FAQ Categories

Outpatients

Q.	When should I consider oseltamivir or zanamivir for patients without known risk factors for influenza complications who are not being hospitalized?

Most patients without risk factors will experience typical influenza symptoms with a self-limited course. However, patients who are not known to have risk factors for influenza-related complications may still benefit from timely antiviral therapy. Patients who present with significant illness (e.g., fever, moderate to severe headache or myalgias, prostration, etc.) are most likely to benefit from antiviral therapy. Benefits demonstrated in randomized, placebo-controlled clinical trials include shortened illness, and faster return to school or work. A potential benefit is reduced likelihood of transmission to family members based upon a shortened duration and quantity of viral shedding with antiviral treatment. In addition, previously healthy persons can develop severe influenza illness requiring hospitalization. To date, approximately 40% of children and 20% of adults hospitalized with complications of 2009 H1N1 did not have recognized risk factors for complications of influenza and it is possible that early neuraminidase inhibitor treatment of such patients might prevent progression to more serious illness.

The potential benefits from treating healthy outpatients are likely modest, and should be weighed against the potential for antiviral side effects and medication cost. The benefit will be greatest if treatment can be started as early as possible in the course of illness. In one study that looked at the effectiveness of oseltamivir based on the time from symptom onset to starting the drug, treatment started within 12 hours of symptom onset reduced the duration of illness by more than 3 days (1). In general, patients with no risk factors for influenza complications who present more than 48 hours after onset and are improving, or who have mild symptoms do not require antiviral treatment.

Aoki FY et al. J Antimicrobial Chemotherapy 2003; 51:123–129

Q.	Should I consider oseltamivir or zanamivir treatment for outpatients and inpatients who are still very ill but more than 48 hours have elapsed since symptom onset?

Yes, treatment can be considered even if more than 48 hours have elapsed since illness onset for severely ill patients. However, only a few observational studies have addressed this question. Among healthy adults and children without underlying medical conditions who presented for outpatient care with typical influenza illness, delayed initiation of treatment (e.g. treatment initiated beyond 48 hours since the time that symptoms began) was not associated with a reduction in clinical symptoms compared to placebo. (1). However, hospitalized patients often have a prolonged illness, and several observational studies of persons hospitalized with seasonal influenza, including elderly persons with underlying medical conditions, found that treatment was beneficial at reducing mortality and hospital stay even when treatment was initiated more than 48 hours after symptom onset (3-5). Starting neuraminidase inhibitor treatment (primarily oseltamivir) within 2 days of symptom onset was significantly associated with lower risk of ICU admission or death in hospitalized 2009 H1N1 patients in the U.S. compared to later treatment (6). In Mexican ICU patients with 2009 H1N1, survivors were significantly more likely to have received neuraminidase inhibitor treatment than fatal cases (7). Based on current knowledge, it is strongly recommended that hospitalized patients with influenza therefore should be treated even if more than 48 hours has passed since illness onset.

At this time there are no studies evaluating the effectiveness of initiating treatment more than 48 hours after illness onset for persons who are not hospitalized but have debilitating illness. In the absence of clinical studies, a clinician should weigh the potential benefit of late treatment for patients who are not hospitalized but remain very ill, with potential side effects and cost of the drugs. If the patient is at high risk for complications due to influenza and has had no clinical improvement, it is reasonable to consider antiviral therapy even if begun > 48 hours after symptom onset. If a patient presents with debilitating illness (e.g. requiring them to stay home in bed), it is reasonable to consider antiviral therapy even if begun > 48 hours after symptom onset. The clinician should discuss the pros (e.g., possible reduced symptoms and complications) and cons (e.g., no evidence yet to prove effectiveness and possible adverse effects of the drug) with the patient. Initiation of treatment should not be delayed while waiting for test results.

Q.	When is it worth performing influenza testing on outpatients with suspected H1N1 influenza?

A number of questions should guide testing: 1)Will influenza testing help in the management of this particular patient? 2) Will influenza testing help in the management of contacts or in infection control? 3) Is influenza testing needed to understand the current epidemiology in my local community? 4) How good are available influenza tests?

