Thursday, October 27, 2011

In Part Curing Hepatitis C -John Bartlett's Game Changers in Infectious Disease: 2011

John Bartlett's Game Changers in Infectious Disease: 2011

From Medscape Infectious Diseases ; Expert Reviews and Commentary

John G. Bartlett, MD

Posted: 10/26/2011

Game Changers in the Field of Infectious Disease

The papers selected for this review contain important observations that are "game changers," defined as scientific observations that are likely to have substantial impact on the field of infectious diseases. In many instances, the paper selected is one of several that contribute to the issue but, in the author's opinion, is particularly important for its contribution to the totality of the issue.

New Mechanisms of Antibiotic Resistance

Kumarasamy and colleagues[1] reported their experience with gram-negative bacilli that are resistant to all carbapenems as a result of the newly recognized New Delhi Metallo-betalactamase 1 (NDM-1). These investigators described 37 strains identified in patients from England and 70 strains in patients from India and Pakistan. The isolates (Enterobacteriaceae with the bla NDM-1 gene) showed sensitivity limited to tigecycline (67% of strains) and colistin (100% of strains). The review also included an analysis of the air travel of these organisms as these patients flew from India or Pakistan to the United Kingdom.

The gene that confers this resistance pattern is plasmid mediated, harbored in the gut, and potentially transferrable to multiple coliforms, primarily Escherichia coli and Klebsiella. Factors contributing to this unusually challenging resistance pattern were obviously diverse, but the use of nonprescription antibiotics in India and Pakistan may have been important. In the study authors' view, this resistance pattern signaled the diminished and possible loss of value of beta-lactams, fluoroquinolones, and aminoglycosides.

Why Is This a Game Changer?

Resistance is the "elephant in the room" in the field of infectious diseases. Everyone in hospital practice is well aware of the issue, but now the future appears to be particularly ominous. We have always had the problem of resistance, as a result of antibiotic use and Mendelian laws, but in the past we have been bailed out by the production of new antibiotics. Pharmaceutical companies are no longer interested in antibiotic development and production for a variety of reasons, mostly economic.[2] As one pharmaceutical executive told me: "You take an antibiotic for 1-2 weeks but you take a statin for a lifetime. What would you make?"

The issue is far more complex, but to illustrate its magnitude, from 1983-1987, 16 new antibiotics were approved by the US Food and Drug Administration (FDA), but from 2008-2011, just 2 new systematic antibiotics were approved and neither addressed the issue of resistance. In fact, in 1990, 19 companies developed antibiotics, and now that number has declined to 4.[3]

The problem of antibiotic resistance is global. Kumarasamy and colleagues traced the NDM-1 to India, with the inference that abuse of over-the-counter antibiotics in that country was harmful to the rest of the world. As anticipated, with international travel, this plasmid with NDM-1 is now found in the United States.

The antibiotic resistance issue has not gone unnoticed and is currently receiving substantial attention from all corners. President Obama has asked the Trans-Atlantic Antibiotic Resistance Task Force to address the problem, indicating recognition of its international reach. Two bills introduced in Congress (the GAIN bill in the House and the STARR Act in the Senate) include proposals for financial incentives for the pharmaceutical industry to produce new antibiotics. Nevertheless, no antibiotics currently in phase 3 development are likely to resolve the problem of gram-negative bacilli resistance, so it will continue to evolve with no anticipated deterrence until 2016 at the earliest, considering the snail speed of the regulatory process.

What Does This Mean to the Practitioner?

Prepare to use a lot of colistin and anticipate more regulation. Colistin may be the only solution for many of these resistant bacteria, but the drug has been used with trepidation for nearly 50 years. Relatively little is known about colistin except that it is nephrotoxic[4] and colistin-resistant Klebsiella has already been reported.[5] Practitioners should prepare for more regulation because infection control and antibiotic stewardship are the primary weapons still available to slow the inevitable evolution of resistance. The emphasis will be on antibiotic restraint (for conditions such as otitis, sinusitis, bronchitis, etc.), pathogen-directed therapy, and short-course treatment.

