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patients included in this study were identified , retrospectively , through a request to all registered medical microbiologists in the netherlands .
all patient data were reported anonymously . the decision to start iv zanamivir and the duration of therapy were not standardized and depended on the clinical judgment of the treating physician .
initially , compassionate use was granted by glaxosmithkline ; from january 2010 onward , this was continued by the national institute for public health and the environment .
intravenous zanamivir was provided for patients unable to use oseltamivir or in whom treatment with iv zanamivir was considered desirable for other reasons .
nasopharyngeal swabs , nose washes ( upper respiratory tract [ urt ] samples ) , tracheal aspirates , and broncheo - alveolar lavages ( lower respiratory tract [ lrt ] samples ) were collected during routine care .
inclusion criteria for patients in this study were as follows : laboratory - confirmed pandemic influenza a ( h1n1 ) infection by real - time reverse - transcription polymerase chain reaction ( rt - pcr ) ; admission to an intensive care unit ( icu ) in a dutch hospital ; use of iv zanamivir for > 48 hours ; and availability of follow - up virological samples .
patients with proven resistance to zanamivir at baseline or at icu admittance were excluded from the study .
detection and quantification of viral rna and screening for the neuraminidase ( na ) h275y oseltamivir resistance mutation was performed in all centers by means of standardized rt - pcr  based methods . to obtain sequences of na genes ,
viral rna was reverse transcribed and subsequently amplified using gene - specific primers ( sequences are available upon request ) .
attempts to culture virus were made at sample viral loads of > 4  10 virus particles ( vp ) per milliliter .
phenotypic sensitivity to oseltamivir and zanamivir was measured using the na - star neuraminidase inhibitor resistance detection kit ( applied biosystems , nieuwerkerk aan den ijsel , the netherlands ) .
immunosuppression was defined as any of the following : receipt of treatment for any cancer within 6 months before influenza infection , the use of any immunosuppressive medication to prevent transplant rejection or for management of pulmonary or autoimmune conditions , or a diagnosis of aids .
acquired respiratory distress syndrome ( ards ) was defined as bilateral infiltrates on chest radiographs , with a pa o2/f io2 ratio of < 200 mm hg in the absence of cardiogenic pulmonary edema .
the viral response to treatment with iv zanamivir was determined by the differences in viral load between a sample collected closest to the day of the start of iv zanamivir ( baseline sample ) and those obtained at follow - up .
sustained reduction of the viral load was defined as a decrease of 1 log10 vp / ml for at least 10 days . in case of death or cessation of iv zanamivir treatment ,
the last sample collected while the patient was still receiving therapy was considered for the endpoint of analysis . if the reduction of the viral load took > 7 days of treatment to occur , it was considered not to be treatment related . for statistical analysis between groups , the mann -- whitney u test was used .
p values of < .05 were considered to be significant . the study protocol was reviewed and approved by the medical ethics board of the erasmus university medical center ( study no .
there was no sponsor involvement in the design , data collection , and analysis of this study .
based on data provided by glaxosmithkline during the influenza season in the netherlands , 26 icu patients were treated with iv zanamivir .
reasons for exclusion from the study were death ( n = 2 ) , recovery and treatment interruption within 48 hours after start of iv zanamivir ( n = 2 ) , absence of samples for virological evaluation ( n = 1 ) , and proven resistance to zanamivir before admittance to the icu ( n = 1 ) .
all patients were pretreated with oral oseltamivir for a median period of 5 days ( range , 118 days ) .
oseltamivir was dosed at 75 mg every 12 hours or its pediatric equivalent , except in 3 patients ( patients 4 , 5 , and 8) in whom 150 mg every 12 hours was used .
three patients received iv zanamivir monotherapy ( patients 7 , 9 , and 13 ) , whereas the remaining 10 patients received iv zanamivir combined with continued use of oseltamivir .
reference median inhibitory concentration ( ic50 ) values ( n = 60 ) for oseltamivir are 0.20  0.08 nmol / l ( median + / 95% ci ) and for zanamivir are 0.22  0.12 nmol / l .
ards , acquired respiratory distress syndrome ; h , histidine ; ic50 , median inhibitory concentration ; lrt , lower respiratory tract ; na , neuraminidase ; nd , not detectable ; nr , no result could be obtained ; r , resistant ; s , susceptible ; urt , upper respiratory tract ; vp , virus particles ; y , tyrosine . plus inhaled zanamivir therapy for 9 days .
the median baseline viral load was 3  10 vp / ml , ( range , < 171.2  10 vp / ml ) in the urt samples and 2.3  10 vp / ml ( range , < 179.8  10 vp / ml ) in the lrt samples .
two patients ( patients 1 and 12 ) had an undetectable viral load in the urt sample but a high viral load in the lrt sample at baseline .
one patient ( patient 5 ) had an undetectable viral load in the lrt sample but a high viral load in the urt sample at baseline .
the response analysis was complicated for 2 patients because their baseline samples were obtained 3 days before iv zanamivir initiation ( patients 8 and 10 ) .
overall , sustained reduction of the viral load was observed in only 6 patients ( figure 1 ) .
three patients had persistent undetectable viral loads after 7 days of treatment ( patients 7 , 9 , and 13 ) .
there were no significant differences between baseline viral loads in the urt and lrt samples of patients with and without viral load reduction ( p = .315 and p = .250 , respectively ) .
overall , the median interval between first onset of symptoms and start of iv zanamivir was 11 days ( range , 421 days ) .