For influenza testing to help the individual patient, results are needed in a timely manner, as earlier initiation of antiviral treatment is more likely to decrease the severity, complications and duration of illness compared to delayed treatment. Antivirals are most effective if administered within 48 hours of illness onset. Thus, a test result that will be available in 3 or 4 days is unlikely to help management of an outpatient; however, such results might be useful for management of close contacts or for infection control purposes, such as treatment or chemoprophylaxis of exposed health care workers. Initiation of treatment should not be delayed while waiting for test results.

A second issue is the likelihood of the illness being novel H1N1. If the patient has typical influenza symptoms and the local epidemiology supports circulating 2009 H1N1 virus, then clinical judgment is likely to be at least as accurate as rapid antigen tests. However, if the presentation is somewhat atypical, then testing might be helpful to determine the cause of illness. The accuracy of clinical judgment varies by the presence of typical symptoms of fever and cough, current prevalence of influenza, and by the experience and expertise of the clinician (1).

The third issue is the characteristics of the tests readily available to the clinician. Rapid antigen tests allow an answer at the point of care but have reported sensitivities of 10-70% and a specificity of 99% for detecting the 2009 pandemic H1N1 virus (2-4). The sensitivity of rapid tests may be somewhat higher in children and immunocompromised patients compared to healthy adults. However, a negative rapid antigen test should never be used to “rule out” influenza. Culture is highly sensitive and specific but requires days for a test result. Immunofluorescence assays (DFA) are reported in 2 to 4 hours and have intermediate sensitivities between rapid tests and culture or rRT-PCR. Real-time reverse transcriptase polymerase chain reaction (rRT-PCR) is the most sensitive and specific but a limited number of laboratories are currently able to perform this test. Many of the laboratories that can conduct rRT-PCR may be overwhelmed with specimens during the current pandemic and may be forced to prioritize samples (e.g., specimens from hospitalized patients before outpatients) thereby delaying reporting of results.Detection may vary by patient’s age, immune status, time from illness onset, specimen source and quality, clinical complications, and specimen processing.

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Pregnancy

Q.	When should I treat pregnant women with oseltamivir?

Pregnant women have had higher rates of hospitalization, ICU admission and death during the current 2001 H1N1 influenza pandemic (1, 2). The risk of hospitalization or ICU admission appears to be 4-6 times higher than for the general population. Increased risk for complications of 2009 H1N1 influenza in pregnant women has been seen in virtually all countries that have reviewed their experience. The reasons for the increased rates of complications may include immunosuppression in late pregnancy, decreased lung volume and respiratory reserve, and cardiovascular changes. In addition, antiviral treatment for pregnant women has often been delayed or withheld because of reluctance to prescribe medications.

Pregnant women in whom 2009 H1N1 influenza is suspected or documented should be treated with oseltamivir or zanamivir immediately, without waiting for confirmatory tests. If accurate and sensitive tests such as PCR are available, confirmatory tests should be performed so that antiviral therapy can be stopped if the woman tests negative. Because of the high frequency of false negatives, a negative rapid antigen test should not be used for treatment decisions. Oseltamivir is generally preferred for pregnant women because of greater systemic exposure and more data supporting safety. Data from limited studies conducted among animals and humans do not indicate that oseltamivir is a human teratogen (3), although the data are not adequate to exclude any risk of oseltamivir in pregnancy. However, high fever caused by influenza is dangerous to the fetus, and the potential for severe maternal disease and hypoxemia greatly outweigh the theoretical risk of administering either oseltamivir or zanamivir to a woman with suspected or documented uncomplicated influenza. Any pregnant woman who is hospitalized with suspected or documented influenza should be treated with oseltamivir as soon as possible.

The risk-benefit balance for antiviral chemoprophylaxis in pregnant women may be different. The risk of infection after exposure among household contacts is reported to be 20-25%, and likely is much lower for occupational exposure. Close monitoring and early antiviral treatment might provide adequate reduction in the risk of severe disease and reduce the number of women who will be exposed.

