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• W1693193623 abstract "Pathogen inactivation (PI) technologies promise definitively and prospectively to reduce the risk of bacterial sepsis associated with platelet (PLT) components. Three technologies are in various stages of commercial development: amotosalen plus ultraviolet-A (UVA) light (Intercept Blood System, Cerus Corporation, Concord, CA) is Food and Drug Administration approved, Comformité Européenne (CE) marked, and marketed widely; riboflavin plus UV light (Mirasol Pathogen Reduction Technology, TerumoBCT, Lakewood, CO) is CE marked, undergoing clinical trials in the United States, and marketed outside of the United States; and UV-C light (Theraflex UV-PLTs, MacoPharma USA, Duluth, GA) is CE marked and is still under clinical development. The efficacy of each PI technology is described in terms of log reduction factors, defined as log of the ratio of the pathogen loads in spiked preinactivation and postinactivation materials, in accordance with World Health Organization (WHO) guidelines.1 The published results for each technology are not directly comparable as the measurements were not performed using standardized techniques, pathogen strains, or PLT products. However, these data and a single head-to-head comparison of the amotosalen/UVA light and riboflavin/UV light systems2-4 confirm that there are considerable differences, suggesting that the technologies may differ in their manner of optimal use. Many observers note the potential weakness of available PI technologies for certain pathogens: Prions are not inactivated; certain nonenveloped viruses (e.g., hepatitis A, parvovirus B19, hepatitis E) as well as bacterial spores (e.g., Bacillus spp.) may be relatively resistant.5, 6 Three studies describe further limitations of bacterial PI: In this issue, Schmidt and coworkers8 describe failures that occur with an extended delay between spiking and PI treatment, due to bacterial proliferation to high concentrations that exceed the capacity of the inactivation system;7, 8 and two related studies previously demonstrated occasional idiosyncratic failures to inactivate to sterility at low bacterial concentrations with another technology.4, 9 Schmidt and colleagues8 describe a novel challenge to the amotosalen/UVA light PI technology. Noting that bacteria proliferate over time in PLT components, they spiked apheresis PLTs (APs), pooled buffy coat PLT concentrates (PPCs) in PLT additive solution (PAS), and whole blood (WB) from four different donors with moderate to high numbers (approx. 100 colony-forming units [CFUs] or approx. 1000 CFUs per component) of one of eight clinically relevant strains of bacteria. The APs and PPCs were treated with amotosalen/UVA light 12 hours after spiking. In another series of experiments, the spiked WB units were manufactured into buffy coat PLTs 23 hours after inoculation and treated with amotosalen/UVA light 35.5 hours after inoculation. The report is ambiguous whether these were treated as individual buffy coats units or combined in pools with units that had not been spiked. In all experiments, bacteria counts were assessed at multiple time points, including just before PI treatment and at outdate 5 to 7 days after inoculation, when BacT/ALERT 3D (bioMérieux, Inc., Hazelwood, MO) culture testing was performed to confirm sterility. The majority (184/192, 95.8%) of PI-treated PLTs were sterile at outdate, including all APs at both levels of inoculation and the spiked WB-derived PLTs contaminated at 100 CFUs/unit. However, in eight instances, breakthrough contamination was documented. These occurred with Bacillus cereus (PEI-B-07-23; two each in WB and PPCs spiked with 1000 CFUs) and with Klebsiella pneumoniae (PEI-B-08-09; one with WB spiked with 1000 CFUs, two with PPCs spiked with 1000 CFUs, and one with PPCs spiked with 100 CFUs). All units spiked with a second strain of K. pneumoniae (GRC-05-01) were sterile at outdate. In each case of breakthrough contamination, the concentration of bacteria at the time of PI treatment exceeded the published capacity of the PI system. Indeed, for each of the 8 of 12 units spiked with the breakthrough strains that were shown to be functionally sterile at outdate (presumably < 1 CFU/unit [<0.005 CFU/mL] immediately after PI treatment), the measured log reduction factor was more than 8.0 for K. pneumoniae (PEI-B-08-09; with a mean pretreatment concentration of approximately 106 CFUs/mL) and more than 6.0 for B. cereus (PEI-B-07-23; with a mean pretreatment concentration of approx. 