Application of copper to prevent and control infection. where are we now?

Available online at Journal of Hospital Infection Application of copper to prevent and control infection.
Where are we now? J. O'Gorman ,, H. Humphreys a Department of Microbiology, Beaumont Hospital, Dublin, Irelandb Department of Clinical Microbiology, Royal College of Surgeons in Ireland, Dublin, Ireland Background: The antimicrobial effect of copper has long been recognized and has Received 18 February 2012 a potential application in the healthcare setting as a mechanism to reduce environmental Accepted 21 May 2012 contamination and thus prevent healthcare-associated infection (HCAI).
Available online xxx Aim: To review the rationale for copper use, the mechanism of its antimicrobial effect,and the evidence for its efficacy.
Methods: A PubMed search of the published literature was performed.
Findings: Extensive laboratory investigations have been carried out to investigate the biocidal activity of copper incorporated into contact surfaces and when impregnated into textiles and liquids. A limited number of clinical trials have been performed, which, although promising, leave significant questions unanswered. In particular there is a lack of Infection prevention and consensus on minimum percentage copper alloys required for effectiveness, the impact of organic soiling on the biocidal effect of copper, and the best approach to routine cleaningof such surfaces. Limited information is available on the ability of copper surfaces toeradicate spores of Clostridium difficile.
Conclusion: Additional studies to demonstrate that installing copper surfaces reduces theincidence of HCAI are required and the cost-effectiveness of such intervention needs to beassessed. Further research in a number of key areas is required before the potentialbenefits of using copper routinely in the clinical setting to prevent and control infectioncan be confirmed and recommended.
Ó 2012 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.
Egyptian papyrus written between 2600 and 2200 BC describesthe application of copper to sterilize chest wounds and to Copper, a metal utilized by human civilization for more than purify drinking water. Later, Hippocrates recommended the 10,000 years, has become the focus of renewed scientific topical application of copper to treat leg ulcers, and, in the interest for its antimicrobial properties and potential applica- pre-antibiotic era of the nineteenth and twentieth centuries, tion in the healthcare setting. Although the exact mechanisms copper preparations were widely used in the treatment of skin by which this metal exerts its biocidal effect are not fully conditions, syphilis and understood, its benefits have long been recognized. An In the modern healthcare setting one of the most widespread and successful applications of the antimicrobial effect ofcopper is in the control of legionella and other bacteria in * Corresponding author. Address: Department of Clinical Microbi- hospital water distribution systems using the method of copper ology, Beaumont Hospital, Dublin 9, Ireland. Tel.: þ353 1 8093320; and silver However, recent research into the anti- fax: þ353 1 8092871.
microbial effects of copper has focused on the mechanism by E-mail address: (J. O'Gorman).
0195-6701/$ e see front matter Ó 2012 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: O'Gorman J, Humphreys H, Application of copper to prevent and control infection. Where are we now?, Journalof Hospital Infection (2012), J. O'Gorman, H. Humphreys / Journal of Hospital Infection xxx (2012) 1e7 which there is ‘contact killing' of microbes on exposure to humans can occur at high concentrations, in general exposure copper surfaces and the impact this may have on reducing to copper is considered safe, as is evidenced by the widespread environmental contamination. In 2008 commercial interest in use of copper intrauterine devices and the documented low this potential application of copper increased due to the deci- risk of adverse reactions due to dermal contact with sion of the US Environmental Protection Agency (EPA) to grant copper.The low sensitivity of human tissue to copper can recognition to copper surfaces as having antimicrobial efficacy.
be contrasted with micro-organisms which are extremely Copper is the first metal to be awarded such a status and to date sensitive to its toxic effects.
almost 300 copper and copper alloy surfaces have demon- The exact mechanisms by which copper exerts its biocidal strated their biocidal effect against five strains of bacteria effect is a source of ongoing investigation. It is thought that the when tested according to US EPA In addition to its cause of cell death is multifactorial rather than the result of use as a material for contact surfaces, the biocidal effects of a single universal A key property of copper which a wide variety of copper-impregnated textiles and liquids have significantly contributes to its toxic effect is its ability to been reported, with particular speculation about their poten- accept and donate single electrons as it changes oxidation tial to reduce healthcare-associated infection (HCAI).