Q.	Is it reasonable to give a higher dose of antivirals to pregnant women in the 3rd trimester of pregnancy?

This is an important question in light of the changes in drug metabolism that occur during pregnancy and the increased risk of severe influenza in pregnant women. We do not yet have actual data on serum or lung levels of oseltamivir in pregnant women, so we have to look at what is known about the metabolism of oseltamivir and make predictions. Keep in mind that mechanistic predictions about drug levels in pregnancy sometimes prove wrong.

Oseltamivir phosphate (the oral pro-drug that is in the capsule) is metabolized to oseltamivir carboxylate that has a volume of distribution roughly equivalent to total body water. The active carboxylate metabolite has low protein binding and is excreted unchanged by glomerular filtration and tubular secretion (1). In the third trimester of pregnancy, total body water increases, as does renal filtration. Given this, the serum concentration might be predicted to decrease moderately in the third trimester. Some experts suggest that an increased dose of oseltamivir (e.g. 150 mg bid) should be considered in patients who are critically ill, such at those on a ventilator or with multiple organ dysfunction. There are no data yet showing greater clinical benefit of the higher dose. However, the safety of 150 mg po BID was established in clinical trials.

Given the uncertainty, and considering the overall safety profile of oseltamivir, it would be reasonable to use a higher dose of oseltamivir in a critically ill pregnant woman, as one would for a non-pregnant patient. This makes particular sense in the third trimester when the drug levels may be lower, and any risk of teratogenicity is minimized. Until better data are available, increasing the dose of oseltamivir for pregnant women who are not critically ill is not recommended.

Oseltamivir is generally preferred for pregnant women because of greater systemic exposure and more data supporting safety. Data from limited studies conducted among animals and humans do not indicate that oseltamivir is a human teratogen (2), although the data are not adequate to exclude any risk of oseltamivir in pregnancy.

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Infants

Q.	How should I dose oseltamivir (Tamiflu®) in young infants?

Dosing of oseltamivir for infants less than 12 months of age is currently under investigation, but preliminary pharmacokinetic (PK) data were reviewed by the US Food and Drug Administration and have recently been presented at a national infectious diseases conference (1). Based on PK data from 33 infants (94% were 6 months of age or greater, and no infants studied were under 3 months of age), the FDA issued a time-limited Emergency Use Authorization (not the equivalent of an FDA approval) in April 2009 for age-based dosing for infants under 12 months of age, with extrapolation of dosing recommendations for infants under 3 months of age. With no data on PK or safety for infants under 3 months of age, prophylaxis of clinically well infants was not routinely recommended.

An evaluation for weight-based dosing in infants under 12 months of age has also been considered by CDC and IDSA, in order to provide more accurate oseltamivir drug exposure both for very young infants who are premature, and for older infants who may be in the highest percentiles of weight for age. Both age-based and weight-based recommendations are currently posted on the CDC website at: http://www.cdc.gov/h1n1flu/recommendations.htm. Dosing guidelines based on data from the recent PK study of oseltamivir in infants (1) are provided below:

Weight-based dosing recommendations for antiviral treatment or chemoprophylaxis of children younger than 1 year using oseltamivir.
Age	Recommended treatment dose for 5 days	Recommended prophylaxis dose for 10 days *
Younger than 9 months	3.0 mg/kg/dose twice daily	3.0 mg/kg/dose once daily (Not recommended for infants younger than 3 months unless situation judged critical due to limited data on use in this age group)
9-12 months months	3.5 mg/kg/dose twice daily	3.5 mg/kg/dose once daily

*Because of the limited safety and PK data in infants, prophylaxis is generally discouraged in this age group based on the current risk benefit ratio.

The FDA EUA Age-based dosing recommendations are: for infants < 3months of age, 12 mg BID for treatment, and once daily for prophylaxis; for infants 3-5 months of age, 20 mg BID for treatment and once daily for prophylaxis; and for infants 6-11 months of age, 25 mg BID for treatment and once daily for prophylaxis.