Curing Hepatitis C

With a combination of a nucleoside and a polymerase inhibitor, Gane and colleagues[6] have shown a high rate of success in suppressing hepatitis C virus (HCV) to undetectable levels in 14 days without the need for peginterferon and ribavirin. Although based on limited sample size and long-term follow-up, these findings represent enormous progress in the field of hepatitis C treatment.

The standard treatment for the most common and difficult to treat form of HCV infection, genotype 1, has been peginterferon plus ribavirin. Cure was achieved in only 30%-40%, and toxicity was often severe, but this combination represented the state of the art for many years until telaprevir and boceprevir were approved by the FDA in May 2011.[7-9] These protease inhibitors substantially augmented the probability of achieving "sustained viral response" (indicating cure) when added to peginterferon plus ribavirin. The INFORM-1 trial suggests that we will be able to achieve this goal with greater success and far less toxicity within 1-2 years with the avalanche of these and other new drugs that are currently being tested.[7]

Why Is This a Game Changer?

Unlike antibacterials, drug development for HCV is exploding. At present, new drugs for HCV include 4 agents in phase 3 and 2 agents in phase 2 FDA testing. Although these new drugs are clearly "game changers" for patients with hepatitis C, their use is restricted to specialists as a result of the complexity of the regimens, toxicity, resistance issues, drug interactions, and cost.

In contrast to treatment of HIV or hepatitis B, the goal of hepatitis C treatment is a cure. With the 2 recently approved protease inhibitors, a cure is likely to be achieved in more than 70% of patients, and in almost all patients when the new drugs in the pipeline become available. Nevertheless, economics will be an issue because current costs of treatment are $50,000-$70,000/patient.

What Does This Mean to the Practitioner?

  • About 1% of people in the United States (approximately 300,000 individuals) are infected with hepatitis C, and 70% of these people do not know they are infected. It will be important to screen patients with HCV antibody serology and evaluate those who are positive with liver function tests, genotyping, and HCV viral load, all tests that are readily available.
  • The decision for treatment depends on results of baseline tests and confounding issues such as substance abuse, mental health, and other comorbidities. These issues can be resolved at the primary care or specialty level.
  • Decisions about who to treat must take into account the stage of the patient's disease because it is likely that the newer drugs that are anticipated for 2012-2013 will more effective, less toxic, and possibly less expensive. The urgency of treatment typically depends on the liver fibrosis score, which predicts the consequences of a delay in treatment. It is probably wise to urge patients who can delay therapy for 1-2 years to wait.

    Central Line-Associated Bloodstream Infections

  • A sentinel hospital study, conducted by the Centers for Disease Control and Prevention (CDC), analyzed systematic data from 19 hospitals that were thought to be representative of hospitals in the United States. Central line-associated bloodstream infections (CLABSI) for 2009 (18,000 cases) were compared with those for 2001 (43,000 cases) (Table1).

    Table 1. Estimated Number of CLABSI in the United States, 2001 and 2009

    Setting Year No. (95% CI)
    Intensive care units 2001
    43,000 (27,000-67,000)
    18,000 (12,000-28,000)
    CI = confidence interval
    Data from CDC.[10]

    A 58% reduction in CLABSI was demonstrated, an incredible achievement. CDC study authors estimated that if all hospitals reduced their CLABSI rates by this amount, 27,000 lives and $1.8 billion/year would be saved. The future of healthcare in the United States places great emphasis on saving lives and dollars. This CLABSI story is right in the center of healthcare reform and, to a large extent, predicts that "harm reduction" will receive even more attention in any new healthcare policies and plans. The question is: how did we reduce the frequency of CLABSI by this much? This result was not circumstantial but followed a crafted and logical series of events:

    2001: A 5-step CLABSI "bundle" was defined to include: hand hygiene, full barrier precautions, skin cleansing with chlorhexidine, avoidance of the femoral site, and prompt removal of unnecessary catheters.

    2003-2005: The Keystone Project implemented this bundle in 103 intensive care units (ICUs) in Michigan and showed a decline in rate of CLABSI from 7.7% to 1.4%.[11]

    2008: The Department of Health and Human Services (HHS) rolled out 28 state programs to incorporate this bundle with the target of reducing CLABSI by 75%.