state between Cuþ and Cu2þ [Cu(I) and Cu(II)]. This allows This article reviews the rationale, mechanism of antimi- copper to act as a catalyst for the generation of reactive crobial effect, efficacy and clinical studies on copper to reduce oxygen species (ROS) such as hydroxyl radicals and superoxide the microbial load on contact surfaces. The addition of copper anions. These ROS have the potential to cause oxidative in water systems to prevent legionella is well established and damage to vital cell constituents such as proteins, nucleic acids represents its use to prevent a specific waterborne pathogen; and lipids (including those in the cell membrane).eFree this aspect is not addressed here. A PubMed search of the copper ions may compete with zinc or other metal ions for available literature was conducted using such terms as important binding sites on proteins, leading to conformational ‘copper', ‘antimicrobial copper', ‘copper-based biocide', change and the loss of protein function.Copper ions can also ‘copper resistance', ‘hospital acquired infection', ‘infection inactivate proteins by damaging FeeS clusters in cytoplasmic prevention and control', ‘hygiene', ‘cleaning' and ‘environ- enzymes needed to make branched-chain amino mental contamination'. The search was limited to articles Recent research into the biocidal properties of copper published in English. References from bibliographies of articles surfaces has focused on establishing the primary mechanisms included in the search were also assessed.
which result in cell death, and on the effect of copper onbacterial DNA. One set of studies, involving enterococci Rationale for using copper surfaces in the (including VRE) exposed to copper alloys, reported that celldeath results from the action of released copper ionic species healthcare setting and the generation of superoxide, leading to arrested respirationwith the substantial disintegration of both plasmid and genomic Environmental surfaces are a likely reservoir for potential DNA as a primary effect.Research from this group also pathogens and play a role in the acquisition of healthcare suggests that different mechanisms of toxicity are observed in Studies have demonstrated that hard surfaces can Gram-negative bacteria such as Escherichia coli and Salmonella be contaminated with isolates such as meticillin-resistant spp. with depolarization of the cytoplasmic membrane playing Staphylococcus aureus (MRSA), vancomycin-resistant entero- a key role and DNA degradation occurring at a slower ratBy cocci (VRE) and spores of Clostridium difficile which can contrast, other studies have proposed that depolarization of the remain viable for several weeks to These micro- cytoplasmic membrane is the main target for the antimicrobial organisms from contaminated surfaces may then be trans- effect of copper and that degradation of genomic material only mitted via hands to other inanimate objects or to patients. To occurs subsequent to cell deAlthough investigations standardize the assessment for monitoring hospital cleanliness, into the exact biocidal effects of copper toxicity are ongoing, the benchmarks for assessing hygiene have recently been updated.
consensus that degradation of DNA occurs at some point is The original quantitative standard stated that aerobic colony noteworthy. Compromising DNA in this way has a role to play in counts (ACC) on hand-touch sites should not exceed 5 cfu/cm2 preventing resistance mutations and inhibiting the potential but this has since been reduced to 2.5 cfu/cm2.Achieving transmission of toxin, virulence and antibiotic resistance such a target may be challenging, especially as there is considerable variation in standards and methods of cleaning.In one US study a fluorescent marker solution was employedto determine cleaning efficacy of more than 13,000 surfaces in In vitro evidence for biocidal efficacy of copper 23 hospitals. Terminal room cleaning after patient discharge decontaminated a mean of only 49% of the standardizedsurfaces including <30% of toilet handholds, bedpan cleaners, The use of copper materials in contact surfaces to reduce room doorknobs and bathroom light switches.It is clear that in environmental contamination was first postulated almost 30 addition to routine cleaning, additional strategies to reduce years ago. During a training session to promote hygiene microbial contamination should be considered.