For infants who cannot tolerate oseltamivir by the oral or nasogastric route due to vomiting, diarrhea, or for infants in shock with questionable gastrointestinal absorption, a new intravenous neuraminidase inhibitor, peramivir, can be used. Peramivir received an FDA Emergency Use Authorization in October 2009, and can be obtained through the FDA online, but pharmacokinetic data to guide dosing in children is very limited. More information on peramivir, including current data on safety and efficacy in adults, and links to obtain peramivir for H1N1 infected patients can be found on the CDC’s website at: http://www.cdc.gov/h1n1flu/eua/peramivir.htm.

Kimberlin D, Acosta E, Sanchez P, et al. Oseltamivir (OST) and OST Carboxylate (CBX) Pharmacokinetics (PK) in Infants: Interim Results from a Multicenter Trial [abstract 804]. In: 47th Annual Meeting of the Infectious Diseases Society of America. Philadelphia, PA, 2009

Q.	Should I give oseltamivir prophylactically to an infant born to a mother with ILI or with confirmed 2009 H1N1?

Antiviral chemoprophylaxis is an option for high risk adults and children who have had a close exposure to a symptomatic person with documented or suspected 2009 H1N1 infection. For newborn infants, decisions on chemoprophylaxis are difficult, as there are currently no data on the pharmacokinetics (PK) or safety of oseltamivir in infants less than 3 months of age; nor are there current data on the morbidity and mortality of 2009 H1N1 infection in the newborn infant. Thus, it is difficult to provide a risk/benefit analysis, as neither risks nor benefits can be defined for the newborn.

For the pregnant woman who comes to the hospital, in labor, with ILI, recommendations for management are provided by a number of organizations, including the American Academy of Pediatrics and the CDC (http://www.cdc.gov/h1n1flu/guidance/obstetric.htm). Pregnant women are known to be at high risk of complications of influenza and should be treated with oseltamivir for symptomatic ILI. There is no contraindication for the treatment of the mother either before the birth, or after the birth (only small amounts of oseltamivir are present in breast milk and represent no risk to the infant). However, the additive levels of oseltamivir in babies being given a treatment dose of oseltamivir while breastfeeding from a mother also receiving a treatment dose of oseltamivir are not known and might be of more concern than the additive oseltamivir serum concentrations present in babies receiving a chemoprophylaxis dose and nursing from mothers receiving either a treatment or a prophylaxis dose of oseltamivir. All possible adverse drug reactions to oseltamivir in infants should be reported to the FDA by the MedWatch reporting system (medwatch@fda.gov).

After labor and delivery, antiviral prophylaxis in the infant may NOT be required if the mother’s contact with her infant is monitored by hospital personnel, and she uses a surgical mask and appropriate hand hygiene during contact with her infant (and for breast-feeding mothers, cleansing of the breast prior to infant feeding).

Mothers should continue to avoid close contact with their infants for at least 7 days from the onset of illness, with complete resolution of respiratory tract symptoms and resolution of fever for at least 24 hours (as measured without the use of antipyretics). Shedding of influenza virus may continue to occur even after resolution of symptoms, suggesting that the mother should, in fact, avoid close contact with her infant (e.g., kissing) for an additional 5 to 7 days after resolution of her ILI symptoms.

For situations in which contact between a symptomatic mother and her infant cannot be monitored, or compliance with contact and respiratory precautions by the mother is not likely to occur, chemoprophylaxis of the infant might be considered as there is a high risk for neonatal infection. Chemoprophylaxis might also be considered for the newborn infant going home to a family with other young children with ILI. Data on the optimal dosing and safety of oseltamivir in infants under 3 months are extremely limited, and this should be considered in weighing the risks and benefits of chemoprophylaxis versus early empiric treatment if symptoms develop. Weight-based dosing recommendations for oseltamivir chemoprophylaxis for the neonate are provided below and can be found at http://www.cdc.gov/h1n1flu/recommendations.htm:

Weight-based dosing recommendations for antiviral chemoprophylaxis of newborn infants using oseltamivir.
Age	Recommended prophylaxis dose for 10 days
Younger than 9 months	3.0 mg/kg/dose once daily

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Chemoprophylaxis

Q.	When would you give chemoprophylaxis to exposed household contacts?

General Considerations for Prophylaxis versus Early Therapy. Vaccination is the most effective way to prevent influenza. Vaccines against 2009 H1N1 influenza are becoming more widely available now and are likely to be plentiful in the near future. In general, antiviral prophylaxis is not recommended for healthy people who are exposed to influenza. The risk of illness in due to seasonal influenza in exposed household contacts is about 20-25%. Antiviral chemoprophylaxis would have to be given to 4 to 5 people to prevent one case. A better approach may be to plan on early empiric treatment of household contacts that develop symptoms of flu. Additional concerns about chemoprophylaxis for otherwise healthy household contacts include the expense, side effects, impact on antiviral supplies, and an increased risk of the development of resistance.