    2009: A review of the Michigan ICU data showed that the previously demonstrated benefit had been sustained. Further reductions occurred, adding up to a 70% reduction compared with baseline rates of CLABSI.[12]

    2010-2011: The Joint Commission incorporated the CLABSI bundle. Blue Cross and Blue Shield provided financial incentives for using the bundle and LeapFrog bestowed accolades for its use.[13]

  • Why Is This a Game Changer?

    The totality of this sequence of events is now credited to a large extent with the substantial reduction in the rates of CLABSI along with the impressive accomplishment reported by the CDC. This not only signals an important advance that should be put into practice but it also reflects a change in methodology for healthcare reform. This would not have happened 10 years ago in terms of funding for the study (Blue Cross and Blue Shield) or the method of implementation with rapid engagement by the payers, HHS, The Joint Commission, LeapFrog, and others.

  • What Does This Mean to the Practitioner?

  • Expect more "bundles."
  • These interventions have the attention of the payers and hospital administrators. Incentives for compliance and/or penalties for noncompliance should be anticipated. Medicare performance indicators ("marching orders") will follow.
  • The next bundle will be prevention of ventilator-associated pneumonia, which is already far along in the process.[14

  • Tackling MRSA

  • In Veterans Affairs (VA) hospitals, Jain and colleagues[15] studied morbidity and mortality associated with methicillin-resistant Staphylococcus aureus (MRSA) infections. In 2007, the CDC reported that the burden of healthcare-associated infections involving MRSA in the United States was 94,360 per year, with a yearly mortality of 18,650. This finding contributed to increasing concern about healthcare-associated infections.

    The goal of the VA study was to implement a "MRSA bundle" that included universal MRSA surveillance, contact precautions, hand hygiene, and what was described as a "culture change" based on the principle of "positive deviance." Infection control and prevention would become the responsibility of everyone involved in the care of patients and not just an infection control team. The study was sequential from 2007-2010 and data were collected for 1,934,598 patients. The sequential design included a control period from 2005 through mid-2007 followed by implementation of the bundle.

    At more than 2 years of follow-up, compared with baseline, the frequency of healthcare-associated MRSA infections declined by 48%, with a 62% reduction in ICU patients and a 45% reduction in non-ICU patients. This impressive record of success was attributed to an intensive effort by the VA system to better control the epidemic of nosocomial infections involving MRSA.

    The report by Huskins and coworkers,[16] a similar study addressing the same issue, funded by the National Institutes of Health (NIH), was carried out in 18 ICUs at academic centers. Findings were reported in the same issue of The New England Journal of Medicine. [16] In this study, the ICUs used a cluster randomization protocol for standard contact barrier precautions vs gloves only when taking care of ICU patients whose surveillance cultures of nose or stool indicated vancomycin-resistant enterococcus or MRSA. Results based on intervention in 5434 patients vs 3705 control patients showed no benefit in reducing infections involving either of these pathogens (hazard ratio 1.05; 95% confidence interval 0.8-1.4).

    Thus, the VA study and the NIH-funded ICU trial addressed similar issues using surveillance cultures and barrier precautions to control MRSA infections in the hospital, and, although neither study was perfect, they came to opposite conclusions. Criticism of the VA study includes the problem of sequential design because many other factors could change rates of MRSA infections, including the previously noted data for CLABSI.[6] The most serious concern about the NIH-funded ICU trial is that the cultures were processed in Bethesda, Maryland, resulting in a prolonged delay (averaging about 5 days) before the results were known to the investigators.

  • Why Is This a Game Changer?

    The more important conclusion of these 2 studies is that there is no conclusion. We had a similar controversy in 2008 when, using standardized infection control methods, a study in Chicago showed a 45% reduction in MRSA infections,[17] and a study in surgical patients in Finland showed a 10% increase in S aureus infections.[18] Everyone in hospital practice is aware of the enormous concern for MRSA and the repeated emphasis on the ritualistic methods of infection control.

  • What Does This Mean to the Practitioner?

