Preparing for Oseltamivir Shortage

The influenza season, it appears, is coming on strong this year, and our intensive care unit seems to be reflecting that: I think about 15% of the patients in the ICU have influenza A. Although not all of the admissions to the unit were secondary to influenza disease, we have had to utilize IV zanamivir in 2 cases already this season for severe influenza disease.

Fortunately, most cases can be treated as an outpatient with either ostelamivir or inhaled zanamivir. The inhaled zanamivir is indicated for children > 7 year of age and probably won’t be too effective for patients with pneumonia due to influenza since drug deposition into the airways is needed for efficacy. (Although this makes me wonder how often inhaled zanamivir is used since most patients have pulmonary manifestations of influenza…) Thus oral oseltamivir is widely used to treat influenza.

The one question that comes up is whether or not there is the potential for drug shortage of osteltamivir during the influenza season. Currently, the FDA and ASHP do not report any shortage of oseltamivir at the moment. Although they don’t report any issues as of yet, it appears that our distributor had limited quantities for allocation – especially the liquid formation of oseltamivir – which in turn means that there is a potential for drug shortage in the near future.

Pharmacies should be increasing their inventories to meet the demand for influenza treatment. Determining which pharmacies have a good supply of oseltamivir could be helpful as you can send your patients to a place that will carry the medication (also, you should check which ones are willing to compound medication if needed). However, finding the pediatric liquid formulation may be difficult in some areas, and there are other options to be able to provide oseltamivir to children.

For infants, the liquid suspension should be used, since weight based dosing is preferred when available (3 mg/kg/dose PO q12h for 5 days). The liquid formulation is available at a 6 mg/mL strength. The bottle size is 60 mL and pharmacies may consider dispensing only the required volume to optimize their inventory (although somewhere in the back of my head, this seems like repackaging).

If in case there is a shortage of commercially available oseltamivir, an extemporaneous preparation can be made from the capsules in emergency situations (the recipe is available in drug information sources such as Lexicomp). Being familiar with pharmacies that are willing to compound the medication may come in handy if there is a shortage of oseltamivir suspension.

For children, capsules can be opened and mixed with sweetened liquid – considering that Lexicomp provides example such as chocolate syrup, brown sugar dissolved in water, you can probably mix it with a number of different things. Osteltamivir comes in 30 mg, 45 mg, and 75 mg capsules and the recommended dosing for children is:

Weight	Dose	Capsule Size per Dose
≤ 15 kg	30 mg PO q12h for 5 days	One 30 mg capsule
> 15 – 23 kg	45 mg PO q12h for 5 days	One 45 mg capsule
> 23 – 40 kg	60 mg PO q12h for 5 days	Two 30 mg capsule
> 40 kg	75 mg PO q12h for 5 days	One 75 mg capsule

IV Zanamivir Expanded Access

Well, influenza season is officially upon us. Our institution has been participating in a multi-centered GlaxoSmithKline (GSK) study looking at pharmacokinetics and efficacy of IV zanamivir for severe influenza virus in pediatric patients, which was very helpful last year during the influenza season. It appears that everyone had "good" recruitment last year, so only a limited number of age groups are still open for the study.

Fortunately, GSK has announced that compassionate use IV zanamivir will be available to patients with severe influenza who do not qualify for the GSK-sponsored study. Unfortunately, that means that IV zanamivir will have to be obtained under an emergency investigational new drug (EIND) application... Which we all know, will occur on a Friday afternoon and all hell breaks loose. If you happen to have a nice ID pharmacist on your team, that usually means he/she will be stuck doing the application. (Hopefully I don't sound too bitter from too many EIND encounters.)

To combat this issue, we are planning on obtaining an overall institutional review board (IRB) approval for expanded access. This may only eliminate one step in the whole process, but for us, often seems to be the most rate-limited step in an EIND. GSK was very helpful in that they were willing to provide a copy of the Physician Document Guide which helped us in writing our informed consent.

We've also developed a step-by-step guide/checklist for our ID physicians as to standardize their process and to ensure everything is completed.

Hopefully this is helpful to someone!

Step-by-Step Guide:

Expanded Access for IV Zanamivir for Patients with Severe Influenza Illness

1. Consider obtaining IRB approval for multiple use

• Advantages: 
• Streamlines the first step of emergency IV zanamivir use (won’t have to fill out IRB paperwork multiple times, informed consent form already approved, won’t have to find an IRB Board Member on the weekend to approve)
• Also will know what to expect from the GSK paperwork and will help with standardizing approach
• Disadvantages: will have to undergo full Human Subjects Review (maybe not for all institutions)

2. Obtain Informed Consent from patient legal guardian 

• Review Physician Document Guide for information to include into the Informed Consent Form
• Also obtain Informed Consent for Sharing Clinical Data with GSK (separate from your institutional Informed Consent)

3. Contact Investigational Drug Services to inform them that someone may qualify for the study

• As a pharmacist, it would be nice to do this early as to avoid surprises and to streamline receipt of medication, preparation, etc.

