on RSV hospitalizations on a population basis, no measurable effect on mortality, and a minimal effect on subsequent wheezing
• technical review for the 2014 updated American Academy of Pediatrics (AAP) guidance for palivizumab prophylaxis indicates that palivizumab "cannot be considered as high-value health care for any group of infants" because its high cost is associated with minimal benefit
• Prophylaxis must be provided to many infants to prevent one hospitalization while the cost to provide prophylaxis to a single infant (approximately $5,600) exceeds that of a typical RSV hospitalization (three or four days).

Recommended Use

High Risk	Defination	Recommendation
hemodynamically significant CHD or CLD	need for oxygen at 36 weeks’ GA, who require ongoing diuretics, bronchodilators, steroids or supplemental oxygen	·         should receive palivizumab if they are <12 months of age at the start of RSV season. ·         not indicated during the second RSV season for infants with CHD ·         not indicated for majority of children with CLD (with the exception of those still on or weaned off of supplemental oxygen in the past three months)
preterm infants without CLD	born before 30 + 0 weeks’ GA who are <6 months of age at the start of RSV season	·         reasonable (but not essential) to offer palivizumab ·         Infants born after 30 + 0 weeks’ GA have RSV admission rates that are consistently ≤7% (90 doses of palivizumab to prevent one RSV admission) ·         not recommended in the second year of life on the basis of a history of prematurity alone
preterm infants with CLD	gestational age <32 weeks, 0 days and a requirement for >21% oxygen for at least the first 28 days after birth	·         Prophylaxis may be considered during the RSV season during the first year of life
immunodeficiencies, Down syndrome, cystic fibrosis, upper airway obstruction or a chronic pulmonary disease other than CLD		·         should not routinely be offered palivizumab However, prophylaxis may be considered for children <24 months of age who are on home oxygen, have had a prolonged hospitalization for severe pulmonary disease or are severely immunocompromised
pulmonary abnormality or neuromuscular disease	disease that impairs the ability to clear secretions from the upper airways	·         No prospective studies or populationbased data are availabl ·         may be considered for prophylaxis during the first year of life (due to risk for a prolonged hospitalization related to lower respiratory tract infection)
health care-associated RSV	prevention	·         not recommended
breakthrough RSV infection	breakthrough RSV infection during monthly palivizumab	·         Continuation of monthly palivizumab is not recommended ·         Repeat RSV infections in one season are not common

Recommendation

• Good hand hygiene in the home and avoiding contact of high-risk children with people with RTIs, where practical, remain paramount for RSV prevention.
• Breastfeeding and avoidance of exposure to cigarette smoke should be encouraged.
• Given that the efficacy of palivizumab is <50% in the highest-risk groups (CLD or CHD), and that most hospitalizations occur in healthy term infants, more education should be directed at such prevention strategies
• Based on lack of evidence that palivizumab prevents severe outcomes, palivizumab is unlikely to be cost-effective in children with prematurity, CLD or CHD, and can only be potentially cost-effective in settings where RSV hospitalizations are exceedingly common and very expensive

References:

1. www.uptodate.com
2. www.bestpractice.BMJ.com
3. Preventing hospitalizations for respiratory syncytial virus infection. Canadian Paediatric Society Infectious Diseases and Immunization Committee Paediatr Child Health 2015;20(6):321-26. Updated: May 12 2016
4. Updated Guidance for Palivizumab Prophylaxis Among Infants and Young Children at Increased Risk of Hospitalization for Respiratory Syncytial Virus Infection. PEDIATRICS Volume 134, Number 2, August 2014.
5. Cost-effectiveness of palivizumab compared to no prophylaxis in term infants residing in the Canadian Arctic. cmajo October 18, 2016 vol. 4 no. 4 E623-E633
6. A cost-effectiveness analysis of respiratory syncytial virus (RSV) prophylaxis in infants in the United Kingdom. Health Economics Review20133:18