  • MRSA is an incredibly important pathogen in nosocomial infections.
  • Practitioners need to be aware that these reports[15,16] came to diametrically opposed conclusions. Practice justified by one study needs to be balanced by consideration of the other.
  • Infection control of MRSA and other resistant pathogens is critically important to clinicians, health systems, payers, and patients, as nicely pointed out by Platt[19] in his editorial accompanying these conflicting studies in The New England Journal of Medicine.
  • We need to be cautious about the "bundle" that looks good in terms of scientific methods. Either study, considered on its own, could drive decisions and have a massive impact on practice, with tremendous allocation of resources and no clinical benefit. This emphasizes the need for fastidious attention to study design and, possibly, the need for 2 multicenter trials.

    Rapid Microbial Detection

  • In a study by Bauer and colleagues,[20] molecular techniques were used to rapidly detect MRSA in blood cultures. The outcomes of management of S aureus bacteremia in 2008, predating the use of polymerase chain reaction (PCR) technology at this hospital, were compared with those in 2009, after PCR was implemented. The results are summarized in Table 2, which indicates incredible differences in length of stay and cost.

    Table 2. Rapid Detection of MRSA in Blood Cultures

    Variable Before PCR After PCR Difference
    Length of stay (median) 22 days 15 days -6.2 days
    Cost (mean) $69,737 $48,350 -$21,387
    Data from Harbath et al.[18]
  • Why Is This a Game Changer?

    In most clinical labs, microbiology is performed the way Louis Pasteur did it in 1850. Specimens are cultured on seaweed and incubated and, 24-48 hours later, whatever has grown is identified. This system seems primitive compared with the modern chemistry laboratory. Chemistry methods are fast, smart, simple, and highly accurate compared with previous methods that were time consuming, complicated, or simply not available.

    The introduction of molecular methods for microbial detection represents a quantum leap into the 21st century, having bypassed the 20th century almost completely. Perhaps the best example of use of this technology is the rapid detection of Mycobacterium tuberculosis, which permits conclusions about diagnosis and treatment of tuberculosis (the second most common infectious disease cause of death on earth) in less than 2 hours compared with standard techniques that generally require 4-6 weeks.[21]

    In their editorial comment, Small and Pai rightfully referred to rapid detection technology as a "game changer."[22] I selected the Ohio State report because it is probably more relevant to Medscape readers and represents the rational use of this technology in daily practice. Nevertheless, it should be acknowledged that hundreds of similar reports deal with the sudden surge of new opportunities for microbial detection. More importantly, rapid detection promotes optimal antibiotic use in the face of concerns about resistance, abuse, toxicity, and cost.

  • What Does This Mean to the Practitioner?

    PCR technology can be applied to virtually all living microbes, but caution is needed because the methods are incredibly sensitive and specific, to their advantage as well as their disadvantage. Detection of S pneumoniae is useful in the diagnosis of pneumococcal pneumonia if it is from a normally sterile source (empyema or blood), but it is not useful in sputum except to exclude this pathogen or unless quantitation is used. The problem is the high rate of asymptomatic carriage and false positive results.[23]

    This technology is readily available for rapid detection of most respiratory tract viral pathogens, but we are now learning that about 15% of healthy adults harbor a respiratory viral pathogen (but not influenza) despite apparent good health.[24] Thus, particular attention needs to be paid to the recovered pathogen, the specimen source, and the "background noise." Examples of optimal use of rapid detection technology are ocular specimens for detecting Herpes simplex, Chlamydia trachomatis, Varicellazoster, Acanthamoeba, and Toxoplasma[25] and respiratory specimens for the detection of pathogens that should never be present in the airways, such as Legionella, C pneumoniae, tuberculosis, influenza, or M pneumoniae. [23]

  • Point-of-Care Test for Hepatitis C

    Point-of-care testing for hepatitis C is a newly developed rapid test that can be performed in a clinic, emergency department, church, or home without the need for a lab technician or machine, providing results in 20 minutes. This test was compared with standard laboratory methods (enzyme immunoassay, recombinant immunoblot assay, and PCR) to determine sensitivity and specificity. Specimens were obtained from 2206 volunteers who were considered at risk for HCV infection and had a 34% positive rate with the standard test.