104 CFUs/mL). The authors conclude that the PI process was not 100% effective and the delay between blood donation and PI treatment should be minimal to ensure PLT safety. In cases where PI cannot be performed immediately after preparation, they suggest a combination of PI technology and a rapid screening test on Day 4 or 5 of storage to prevent bacterial transmission. The authors do not define their understanding of the words “minimal” or “immediately” in this context. Previously, Goodrich and coworkers9 described an alternative, idiosyncratic mode of breakthrough contamination. In a large study, a panel of 29 clinically relevant bacterial strains were spiked in triplicate at low concentrations (<100 CFUs/component) into split units of leukoreduced APs suspended in plasma. The test split units were treated with riboflavin and UV light 2 hours after inoculation and then held under routine conditions. Culture screening of both test and control units was performed on Day 7. The vast majority (91%) of test units were sterile (defined as a negative culture screen at outdate) whereas all the control units tested culture positive. However, isolated test units of PI-treated PLTs screened culture positive with Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus agalactiae, Enterobacter cloacae, and Acinetobacter baumanii bacterial species, indicating failure to inactivate to sterility. Similarly, Kwon and coworkers4 describe breakthrough contamination after riboflavin/UV light treatment of two pairs of units of pooled, nonleukoreduced, WB-derived PLT-rich plasma PLTs in 100% plasma, spiked with 46 to 152 CFUs of S. aureus or Bacillus subtilis and PI treated immediately. In contrast, 2 units spiked with 82 to 84 CFUs of Escherichia coli under these conditions were found to be sterile on reculture 5 days after spiking. In both of these reports, the bacterial concentrations were presumably (this was not measured at the time of PI treatment in the report by Goodrich et al.10) within the published log reduction capabilities of the PI system. Schmidt and coworkers’ recommendation to perform additional rapid bacterial screening on Day 4 or 5 in combination with PI might be effective in managing both modes of failure described; however, this simplistic solution fails to consider a more fundamental truth highlighted by their data. Manufacturers of PI technologies should define the limitations of their systems and stipulate the conditions of effectiveness, setting guard bands for inactivation that ensure patient safety. Thereafter, blood collectors should validate the processes for their final intended use. Use outside of those guard bands might be expected to fail. Within those guard bands, secondary bacterial screening should be unnecessary. Schmidt and colleagues demonstrate that the delay between blood donation and PI treatment is critical and that the outcomes differ by bacterial species, the method of PLT preparation, and the number of spiked bacteria. Almost certainly, different results would have been obtained using the riboflavin/UV light or UVC light PI processes.3 Manufacturers of PI systems have not published studies to determine the maximum delay between blood donation and PI treatment and it is unclear how the periods stipulated in current regulatory approvals were determined (e.g., amotosalen/UVA light treatment currently must be performed within 24 hours of AP collection in the United States). The maximum delay between collection and inactivation should be defined for each intended use and may differ between APs, WB PLTs produced by the buffy coat method, or WB PLTs produced by the PLT-rich plasma method. The timing of leukoreduction and the use of PASs may also be important variables. The question then is, “How can we select experimental conditions to mimic routine use in such validation studies?” The following criteria are proposed from first principles: Outcomes measured: Since PI is performed soon after donation and even small numbers of surviving bacteria can proliferate during posttreatment storage, a clinically relevant outcome is sterility as determined by culture of a large sample volume (≥8 mL) at outdate. Bacterial species to be tested: The use of standard, clinically relevant bacterial strains with proven ability to grow in PLT products would greatly assist in validation studies. The WHO has established an international registry of