awareness, cleaning staff in a US hospital were asked to takeenvironmental swabs from a variety of locations and it was Mechanism by which copper exerts its noted that brass doorknobs (an alloy of typically 67% copper antimicrobial effect and 33% zinc) had very sparse bacterial growth in comparisonwith swabs from doorknobs of stainless Initial labora- Copper is an essential trace element involved in numerous tory protocols to investigate this phenomenon in a standard- physiological and metabolic processes.Although toxicity in ized way were derived from a testing method developed in Please cite this article in press as: O'Gorman J, Humphreys H, Application of copper to prevent and control infection. Where are we now?, Journalof Hospital Infection (2012), J. O'Gorman, H. Humphreys / Journal of Hospital Infection xxx (2012) 1e7 Japan: JIS Z 2801 (Japanese Industrial Standards Association, study to facilitate ageing and for staff to become accustomed 2000). However, this method is not representative of actual to them. To further reduce bias the study was designed as surface contamination events in a hospital setting, since it a cross-over trial with the copper- and non-copper-containing involves applying a dilute liquid inoculum to the surface area, controls interchanged after five weeks. Items were sampled which is maintained at a relative humidity of >90% for a period on a weekly basis for the presence of micro-organisms. A of 24 h, and incubated at a higher than ambient temperature of benchmark value for all bacteria of <5 colony-forming units per cm2 (cfu/cm2) was used in line with standards which had In an attempt to replicate in vivo situations, two main been proposed at the time.The results of the study showed experimental techniques have since been described, a moist that, based on median total aerobic cfu counts, 5/10 controls inoculation technique and a dry inoculation technique. Incu- and 0/10 copper sample points failed the proposed benchmark bation temperatures and relative humidity in both methods are value of <5 cfu/cm2. Although this benchmark value has also modified to more accurately reflect indoor settings. In subsequently been lowered to 2.5 cfu/cm2 the overall findings studies using a moist inoculation technique, small volumes of that median numbers of micro-organisms harboured by the liquid suspensions of bacteria are applied to metal plates copper-containing items were between 90% and 100% lower (coupons) and can take >30 min to dryIt has been suggested than their control equivalents remain significant. An additional that the aqueous nature of the contaminating inoculum may finding of the 10-week study was that although no isolates of have an impact on the toxicity of the copper surface, and this MRSA and C. difficile were isolated from either type of surface, technique, which mimics a wet contamination incident such as meticillin-susceptible Staphylococcus aureus (MSSA), VRE and a sneeze or a wipe, does not reflect the contamination of dry E. coli were found only on the control surfaces.
surfaces encountered in healthcare In an attempt to A second extended phase of this hospital trial was carried address this issue, a second method has been developed which out over a six-month Fourteen types of frequently involves the application of liquid cell suspensions to metal touched items made of copper alloy were installed in an acute plates using a cotton swab. This provides a higher concentra- medical care ward three months prior to the study. These tion of inoculum in the form of a thin film of liquid which included door handles, push plates, toilet seats and flush evaporates within seconds and may more accurately reflect the handles, grab rails, light switches, pull-cord toggles, sockets, clinical scenario.
overbed tables, dressing trolleys, commodes, taps, and sink Studies have been published demonstrating the ability of fittings. The percentage copper content of the alloys used copper to inactivate a multitude of bacteria, fungi and viruses ranged from 58% to 99.95%. After 12 weeks the copper and in the laboratory setting. These include MRSA, enterococci, standard items were switched over. Weekly sampling was Pseudomonas spp., Acinetobacter spp., Klebsiella spp., carried out for 24 weeks. The study found that 8/14 item types Escherichia coli, Listeria spp., Campylobacter spp., Salmonella demonstrated significantly lower cfu counts on the copper spp., Staphylococcus warnerii, influenza A, Mycobacterium surfaces than on the standard materials with the other six types tuberculosis and Candida eThe majority of these showing reduced microbial numbers on the copper surfaces but laboratory studies have been carried out using a ‘wet inocula- the difference did not reach statistical significance. The study tion' technique and there is wide variation in incubation also assessed the presence of five indicator organisms MRSA, temperatures, relative humidity and copper content of the MSSA, VRE, C. difficile and coliforms. All five bacteria were alloys tested. Nonetheless a number of consistent findings are recovered from both control and copper-containing surfaces.
reported. In general, micro-organisms are inactivated within However, significantly fewer copper surfaces were contami- hours although the greatest efficiency is seen in alloys with nated with VRE, MSSA and coliforms than were the controls.
higher copper content. The percentage copper required for A third trial was conducted in the consulting rooms of significant biocidal effect has been reported to range between a walk-in primary care clinic in South Africa. Contact surfaces 55% and 100%.Temperature and humidity both have an such as a desk, trolleys, the top of a cupboard and windowsills important impact on the kill rate for bacteria with a slower, were covered with copper sheets (99.9% copper alloy). Over six though still significant, impact evident at 4 C and evidence that months the surfaces were sampled every six weeks for a 4.5- higher relative humidity increases the efficacy of contact day period with multiple samplings per day. An overall 71% It appears also that dry surfaces bring about reduction in the bacterial load on the copper surfaces bacterial killing more rapidly than moist ones, though the was observed compared with that of the control surfaces.
mechanism for this is as yet unclear.