Antiviral chemoprophylaxis is appropriate for exposed, susceptible persons at high risk for severe complications of influenza. However, antiviral chemoprophylaxis can be considered in household settings when one or more individuals has known or highly suspected influenza infection; another individual in that household is at high risk of influenza complications (e.g. an immunosuppressed patient), and vaccination has not been completed or is likely to be ineffective. In household settings where one or more individual(s) are at high risk of serious sequelae from influenza due to an immunocompromised condition, age, or other high risk medical status, chemoprophylaxis for the entire family should be considered.

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Immunocompromised Patients

Q.	Should I do follow up tests for viral shedding? When and how often?

Sensitive and specific viral testing should be utilized initially in immunocompromised patients suspected of being infected with 2009 H1N1 virus, but the issue of follow-up testing is not simple. Sensitivity of rapid antigen detection testing is not optimal, and even detection of influenza antigen using fluorescent antibody methods may be less sensitive with 2009 H1N1 influenza virus than for seasonal influenza viruses (1). An accurate diagnosis in high risk patients including those patients undergoing chemotherapy or transplantation is critical to determine treatment, and if follow-up testing is done, it should be done with culture or rRT-PCR methods and not rapid antigen detection methods.

The question as to when follow-up viral testing is required has not been prospectively studied, but in light of the development of oseltamivir-resistant 2009 H1N1 virus (2), the following approach is recommended for severely immunocompromised patients (e.g. those with hematopoietic stem cell transplants or recent solid organ transplant). This does not apply to patients who were previously healthy or have milder degress of immune dysfunction:

1.	Assess initial infection with sensitive viral detection method in symptomatic patients. It is reasonable to begin testing with a rapid test such as antigen detection kits or direct fluorescent antibody-detection, but if these tests are negative, or a definitive answer is wanted, rRT-PCR is the preferred test.
2.	After a standard 5-day treatment course of antiviral therapy is completed (with either oseltamivir, zanamivir, or peramivir), repeat testing should be performed to document a poor response to therapy, or to detect the development of antiviral resistance if:
	a.	The patient demonstrates no improvement or worsening of respiratory symptoms, including rhinorrhea, cough, oxygen requirement, or radiographic abnormalities, or
	b.	The patient has unexplained fever or myalgia.
	c.	If the patient requires further inpatient treatment for any reason – even for reasons unrelated to influenza, testing should be performed for infection control purposes.
	Patients who will be seen only intermittently as outpatients may not need follow-up influenza tests for shedding if they are asymptomatic and they can be adequately isolated in the outpatient clinic. Importantly, these patients may still be shedding low levels of virus (either sensitive or resistant to oseltamivir). If they are not in contact with other high-risk patients, and are truly asymptomatic, further testing may not be needed. However, to remove an inpatient from droplet precautions it is important to document viral clearance using a sensitive, rapidly available test such as PCR.
3.	Continued viral shedding in a symptomatic severely immunocompromised patient who has received 5-10 days of antiviral therapy should lead to the consideration of antiviral resistance. If resistance is suspected, repeat viral testing with PCR and/or culture should be performed. A change in antiviral therapy should be strongly considered (example: from oral oseltamivir to inhaled zanamivir, or potentially from oral therapy to intravenous peramivir or zanamivir). At the same time, testing of the patient’s virus for mutations causing antiviral resistance can be performed (either from cultured virus or respiratory secretions). Testing for common mutations can be obtained in some commercial laboratories. For information on how to obtain testing at CDC contact your state public health laboratories, or the CDC Emergency Operations Center (eoclaboratory@cdc.gov). Information on antiviral resistance testing and an algorithm for testing from the Association of Public Health Laboratories (APHL) are available.