    The results indicate that any of the following specimens could be used: serum, plasma, fingerstick blood, venipuncture, or saliva. Results compared with the standard alternative tests were 99.7%-99.9% for sensitivity and 99.6%-99.9% for specificity. The exception was a slight decrease in sensitivity with saliva, which showed 98.1% sensitivity and 99.6% specificity. The investigators concluded that this technique shows performance results comparable to standardized tests and consequently should be considered adequate for FDA approval.[26]

  • Why Is This a Game Changer?

  • Identifying people with hepatitis C infection is of great importance; a challenge comparable to that of HIV detection in the sense that many are not aware that they are infected. Treatment of both conditions would result in substantial health benefits to the individual and also important public health benefits in reducing or eliminating the risk for transmission to other individuals. The challenge of finding patients with HIV is likely to be repeated for HCV. The rapid test for HIV has revolutionized the disease in most of the world, and the report card after several years of experience shows that the rapid test for HIV read by minimally trained personnel is nearly flawless.
  • This report calls attention to the potential benefits of point-of-care testing in the 21st century, as the laboratory has become increasingly distant from the bed or the clinic. With point-of-care testing, the results are available on site, usually within 20 minutes, and performance characteristics are close to or equal to those of conventional testing. Of importance, the preliminary results or definitive diagnosis can be made while the patient is in the clinic or the emergency department.
  • Point-of-care testing has evolved rapidly, with emphasis on the ASSURED criteria, which stands for Affordable, Sensitive, Specific, User-friendly (minimal training requirement), Rapid (< 20 minutes), Equipment (no expensive equipment) and Delivered (FDA-cleared).[27]
What Does This Mean to the Practitioner?
  • Who can do these tests? It depends on the Clinical Laboratory Improvement Amendments (CLIA) waiver, an FDA decision. If the test (such as the rapid HIV test) is CLIA-waived, a person working in your clinic or emergency room could be certified by the laboratory director as "CLIA certified," permitting this person to interpret the test at the site of care with no requirement for specimen transport to the laboratory. CLIA-waived tests have the potential advantage of 24-hour service. In general, the only skill needed to perform these tests is the ability to recognize a red line. Point-of-care molecular tests may be more expensive and require a licensed laboratory technician.
  • A concern about point-of-care tests is that because they are not conducted in the laboratory, the results either do not get into the medical record system; or if they do, they are typically not included with other laboratory test results so they may be difficult to find.
  • Point-of-care tests are defined by the short time required for results -- usually within 1-2 hours.
  • The ultimate goal is for these tests to be available commercially to consumers and sold in drugstores to facilitate self diagnosis, improve disease detection, and reduce cost.
  • Particularly attractive has been the use of these tests for detection of sexually transmitted infections in adolescents who have reservations about addressing these concerns to parents or medical providers and have established a strong track record for self diagnosis using this technology.[28] It is likely that physicians in the near future will encounter more patients who present with either preliminary or definitive test results. Healthcare professionals will worry about quality assurance with self testing by consumers, but it certainly has worked well with pregnancy tests, and the initial testing for sexually transmitted infections is very promising.

    Measles Outbreak

  • In 2008 a traveler from Switzerland visited a hospital in Tucson, Arizona and subsequently became the source of 14 cases of healthcare-associated measles.[29] Half of these patients were over the age of 18 years, 4 were hospitalized, 7 acquired measles in the healthcare setting, and none had evidence of measles vaccination. Two hospitals were involved, and the total cost of the evaluation was $799,136.

    Serologic testing of the potentially exposed healthcare personnel indicated that measles immunity was lacking in 1776 of 7195 (25%) tested individuals. Most of the costs were for contact tracing, a measles vaccine program for healthcare workers in 7 community hospitals, and a total of 15,120 hours lost in healthcare worker furloughs. The evaluation involved 8231 contact investigations, including 6470 (79%) investigations for contact with the index case, largely as a result of delayed diagnosis. The result was a mean cost per case of $105,347 in one hospital and $167,052 in the second hospital.