Comparable numbers of bacteria were counted when surfacesremained untouched for 71 h over the weekends but this wasnot investigated further In vivo evidence for biocidal efficacy of copper A fourth study was carried out on medical wards of a German Touch surfaces such as push plates, doorknobs andlight switches were replaced with new copper-containing alloys The efficacy of copper in the contact killing of microbes has (percentage of copper alloy not stated). The trial was carried been the subject of extensive laboratory investigation.
out over 32 weeks equally divided between summer and winter.
However, in vivo studies are limited and to date there have The number of aerobic heterotrophic cfu on the surfaces was been only five reports published in the literature.
determined once or twice per week and the presence of The first study was a 10-week trial in a busy acute medical ciprofloxacin-resistant S. aureus (CRSA) was chosen as an ward of a UK A plastic toilet seat, a chrome set of indicator organism for the presence of resistant nosocomial tap handles and an aluminium ward entrance door push plate bacteria. The study found that the total number of cfu on were replaced by equivalent items containing a minimum of metallic copper surfaces was 63% of that on control surfaces 60% copper. The items were installed six months prior to the with statistically significant differences noted between door Please cite this article in press as: O'Gorman J, Humphreys H, Application of copper to prevent and control infection. Where are we now?, Journalof Hospital Infection (2012), J. O'Gorman, H. Humphreys / Journal of Hospital Infection xxx (2012) 1e7 knobs. No significant difference in survival of CRSA on copper reduction in the sensitivity of cellular targets to copper ions.
surfaces versus controls was noted. Following initial sampling Although the genes responsible for such processes can be each morning all surfaces were cleaned with disinfectant. It encoded by transmissible plasmids, the potential emergence of was noted that surfaces repopulated at different rates, widespread bacterial strains resistant to copper surfaces 12.4 cfu/h for copper surfaces and 22.5 cfu/h on other appears unlikely given the rapid rate of contact killing and the complete degradation of DNA known to occur.
The final in vivo study of the contact killing effect of copper Studies to investigate this issue have focused on known surfaces was carried out in a critical care unit.This small trial plasmid-borne copper resistance mechanisms. One such target compared the contamination of copper versus stainless steel is the tcrB gene identified in certain strains of E. faecium and pens after use over a 12 h clinical shift. In total 25 pens of each E. faecalis. This gene encodes for a membrane-bound protein type were examined. A lower total number of cfu was found on involved in copper homeostasis and is thought to originate from copper pens sampled immediately after collection but this did pigs fed with copper sulphate-supplemented food.Although not reach statistical significance. When pens were left in isolates containing the tcrB gene exhibit growth on braineheart storage for 11 h (reflecting the time lapse between shifts) infusion agar plates containing high concentration of copper significantly fewer copper-containing pens were contaminated sulphate, it is thought that their resistance mechanism is not compared with stainless steel pens. A summary of each in vivo sufficient to prevent cell death when exposed to copper assessment and its findings is outlined in surfaces.Other studies of E. coli strains containing a resis-tance plasmid PCo demonstrated a decreased killing rate whenexposed to copper surfaces but did not prevent cell death.
Copper-impregnated textiles and liquids Efforts to assess the potential for resistance to develop in bacteria in continual contact with copper led to a novel In addition to its use as a contact surface, the antimicrobial investigation of isolates colonizing European 50 cent coins.