Q.	When should I suspect oseltamivir resistance in a transplant patient and how do I test for resistance?

The development and possibly acquisition of antiviral resistance during treatment has been documented among persons with severe immunosuppression, such as those with stem cell or organ transplantation (1-4). Resistance should be suspected if a patient with severe immunosuppression fails to show clinical improvement despite 5 days of oseltamivir treatment and virus is still detectable.

Oseltamivir resistance among 2009 H1N1 viruses is associated with a mutation, H275Y, in the neuraminidase protein. The presence of this mutation can be detected by sequencing or pyrosequencing. These assays will not detect oseltamivir resistance due to other mutations and will not detect zanamivir resistance. Currently, only a few academic centers, commercial laboratories, state public health laboratories, and CDC can test for the presence of the H275Y mutation. For information on how to obtain testing at CDC contact your state public health laboratories, or the CDC Emergency Operations Center (eoclaboratory@cdc.gov). Information on antiviral resistance testing and an algorithm for testing from the Association of Public Health Laboratories (APHL) are available. To optimize the chances that you will have an informative result, it is best to confirm that the virus is still detectable prior to testing.

Q.	In patients who are immunocompromised and have been vaccinated for H1N1 (or seasonal influenza) while on chemotherapy, should they be re-vaccinated once chemotherapy has ended?

There is minimal data to address the utility of revaccination in immunocompromised patients who finish chemotherapy or have improvement in their immune system. In children, data from liver transplant recipients compared to their siblings have demonstrated significant differences between healthy and immunocompromised patients (1), and these pediatric transplant recipients had some improvement in antibody response after the second dose.

A recent study in adults showed that the influenza subunit vaccine was slightly more immunogenic than the virosomal vaccine with comparable reactogenicity, but the overall levels of potential seroprotection were low following one dose of either vaccine (41% vs. 30% of patients, p = 0.03), and vaccine response decreased with increasing levels of immunosuppression. Repeated doses of seasonal flu vaccine can be beneficial: a study of two doses of TIV administered to 41 patients with lymphoma showed improvement in rates of antibody response following the second dose, with responses to H1N1, H3N2, and B of 32%, 24%, and 20% respectively following one dose and response rates of 49%, 41%, and 46% following the second dose (2).

There is experimental data in BMT transplant recipients showing that one dose of inactivated vaccine is poorly immunogenic and that GCS-F as an immunomodulator does not improve immune response (3). Some experts are routinely giving all children < 9 years of age 2 doses of trivalent inactivated vaccine during the first year following transplantation even if they have been immunized previously.

Many experts believe that use of virosomal or adjuvanted influenza vaccines should be studied in immunocompromised patients in hopes of improving antibody responses in this population. Meanwhile, there is good safety data for the use of two doses of inactivated H1N1 vaccines in clinical trials sponsored by the NIH and pharmaceutical companies. Therefore, the administration of a second dose of H1N1 vaccine in all children < 9 years (but probably not a 3rd dose in immunocompromised children) should be routine and is likely to benefit immunocompromised children. The administration of a second dose of H1N1 vaccine to immunocompromised patients who were more suppressed at the time of the administration of unadjuvanted H1N1 vaccine (which is the only type available in the U.S.) and are now more immunocompetent is not currently an established recommendation. However, this could be considered as reasonable both in terms of safety and immune response.

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Critically Ill Patients

Q.	Do I need to dose adjust for renal failure?

Yes. Oseltamivir is excreted almost exclusively by glomerular filtration and tubular secretion and clearance of the active drug, oseltamivir carboxylate decreases linearly with creatinine clearance (CrCl). Bear in mind that the primary toxicity of oseltamivir is nausea and vomiting, and some experts feel that higher doses and higher drug exposures are beneficial in critically ill patients. Peramivir is available from CDC under an emergency use authorization (EUA). Peramivir is also excreted unchanged via the kidney.

Dosing recommendations for patients with renal failure are available from the oseltamivir package insert and from the FDA recommendations for peramivir use and their Q and A document. There are no formal recommendations for oseltamivir in patients on intermittent hemodialysis but a single study has examined drug exposure (1).