4. Contact the GlaxoSmithKline (GSK) Clinical Support Help Desk (CSHD)

• Call: 1-877-221-2913
• Other (Option 4)
• Other (Option 6)
• Talk with an agent of GSK to obtain the compassionate use information (will need your e-mail and a contact number)

5. CSHD will provide an information package that contains the following (4 items):

• 1. GSK Zanamivir Aqueous Solution: Compassionate Use Treatment Request Documents (PDF file)
• 2. Physician Document Guide (DOCX file)
• i. Somewhere in this document, you can find the GSK Informed Consent for Sharing Clinical Data
• 3. Patient Medication Request Form (DOCX file)
• 4. Request for Additional Treatment Form (DOCX file)

6. Obtain EIND from FDA: 

• Required paperwork to submit to FDA (4 articles):
• 1. Filled out Patient Medication Request Form (from GSK)
• The “EIND Number” and “Name of Person Granting the EIND” will initially be blank
• 2. Form 1571 
• Instructions
• 3. Form 1572
• 4. Your CV as the sponsor-investigator (for completion of Form 1572)
• Submit the paperwork 
• If during business hours (8:00AM – 4:30PM EST, Monday – Friday), you can submit via
• i. E-mail: DAVPEINDREQUEST@fda.hhs.gov OR
• ii. Fax:  301-796-9883
• Call 301-796-1500 to notify someone that you submitted by fax
• c. If after business hours (weekdays after 4:30PM EST, weekends, or holidays)
• Call FDA Emergency Coordinator at 1-866-300-4374 or 301-796-8240 to facilitate or grant the EIND request
• NOTE: You may not receive an EIND if obtained after hours. Provide the manufacturer the name of the person who granted/authorized the EIND for release of the drug.
• Remember to provide contact information (e-mail, phone number, pager) if questions arise!

7. After obtaining EIND or the name of the person granting the EIND, send the Patient Medication Request Form to GSK CSHD at gskclinicalsupportHD@gsk.com or by fax (see information packet for fax number)

• Remember to provide your contact information (e-mail, phone number, pager) if questions arise! GSK will contact you to correct the forms if necessary.
• Provide an address/contact person to send IV zanamivir
• GSK will provide and estimated time of arrival
• Coordinate with institutional Investigational Drug Services (also a reason to contact early so they'll know it is coming)

8. Follow-up for FDA EIND Submission (Part 1 of 2)

• Part 1: Mail original FDA paperwork that was e-mailed/faxed to the Division of Antiviral Products to the following address:

                 Food and Drug Administration

                 Center for Drug Evaluation and Research

                 Division of Antiviral Products

                 5901-B Ammendale Road

                 Beltsville, MD 20705-1266

9. If additional treatment is required, submit the “Request for Additional Treatment Form” to gskclinicalsupportHD@gsk.com

10. Follow-up patient and complete Case Report Form (will be provided by GSK after submission of Patient Medication Request Form)

• It appears that physical exams are not specifically requested by GSK, but GSK requests information regarding adverse drug events (non-severe and severe) that may be related to the medication and not necessarily due to disease progress (review Physician Document Guide for specifics)
• Submit to gskzanamivircup@ppdi.com 

11. Follow-up for FDA EIND Submission (Part 2 of 2)

• At the completion of treatment or if the patient dies, submit a request to withdraw the EIND along with the FDA Form 1571 to the following address:

                 Food and Drug Administration

                 Center for Drug Evaluation and Research

                 Division of Antiviral Products

                 5901-B Ammendale Road

                 Beltsville, MD 20705-1266

Amoxicillin/clavulate for ESBL UTI?

Everyone falls a little behind in life (although my hiatus from writing is almost a year!), but instead of making excuses, I need to get myself in gear and start posting again. Here goes:

As most of the adult healthcare providers are aware of (and there is growing knowledge in the general population), there is an increasing amount of extended-spectrum beta-lactamase (EBSL)-producing organisms in the community; however, it seems that some of us in the pediatric side are still a little naïve to this. However, our renal/urology patients are definitely blowing our innocence out of the water and I feel like I see a new patient colonized with ESBL-producing about every few weeks or so. Unfortunately, their isolates are often resistant to oral antibiotics and have to be admitted for intravenous antibiotics for urinary tract infections (UTIs); although, sometimes you will get lucky and one will actually be amoxicillin/clavulante susceptible.