however , among patients who had a sustained reduction of the viral load , the median time to start of iv zanamivir was 9 days ( range , 411 days ) , compared with 14 days ( range , 621 days ) among patients in whom treatment had no effect ( p = .05 ) .
a , change in baseline viral load detected in the upper respiratory tract ( urt ) ; b , change in baseline viral load detected in the lower respiratory tract ( lrt ) .
eight patients were treated for > 10 days , and 5 patients were treated for < 10 days . of those 5 patients , 2 died and 3 clinically recovered , and zanamivir iv medication was stopped ( patients 7 , 9 , and 13 ) . because patient 12 had undetectable viral loads in the urt sample , these data are not included in the figure for change in baseline urt viral load .
data obtained from patients with a sustained viral load reduction are depicted in green , and data for those without a viral response are depicted in red ; the black dashed line represents the delta viral load of 1 log10 virus particles ( vp ) per milliliter .
a sequence could be obtained from viruses isolated from 10 patients before start of iv zanamivir , but sequences could not be obtained from viruses isolated from patients 7 , 9 , and 12 .
viruses isolated from patients 3 , 6 , 7 , and 13 carried the h275y oseltamivir resistance mutation in na as determined by sequencing and/or rt - pcr specific for the h275y mutation .
no other mutations associated with drug resistance were found in the na genes . for 9 patients , phenotypic resistance data could be measured in isolates obtained before start of iv zanamivir .
all 9 isolates were susceptible to zanamivir ( table 1).virus could not be cultured from all 19 samples eligible for culture that were obtained after the start of iv zanamivir , despite relatively high loads with a median of 4.0  10 vp / ml ( range , 4.9  1014  10 vp / ml ) .
twelve patients were admitted to the icu because of respiratory failure ; 1 patient was already admitted .
all patients needed supplemental oxygen : 12 patients were mechanically ventilated and 4 patients required additional extracorporeal membrane oxygenation support . in all mechanically ventilated patients , ards was diagnosed .
there was no relation between viral response and survival , with death occurring in 3 of 6 patients in the group with sustained viral load reduction and in 3 of 7 patients in the nonresponder group .
most deaths ( 5 of 6 ) occurred in patients with an impaired immune system .
the remaining 7 surviving patients were discharged after a median hospital stay of 52 days ( range , 1162 days ) , of which 37 days ( range , 3977 days ) were spent in the icu .
all patients received broad - spectrum antibiotics at least once . in none of the patients was iv zanamivir stopped because of serious adverse events .
in this study , which is to our knowledge the largest published peer - reviewed case series to date , we have retrospectively analyzed the virological response to iv zanamivir treatment in patients pretreated with oral oseltamivir for severe influenza infection . a consistent virological response to add - on iv therapy
there was a trend toward an increased likelihood of response for those who started iv zanamivir at an earlier stage of disease .
due to the retrospective nature , the absence of a control group , and the limited number of patients enrolled , we can not make a definitive conclusion on the clinical efficacy of iv zanamivir .
still , we feel that our observations are important , because they are not in line with previously published reports on individual patients with encouraging results [ 810 ] .
several factors may explain the limited effectiveness of iv zanamivir seen in 7 of 13 patients .
first , the patients included were severely ill as reflected by the high number of immunocompromised patients , poor response to oral oseltamivir , and extended duration of hospitalization .
a potential explanation for the limited virological efficacy may have been the development of viruses resistant to zanamivir .
unfortunately , because we were unable to obtain viral isolates or relevant viral sequences after start of zanamivir therapy , it remains unknown to what extent resistance contributed to the absence of virological response .
another explanation for the absence of response could be that insufficient zanamivir levels were achieved at some sites of active viral replication .
of interest is a recent finding in patients with influenza a ( h3n2 ) infection that the combination of oseltamivir and zanamivir may be associated with a decreased inhibition of viral replication .
however , in that study all patients did clear the virus rapidly . in this light , it is important to note that all patients described in our study had been pretreated with oseltamivir monotherapy .
therefore , we hypothesize that the same mechanism accounts for the limited efficacy of both iv zanamivir and oral oseltamivir .
because of the prolonged viral replication before the start of iv zanamivir , irreversible lung injury may already have occurred .
thus , the relatively late start with iv zanamivir in the course of disease may have compromised its potential efficacy .
this is suggested by the shorter intervals between illness onset and initiation of iv zanamivir in patients with a sustained suppression of the viral load .
the extensive damage to the lungs may have resulted in viral salvage sites inaccessible to the immune system and antiviral medication .
indeed , previously published data show that early start with neuraminidase inhibitors results in a better outcome in hospitalized patients .
finally , it is well recognized that bacterial superinfections may also contribute to clinical deterioration ; we can not rule out the possibility that this has also occurred in our population , despite the fact that all of our patients received antibiotic therapy . in conclusion , the use iv zanamivir as late add - on therapy for h1n1 virus  infected patients in the icu showed limited antiviral effectiveness . in our selected population ,
further studies evaluating earlier start with iv zanamivir monotherapy therapy alone or in combination with other treatment strategies are needed .
a retrospective nationwide study on the use of intravenous ( iv ) zanamivir in patients receiving intensive care who were pretreated with oseltamivir in the netherlands was performed . in 6 of 13 patients with a sustained reduction of the viral load , the median time to start iv 
 zanamivir was 9 days ( range , 411 days ) compared with 14 days ( range , 621 days ) in 7 patients without viral load reduction ( p = .052 ) . 
 viral load response did not influence mortality . 
 we conclude that iv zanamivir as late add - on therapy has limited effectiveness . the effect of an immediate start with iv zanamivir monotherapy or in combination with other drugs need to be evaluated .