transfusion-relevant bacteria reference strains, in collaboration with the ISBT Working Party Transfusion-Transmitted Infectious Diseases (WP-TTID), Subgroup on Bacteria, which is designed to serve this purpose. These strains are available upon request11 and include S. epidermidis (PEI-B-P-06), Streptococcus pyogenes (PEI-B-P-20), K. pneumoniae (PEI-B-P-08), and E. coli (PEI-B-P-19). Development work on 11 additional strains, including spore-forming Bacillus spp. has been completed and these are likely to be included in the registry in the near future. Each strain has been shown to grow promiscuously in both APs and WB PLTs after minimal inocula (10-100 CFUs/PLT component) in multiple international laboratories. In particular, the K. pneumoniae strain (PEI-B-P-08) is derived from the same source as that shown by Schmidt and coworkers to cause breakthrough contamination.12 Klebsiella spp. are particularly important because they are among the fastest growers in PLT components and were the most frequent cause of fatal septic transfusion reactions in the United States before the advent of bacterial culture screening and would likely be so again if screening is no longer performed.13 Number of replicates: Bacteria show varying grow kinetics in PLTs derived from different donors, making it important to perform each study in products derived from at least three donor sources. Concentration of the initial spike: The number of bacteria that initially contaminate PLTs at the time of donation during routine collections is not known. At the time of bacterial sampling for culture screening 12 to 36 hours after donation, the median number of bacteria is calculated at fewer than 62 CFUs per unit based on culture results.14-16 Taken together, these data suggest that the appropriate number of bacteria to be spiked in validation studies should be as low as possible (1-100 CFUs/unit) but sufficient to cause reliable growth before PI in a treated unit or during storage to product outdate in an identical untreated unit used as a positive control. There are no data to support the use by Schmidt and colleagues of spiking with 1000 CFUs per unit as being representative of natural contamination during PLT collection. The data, while informative, could be considered an overly robust challenge to the PI process for validation purposes. With these assumptions, we can speculate on the maximum allowable delay between blood donation and amotosalen/UV light treatment based on published work. For APs in plasma, Schmidt and colleagues provide robust data validating a 12-hour delay between donation and PI treatment at 100 CFUs/unit, and their finding of no breakthrough contamination in units with 1000 CFUs/unit inocula suggests that longer delays would also be successful. In addition, Nussbaumer and coworkers17 tested seven bacterial species inoculated into single APs at 1 to 10 CFUs/unit, 10 to 100 CFUs/unit, and 100 to 1000 CFUs unit and performed amotosalen/UVA light treatment 18 to 20 hours after inoculation (W. Nussbaumer, personal communication, 2014) and found no growth on culture screening 5 days after spiking. Likewise, Wagner and colleagues18 tested the four original WHO reference strains11 (including K. pneumoniae [PEI-B-P-08]) plus an additional K. pneumoniae strain (ATCC 29015) each inoculated into three AP units in PAS at 4 to 53 CFUs/bag and PI treated the units with amotosalen/UVA light 24 hours after spiking.18 Bacterial growth was confirmed before PI treatment and/or in control units at outdate. They found no growth in any PI-treated unit on culture screening 7 days after spiking. These data validate the efficacy of the amotosalen/UVA light PI treatment system with a 24-hour delay. None of the studies above considered the possibility that a PI process might be effective at rendering a product sterile, but the accumulating bacterial organisms might generate sufficient endotoxin to cause a severe transfusion reaction. Jacobs and coworkers19 showed that moderate and severe septic transfusion reactions are reported at bacterial counts of more than 1 × 105 CFUs/mL, implying that endotoxin is less likely to be harmful below this bacterial concentration. In the above studies with APs, such concentrations were not attained in the experiments of Wagner and colleagues within 24 hours after inoculation, but were attained by four replicates of K. pneumoniae (PEI-B-07-23) 12 hours after being spiked with 100 CFUs. Taken together, the data collectively support