Some of our practitioners feel a little leery about using amoxicillin/clavulante alone for UTIs, mostly due to limited experience as well as the idea of how such an everyday antibiotic can work the same wonders as a broad-spectrum carbapenem. But it kind of makes some sense that the addition of clavulante might do the trick: beta-lactamase inhibitors can inhibit Ambler Class A ESBLs, whereas AmpC beta-lactamases (Ambler Class C) are not affected.¹ Phenotypic confirmation of ESBLs can be performed through disk diffusion. The zone of inhibition is compared between ceftazidime and cefotaxime alone and in combination with clavulanic acid and an increase of >= 5 mm confirms the presence of an ESBL (see figure).^2,3 The Clinical Laboratory Standards Institute recommends that all other penicillins, cephalosporins, and aztreonam be reported as “resistant” but does not indicate whether or not amoxicillin/clavulanate should be defaulted as non-susceptible when the MIC <= 8 mcg/mL.

There appears to be very limited studies about the clinical usage of amoxicillin/clavulante in this setting. One study of community-acquired uncomplicated cystitis caused by ESBL-producing E. coli suggests that amoxicillin/clavulate can often be successful if the organism is susceptible (MIC <= 8 mcg/mL) and less so if less susceptible (MIC ³ 16 mcg/mL), 93% vs. 56%.⁴  Additionally, the pharmacokinetic/pharmacodynamics properties of amoxicillin/clavulanate are maximized for uncomplicated UTIs due to the concentration of the antibiotic in the bladder. The challenge, however, is finding an isolate that is susceptible to this beta-lactam/beta-lactamase inhibitor combination since the resistance can be upwards of 70% in E. coli isolates. Thus, empiric use of amoxicillin/clavulanate should be avoided and other agents, such as nitrofurantoin or fosfomycin, can be considered as initial treatment (although treatment spectrum is limited to cystitis).⁵

However, the other question would be whether or not clavulanate in combination with other oral cephalosporins would be adequate as an oral outpatient therapy for UTIs? Which, hopefully, will be explored in the next week or so.

Figure 1. ESBL detection by disk diffusion.

1.     Drawz SM, Bonomo RA. Three decades of beta-lactamase inhibitors. Clin Microbiol Rev. 2010;23:160-201. PMID:20065329

2.     Clinical and Laboratory Standards Institute. 2011. Performance standards for antimicrobial susceptibility testing. Supplement M100-S21.Clinical and Laboratory Standards Institute, Wayne, PA.

3.     Kumar V, Sen MR, Nigam C, Gahlot R, Kumari S. Burden of different beta-lactamase classes among clinical isolates of AmpC-producing Pseudomonas aeruginosa in burn patients: a prospective study. Indian J Crit Care Med. 2012;16:136-140. PMID: 23188953

4.     Rodríguez-Baño J, Alcalá JC, Cisneros JM, et al. Community infections caused by extended-spectrum beta-lactamase-producing Escherichia coli. Arch Intern Med. 2008;168:1897-902. PMID: 18809817

5.     Meier S, Weber R, Zbinden R, Hasse B. Extended-spectrum β-lactamase-producing Gram-negative pathogens in community-acquired urinary tract infections: an increasing challenge for antimicrobial therapy. Infection. 2011;39:333-40. PMID: 21706226

Fungal Peritonitis + Voriconazole

Fungal peritonitis has been haunting us lately and the last few cases have involved Candida krusei, which is intrinsically resistant to fluconazole and has dose-dependent susceptibility with itraconazole.¹  Although I feel relatively comfortable with fluconazole and the echinocandins (kinda) for candidal peritonitis, I hadn’t had much experience with voriconazole in this setting.  (I was looking for an oral option for our patients, because the last thing we really needed was a catheter line associated blood stream infection.)  I looked at my trusty sources to see if there were any data about the penetration of voriconazole in peritoneal fluid (Lexicomp and Micromedex), but alas, there was no information available; however, given the wide distribution of the drug (4.6 L/kg), it suggests that there may be some distribution into peritoneal fluid.²

There is one pharmacokinetic study available that examined the distribution of voriconazole in peritoneal fluid.³  A total of five patients, who were undergoing peritoneal dialysis (PD), were in the study; a 200 mg single-dose of voriconazole was administered to each of the participants and serum and peritoneal dialysate concentrations of voriconazole were drawn.  It appears that voriconazole distributes into the peritoneal fluid, reaching maximum concentrations at the same time as the plasma.  Peritoneal clearance of voriconazole was minimal and the group suggested that dose adjustment was not needed for patients undergoing PD.