Recommendations for Adults with Impaired Renal Function
	Oseltamivir (po or per ng)	Peramivir (IV)
Mild Renal Impairment CrCl 50-80 mL/min	75 mg bid (usual dose)	600 mg daily
Moderate Renal Impairment CrCl 31-49 mL/min	75 mg bid (usual dose)	150 mg daily
Severe Renal Impairment CrCl 10-30 mL/min	75 mg daily or 30 mg bid	100 mg daily
CrCl < 10 mL/min	Not recommended	15 mg/daily
Hemodialysis	30 mg after alternate HD sessions (1)	15 mg/daily

Robson R, Buttimore A, Lynn K, et al: Nephrology Dialysis Transplantation 2006 21(9):2556-2562

Q.	How do I dose adjust for continuous renal replacement therapy?

There are no data available to guide dosing for patients on continuous venovenous hemofiltration. Both peramivir and oseltamivir are likely to be removed by continuous renal replacement therapy. A modeling study estimated that the sieving coefficient for oseltamivir carboxylate was close to one (1). Therefore, clearance should be close to the ultrafiltration rate. The authors of that study estimated that a daily maintenance dose of oseltamivir in milligrams of 0.52–1.27 times the ultrafiltration rate (in mL/min) should maintain steady-state concentrations of oseltamivir carboxylate equivalent to those in patients with normal renal function on high dose oseltamivir (150mg twice daily).

It may be reasonable to adjust dosing of oseltamivir and peramivir based on the estimated CrCl during continuous renal replacement therapy. Consultation with a nephrologist is highly recommended. For patients on ECMO, dose adjustment should be based on adjustments that are used for other drugs cleared by the kidney.

Gruber PC, Tian Q, Gomersall CD, et al. An in vitro study of the elimination of oseltamivir carboxylate by haemofiltration. Int J Antimicrob Agents2007; 30:95-7

Q.	Should antibiotics be given in addition to antivirals in critically ill patients with H1N1 influenza? Which antibiotics make sense?

Antibiotics should be administered when bacterial pneumonia is a consideration in a patient who has influenza. This consideration is usually raised because of the presence of pulmonary infiltrates. The most common causes of pulmonary infiltrates are viral pneumonia or ARDS. However, recent studies also indicate that from 4- 24% of patients have bacterial pneumonia in addition to or secondary to influenza. Furthermore, a report from CDC of 77 patients who died from H1N1 infection and underwent autopsy, found that 29% of patients had evidence of bacterial "co-infection" (1). The predominant pathogens in these reports were S. pneumoniae, S aureus (often MRSA), and S. pyogenes.

We recommend an evaluation for the presence of bacterial pathogens in critically ill patients with radiographic evidence of pneumonia, which should include an appropriate respiratory specimen (e.g., a deep endotracheal aspiration) gram stain and culture, blood cultures, and urinary antigen tests. For adults we recommend empiric therapy as listed in the IDSA/ATS adult CAP guidelines (i.e., for ICU patients without risks for Pseudomonas, combination therapy with a 3^rd generation non-pseudomonal cephalosporin such as ceftriaxone or cefotaxime plus a macrolide or respiratory fluoroquinolone) (2). In an animal model of secondary bacterial pneumonia after inﬂuenza the use of a protein synthesis inhibitor such as azithromycin or clindamycin improved outcomes; however, the clinical relevance of this finding remains to be determined (3). The excess mortality associated with MRSA would also suggest that empirical coverage for this pathogen with vancomycin or linezolid should be considered when MRSA or CA-MRSA is a concern. The presence of any of the following suggest that CA-MRSA should be a concern: 1) a requirement for ICU admission, 2) necrotizing or cavitary infiltrates, 3) empyema in the context of a preceding or concurrent influenza-like illness, 4) presence of gram positive cocci in clusters in a respiratory specimen.

For infants and children, therapy with ceftriaxone or cefotaxime should provide excellent coverage for community strains of pneumococcus and group A streptococcus, but will not provide adequate therapy for staphylococcal pneumonia caused by either methicillin-susceptible or –resistant strains. Either vancomycin or clindamycin should be added to standard therapy for community acquired pneumonia for children who demonstrate any of the high-risk factors cited above.