the recommendation of Schmidt and colleagues that amotosalen/UVA light PI for APs be performed as soon as possible, preferably on the day of donation, although no secondary bacterial screening is necessary even if treatment is delayed until 24 hours after donation. For PLTs manufactured from WB, the finding by Schmidt and colleagues that there was no breakthrough contamination detected in amotosalen/UV light–treated units with WB inoculated with 100 CFUs/unit confirms the safety of their protocol, where buffy coat PLTs were separated and PI performed 23 and 35.5 hours after blood spiking, respectively. The occurrence of breakthrough contamination in WB contaminated with 1000 CFUs suggests that the delays between donation, buffy coat PLT preparation, and PI treatment cannot be extended further. With respect to endotoxin, bacterial concentrations were less than 1 × 105 CFUs/mL for all bacterial species at the time of buffy coat PLT manufacture; however, one K. pneumoniae strain (PEI-B-07-23) and the Serratia marcescens (ATCC 43862) strain exceeded this threshold by the time of amotosalen/UVA light treatment 12 hours later. These data confirm the safety of overnight hold of WB before manufacturing buffy coat PLTs but support the recommendation by Schmidt and colleagues that amotosalen/UVA light treatment be performed as soon as possible, but no later than 12 hours after buffy coat manufacture. These conclusions may not be true for PLTs produced by the PLT-rich plasma method, especially if leukoreduction is performed at a different time point. In contrast, the breakthrough failures observed after spiking of PPCs with both 100 and 1000 CFUs inocula are more difficult to interpret as these levels would not represent the normal timing of contamination during routine blood donation. These data, however, do suggest that the delay between buffy coat PLT preparation and PI treatment is a critical variable for WB-derived PLTs. Less data are available for evaluating the permissible delay between collection and PI treatment with other technologies. For the UVC light system, further studies are needed before any conclusions can be drawn. The riboflavin/UV light system was extensively tested with a 2-hour delay.9 The results showed that while the majority of treated APs were functionally sterile, breakthroughs occurred with 9% of units inoculated with 20 to 100 CFUs/unit and 2% of inocula at 5 to 20 CFUs/unit. It seems reasonable to conclude that the riboflavin/UV light system can be used within 2 hours of collection for APs, possibly with rapid bacterial screening on Day 4 or 5 to ensure complete safety; however, delays beyond 2 hours need additional validation. Studies on the effect of delay of treatment with WB PLTs, processed as either buffy coat or PLT-rich plasma PLTs, are needed. In summary, Schmidt and coworkers demonstrate that the delay between blood donation and PI treatment is important for effective bacterial pathogen reduction by inactivation. With this knowledge, guard bands around the timing of PI treatment should be defined for each type of PLT component. For the amotosalen/UVA light system, PI treatment should be performed on the day of donation for APs and as soon as possible after PLT manufacture for WB PLTs. That being said, all indications are that breakthrough contamination would be prevented for APs with delays up to 24 hours and 35.5 hours for WB-derived buffy coat PLTs. Outside of these guard bands, addition of rapid bacterial screening or further validation studies are necessary to ensure patient safety. The American Red Cross is engaged in a clinical trial of the Cerus Corporation's Intercept pathogen inactivation system in Puerto Rico. RJB has the following personal conflicts: Fenwal, Inc., Scientific Advisory Board; Immucor, Scientific Advisory Board; Cerus Corporation, received lecture honoraria. In July 2015, RJB will take up the Chief Medical Officer position at Cerus Corporation. SJW laboratory has received funding for a study sponsored by Cerus Corporation. Richard J. Benjamin, MD, PhD Stephen J. Wagner, MD e-mail: [email protected] American Red Cross Holland Laboratories Rockville, MD" @default.
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• W1693193623 date "2015-09-01" @default.
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• W1693193623 title "Bacterial pathogen reduction requires validation under conditions of intended use" @default.
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