effect of copper is being exploited in a number of other Although coins have not been confirmed to have antimicrobial settings. This has been facilitated by the development of efficacy as defined by EPA standards, the authors of this study a technique for the mass production of copper oxide- postulated that 50 cent pieces (89% copper alloy) may be ideal impregnated textiles, latex and other polymer products.In surfaces to give rise to natural selection of metallic copper- the area of personal protective equipment, for example, the resistant In total, 294 strains of bacteria (the addition of copper oxide into respiratory protective face masks majority being Gram-positive cocci) were recovered from an has been shown to have anti-influenza biocidal effects without international sample of coins and tested for survival on a pure altering the physical barrier properties of the material.A role copper surface (99% Cu). The survival of the isolates was for copper oxide-impregnated wound dressings has also been compared to matched type-specific control strains. Although investigated with preliminary results from animal models some isolates demonstrated prolonged survival on dry surfaces demonstrating a strong biocidal effect with no adverse reac- compared with their controls, no significant copper-resistant tions in closed skin wounds.Furthermore a novel clinical bacteria were identified. Staphylococcus spp. isolated from study assessing the impact of copper-impregnated socks coins did not have antibiotic resistance profiles more extensive demonstrated improvement in the symptoms of fungal foot than their matching control strains, arguing against the co- selection of copper surface resistance traits.
Although it has been postulated that there may be a role for making hospital soft surfaces such as sheets and clothing fromcopper-impregnated biocidal textiles, there are no clinical Areas for further study data to support the efficacy of such an intervention in reducingHCAI and questions remain unanswered about issues such as Much work has been done to investigate the bactericidal cleaning and the decontamination of such materials.The efficacy of copper as part of a contact surface, but a number of biocidal effects of liquid formulations containing copper have questions remain unanswered about the benefit of the wide- also been assessed; a number of laboratory studies have spread implementation of copper-based products in the postulated a role for copper-based hand rubs and cleaning healthcare setting. Although there is increasing evidence of the products as effective infection prevention and control inter- importance of hand-touch sites in the transmission of patho- ventions.Furthermore, a clinical study assessing the gens, the clinical trials of copper contact surfaces published to performance of ultramicrofibre cleaning technology with the date have not been designed to show a reduction in HCAI rates.
addition of a copper-based biocide (CuWB50) demonstrated Instead a surrogate marker of aerobic cfu compared with a significant reduction in total viable count in the hospital control surfaces has been used. The clinical impact of such environment when compared with ultramicrofibre mops and a reduction is unclear. To address this issue a large-scale, cloths moistened with water multicentre US trial using HCAI rates as an outcome hasrecently been completed. Preliminary assessment of these Resistance to copper unpublished data suggests that significant reductions in HCAIwere observed when copper alloys were used in an ICU As copper is an essential micronutrient but toxic at elevated Hospital trials in Japan, South Africa, Greece and concentrations, micro-organisms have developed complex Chile are underway and it is possible that results from these systems to maintain precise intracellular levels. In addition to trials may provide further evidence in this regard.
specific uptake and efflux pumps, other mechanisms of toler- Concerns also arise with regard to the lack of clinical trials ance include exclusion by a permeability barrier, intra- and assessing the role of copper contact surfaces in eradicating extracellular sequestration, enzymatic detoxification and Please cite this article in press as: O'Gorman J, Humphreys H, Application of copper to prevent and control infection. Where are we now?, Journalof Hospital Infection (2012), J. O'Gorman, H. Humphreys / Journal of Hospital Infection xxx (2012) 1e7 decontamination of surfaces exposed to C. difficile spores is efficacy of contact killing may be improved by the addition of challenging for conventional cleaning methods, the beneficial a spore germinant to cleaning solutions used on the copper effects of copper contact surfaces may have a significant Further research, both into the effect of copper and impact. One laboratory-based study postulated that the the potential role for spore germinants, is required.
Table IThe setting, methods used and findings from five studies in clinical areas of copper-impregnated surfaces Acute care medical Cross-over study.
Based on median total 60e70% copper alloys.
Three existing surfaces aerobic cfu, 5/10 controls Items installed 6 10-week study.
replaced with copper and 0/10 copper sample alloys (toilet seat, tap points failed the benchmark start of study to handles, door push plate).
allow staff to become Total aerobic microbial Median numbers of accustomed to fixtures counts per cm2 monitored micro-organisms on and so fixtures ‘aged'.
weekly and compared with benchmark value of <5 cfu/cm2.
items were 90e100% Also evaluated for indicator 2 (Karpanen Extension of study 1.
Cross-over study.
>58% copper alloys.
Fourteen frequent-touch significantly reduced items replaced with copper alloys.
bacterial load.