Pharmacokinetic Parameter	Study Group, Plasma	Study Group, Dialysate	Population (multiple 200 mg dose)
Cmax (mcg/mL)	0.55 ± 0.20	0.25 ± 0.09	2.08
Tmax­ ­(h)	2.4 ± 0.7	2.8 ± 0.5	1-2.8
AUC24h (mcg*h/mL)	5.8 ±1.3	--	19.86
t1/2 (h)	8.1 ± 1.3	--	6
Clearance/F (mL/min)	440 ± 77	3.7 ±0.6	--
Dialysate/Plasma concentration	--	0.66 ± 0.11	--

Although it appears that voriconazole distributes well into the peritoneal fluid (about 65% of the serum concentration), this was a single-dose study; multiple doses would be able to demonstrate if the distribution is consistent with time.  Also, only peak concentrations were obtained; although serum trough concentrations of voriconazole may be more predictive of efficacy, “trough” peritoneal concentrations may help determine if it is sufficient to treat fungal infections.  Lastly, this study was performed in uninfected patients undergoing peritoneal dialysis; it appears that general management of fungal peritonitis is to remove the PD catheter early and initiate hemodialysis in the patient in addition to antifungal therapy.⁴  The loss of volume in the peritoneal space as well as inflammation may increase the concentration of voriconazole in the fluid; however, further studies are needed to explore this avenue.   

Even though C. albicans is the primary culprit associated with fungal peritonitis, other Candida sp. and non-yeast species have been increasingly noted which has required the use of more broad-spectrum antifungals; although echinocandins have an FDA-labeled indication for disseminated candidiasis (including peritonitis), the role of other triazole antifungals have not been fully established for peritonitis.⁴  When searching the primary literature, there are a number of cases where voriconazole was used successfully to treat peritonitis associated with fungi, including Fusarium, non-albicans Candida, Aspergillus sp., C. bertholletiae (although it was found to be resistant to voriconazole), P. lilacinus (in combination with terbenifine), N. pseudofischeri, and O. gallopava.^4-11  While there are successes, it should be noted that mortality associated with severe fungal peritonitis is high (up to 50%), despite appropriate antifungal pharmacotherapy.^4,10

1.       Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:503-35.  Available at: http://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/Candidiasis.pdf

2.       VFEND® (voriconazole) Prescribing Information. Pfizer Inc. New York, NY. Updated November 2011.  Available at: http://labeling.pfizer.com/ShowLabeling.aspx?id=618

3.       Peng LW, Lien YH. Pharmacokinetics of single, oral-dose voriconazole in peritoneal dialysis patients. Am J Kidney Dis. 2005;45:162-6.

4.       Matuszkiewicz-Rowinska J. Update on fungal peritonitis and its treatment. Perit Dial Int. 2009;29:s161-5. PMID: 13270208

5.       Pimentel JD, Dreyer G, Lum GD. Peritonitis due to Cunninghamella bertholletiae in a patient undergoing continuous ambulatory peritoneal dialysis.  J Med Microbiol. 2006;55:115-8. PMID:16388039

6.       Chang BP, Sun PL, Huang FY, et al. Paecilomyces lilacinus peritonitis complicating peritoneal dialysis cured by oral voriconazole and terbinafine combination therapy. J Med Microbiol. 2008;57:1581-4. PMID: 19018033

7.       Ghebremedhin B, Bluemel A, Neumann KH, Koenig B, Koenig W. Peritonitis due to Neosartorya pseudofischeri in an elderly patient undergoing peritoneal dialysis successfully treated with voriconazole. J Med Microbiol. 2009;58:678-82. PMID: 19369533

8.       García-Martos P, Gil de Sola F, Marín P, García-Agudo L, García-Agudo R, Tejuca F, Calle L. Fungal peritonitis in ambulatory continuous peritoneal dialysis: description of 10 cases. Nefrologia. 2009;29:506-17. PMID: 19935994

9.       Wong JS, Schousboe MI, Metcalf SS, et al. Ochroconis gallopava peritonitis in a cardiac transplant patient on continuous ambulatory peritoneal dialysis. Transpl Infect Dis. 2010;12:455-8. PMID: 20534037

10.   Montravers P, Mira JP, Gangneux JP, Leroy O, Lortholary O. A multicentre study of antifungal strategies and outcome of Candida spp. peritonitis in intensive-care units. Clin Microbiol Infect. 2011;17:1061-7. PMID: 20825438

11.   Ulusoy S, Ozkan G, Tosun I, et al. Peritonitis due to Aspergillus nidulans and its effective treatment with voriconazole: the first case report. Perit Dial Int. 2011;31:212-3. PMID: 21427255