Initial empirical antibacterials may be modified or discontinued depending upon results of the various laboratory tests and the clinical response.

Q.	How long should a patient be treated with antivirals for severe influenza pneumonia if no follow-up viral testing is available?

Severe influenza for this response includes influenza pneumonia, or influenza with clinically important complications such as acute myocardial infarction, congestive heart failure, bacterial pneumonia, respiratory failure or illness resulting in hospitalization. This answer applies to both laboratory confirmed influenza or respiratory illness for which influenza is considered among the most likely pathogens.

In severe influenza, including 2009 A/H1N1, viral shedding may last more than one week, especially in the lower respiratory tract. Viral shedding may also be prolonged in patients receiving high-dose corticosteroids. Often antiviral treatment for such cases is initiated after 48 hours following symptom onset. Despite appropriate antiviral treatment, virus has been detected beyond the usual 5-day treatment course in several reports. For this reason, in patients with laboratory-confirmed influenza who have not improved substantially, repeat RT-PCR testing should be performed (if available) to establish viral clearance before discontinuing treatment. Many experts would continue treatment for an additional five days if the patient is still seriously ill and virus is detected. If testing is not available, clinical judgment should guide the duration of therapy, and clear symptomatic improvement should guide consideration for antiviral discontinuation.

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* IDSA Influenza Experts: John S. Bradley,^1,2 Janet A. Englund,^3,4 Thomas M. File,⁵ Stefan Gravenstein,^6,7 Allison J. McGeer,⁸ Andrew T. Pavia,⁹ Michael L. Tapper,^10,11 and Richard K. Zimmerman¹²

¹Rady Children's Hospital and ²University of California San Diego School of Medicine, San Diego; ³University of Washington School of Medicine and ⁴PATH, Seattle, Washington⁵Summa Health System, Akron, Ohio; ⁶Alpert Medical School, Brown University, and ⁷Quality Partners of Rhode Island, Providence, Rhode Island; ⁸University of Toronto, Ontario, Canada⁹University of Utah School of Medicine, Salt Lake City, Utah; ^9, Lenox Hill Hospital and ¹⁰New York University School of Medicine, New York; ¹²University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Disclosures:J.B. intends to receive a research grant from Roche. J.E. has received research grants from Adamas Inc., ADMA, MedImmune, Novartis and Sanofi Pasteur. T.F. has served as an advisor to Advance Life Services, GlaxoSmithKline, Protez Pharmaceuticals, Nabrivia Pharmaceuticals, Schering Plough, Merck, Pfizer and Wyeth, has received honoraria from Advance Life Services, Astra Zeneca, Boehringer Ingelheim, Schering Plough, Merck, Pfizer and Wyeth, has conducted several grand rounds at medical centers, has received research grants from Forest, Gilead Sciences, Boehringer Ingelheim and has received organizational benefits from Walters Kluwer and UpToDate. S.G. has served as an advisor to Juvaris, GlaxoSmithKline, Roche and Icon, has received honoraria from Juvaris, GlaxoSmithKline, Sanofi Aventis Pasteur, has received a research grant from Juvaris, and has received honoraria from GlaxoSmithKline for speaking engagements. A.M. has served as an advisor to GlaxoSmithKline and Biocryst, has received honoraria from GlaxoSmithKline, Biocrycst and Hoffman-LaRoche and has received research grants from Hoffman-LaRoche and GlaxoSmithKline. A.P. has served as an advisor to NexBio and HealthMatters and has received research grants from CDC, NIAID/NIH and NCI/NIH. M.T. has served on speakers bureaus for Gilead Sciences and Merck. R.Z. has served as an advisor and speaker to Merck and has received research grants from Merck and MedImmune.

Influenza H1N1: Frontline Questions and Expert Opinion Answers

Introduction

FAQ Categories

Outpatients

Pregnancy

Infants

Chemoprophylaxis

Immunocompromised Patients

Critically Ill Patients

FAQ Categories

Infectious Diseases Society of America