24-week study.
6/14 trend towardsreduction but notstatistically significant.
Total aerobic microbial Significantly fewer counts per cm2 monitored difference between weekly and compared with contaminated with copper and control benchmark value of <5 cfu/cm2.
VRE, MSSA and coliforms items colonized with Also evaluated for indicator compared with controls.
Primary healthcare Consulting room refitted with Overall 71% reduction 99.9% copper alloys clinic, Western Cape, copper sheets on touch surfaces in bacterial load of South Africa.
(desk and trolleys, top of cupboard, copper surfaces Comparable numbers 24-week study.
of bacteria counted Sampled every 6 weeks for 4.5 days. that of control Total aerobic colony count.
remained untouchedover the weekends(71 h).
Oncology, respiratory In total 147 push plates, Average 63% reduction Also demonstrated and geriatric ward, doorknobs, light switches in bacterial load of replaced with brass repopulation of copper surfaces less than half (summer and winter).
Sampled once or twice that of controls.
per week for total aerobic Results significant colony count.
for door handles.
CRSA as an indicator organism.
No significant differencein survival of CRSAalthough lower numberson copper surfaces.
Intensive care unit, UK. Comparison of surface Statistical significance microbial contamination only reached when during a 12-h clinical associated with pens of pens left in storage copper alloy vs stainless steel (50 pens in total).
Lower total cfu foundon copper pensimmediately aftershift completed butnot significant.
Cfu, colony-forming units; VRE, vancomycin-resistant enterococci; MRSA, meticillin-resistant Staphylococcus aureus; MSSA, meticillin-susceptible Staphylococcus aureus; CRSA, ciprofloxacin-resistant Staphylococcus aureus.
Please cite this article in press as: O'Gorman J, Humphreys H, Application of copper to prevent and control infection. Where are we now?, Journalof Hospital Infection (2012), J. O'Gorman, H. Humphreys / Journal of Hospital Infection xxx (2012) 1e7 Assuming that a reduction in healthcare infection rates cleaning protocols for copper surfaces should be established. It could be attributed to the use of copper contact surfaces and is fitting that the US EPA requires those making public health impregnated materials, issues arise in relation to cost- claims related to the antimicrobial benefit of copper to clearly effectiveness. In international markets the price of copper state that the use of such surfaces is a supplement to, not continues to The cost-benefit analysis of replacing a substitute for, standard infection prevention and control existing surfaces and materials would need to be established practices. Effective hand hygiene and the routine cleaning of and it would be important to ascertain which surface areas should be targeted for maximum impact, if, for cost or other reducing HCAI, and the additional routine contribution of reasons, all surfaces could not be replaced. Establishing the copper surfaces, while potentially beneficial, remains to be minimum percentage of copper required in alloys for efficacy is also an area of uncertainty with wide variation in surfacestested in laboratory experiments. Studies suggest that anything Conflict of interest statement from 55% to 100% copper composition are required for biocidal H.H. has had recent research collaborations with Steris impact.In choosing which alloy to employ there needs Corporation, Inov8 Science, Pfizer & Cepheid. He has also to be a balance between efficacy and other considerations such recently received lecture and other fees from Novartis, as durability of surfaces and their aesthetic appeal.
AstraZeneca & Astellas.
Concerns regarding the impact of soiling and cleaning on the effectiveness of contact killing surfaces also need to be addressed. The effect of soil residue on antimicrobial surfaces None declared.
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Available online at Schizophrenia Research 105 (2008) 49 – 60 Static posed and evoked facial expressions of emotions Christian G. Kohler ⁎, Elizabeth A. Martin, Neal Stolar, Fred S. Barrett, Ragini Verma, Colleen Brensinger, Warren Bilker, Raquel E. Gur, Ruben C. Gur Neuropsychiatry Division, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, United States


Harvard Journal of Law & Technology Volume 24, Number 2 Spring 2011 REVERSE SETTLEMENTS AS PATENT INVALIDITY SIGNALS Gregory Dolin, M.D.* TABLE OF CONTENTS I. INTRODUCTION .282 II. THE HATCH-WAXMAN ACT .286 A. The Structure and Purposes of the Act . 286 B. The Mechanics of the Hatch-Waxman Act. 290 III. REVERSE SETTLEMENTS .293