    This report documents the health and economic consequences of measles, one of the most important yet largely eliminated pediatric infectious diseases (measles, pertussis, and mumps). These conditions, once believed to be conquered, are now being encountered by physicians, many of whom have never before seen these diseases. Measles is the most contagious of all infections and can be fatal.[30]

    The history of measles eradication began with the single-dose vaccine in 1963, followed by the double-dose measles, mumps, and rubella vaccine in 1989. Elimination of the disease was declared in the United States in 2000.[30] All of the cases in this report were persons who were unvaccinated or had no verification of vaccination. It is unknown how many had actually been vaccinated, but 25% of the healthcare workers sampled had no evidence of measles immunity. This could indicate either lack of vaccine or vaccination with waning immunity.

  • Why Is This a Game Changer?

    The measles cases nicely illustrate the challenge of what we are now encountering in the form of pediatric preventable diseases. The issue of vaccine preventable diseases has also extended to painful lessons with pertussis and mumps. During 2010, 9477 cases of pertussis were reported in California, including 10 infant deaths.[31] This is the most cases of pertussis reported in the last 65 years and has prompted a new California law that requires a booster vaccine for pertussis, tetanus, and diphtheria for all students in grades 7-12. Michigan reported 902 cases of pertussis in 2009, and 964 pertussis cases were reported in Ohio.[28] The same scenario has been seen with mumps, with a surge of cases following late recognition of the index case -- a boy who had visited the United Kingdom in 2009.[32]

    The infamous Wakefield report in The Lancet has now been retracted as a result of well-recognized flaws in reporting and conflicts of interest, but the damage persists.[33] Among the 14 victims of measles in Arizona, none had evidence of vaccination, and this is an increasing concern with both mumps and pertussis. The problem is achievement of sufficient vaccination for herd immunity, which should be successful based on experience with smallpox and H influenzae type B. The current problem is sizeable in terms of numbers of unvaccinated individuals[29] and magnified by the potential vulnerability of those who have been vaccinated but have lost immunity due to immunosuppression, aging, etc.

    Some have opined that individual rights preclude mandated vaccinations without considering the associated societal risks. Mandatory influenza vaccination for healthcare workers illustrates this point.[34] Some pediatricians are now rejecting care of pediatric patients whose parents refuse routine childhood vaccinations.

    This article by Chen was cited because of the importance of recognizing pediatric infectious diseases and to highlight an important ethical debate that pits individual rights vs societal health benefits.

  • What Does This Mean to the Practitioner?

  • Concern is high for vulnerable individuals who have not been vaccinated, or whose immunity is waning or lost, resulting in a reduction in herd immunity. One of the major challenges is early recognition to prevent the very extraordinary and expensive requirement for epidemiologic investigation, which expands exponentially with delayed diagnosis.
  • The standard case definition of measles is: fever (over 38.3ºC), a characteristic generalized maculopapular rash lasting more than 3 days, cough, coryza, and/or conjunctivitis. A patient with these symptoms needs prompt isolation and diagnostic testing.

    Vancomycin Guidelines

  • This paper violates my rule that guidelines should never be selected as the most important publications, owing to the lack of originality, but the article by Rybak and colleagues[35] is included because:

  • Vancomycin is the most frequently prescribed antibiotic in US hospitals[36];
  • The guidelines recommend a significant change in the way we use the drug[35]; and
  • The entire guideline is 3 pages in length.[35]

According to antibacterial claims data for 22 university hospitals from 2000-2006, vancomycin is the most frequently used antibiotic,[36] becoming number 1 in 2004. More recent data are not available, although those who practice contemporary medicine will not be surprised at this ranking.

The new guidelines represent concerns about serum drug levels achieved with the previously standard dose of 1 g of vancomycin, administered intravenously, twice daily.[35] Controversies about this agent touch on some very fundamental issues, which is surprising considering that we have had this drug for more than 50 years. New concerns include: definition of resistance, questions of potency, probable need for higher trough levels, and rebirth of concerns about nephrotoxicity.

In 2006, the recommendation was made to reduce the breakpoint that defines MRSA susceptibility from 4 mg/L to 2 mg/L, based on a 60% clinical failure rate for infections involving strains with a minimum inhibitory concentration (MIC) value of 4 mg/L. More recently, concern has been expressed about increasing resistance at 2 mg/L and the need to establish an area under the serum drug concentration/time curve to MIC (AUC/MIC) ratio of 400, based on the pharmacokinetic-pharmacodynamic requirements of the drug.[37]

Why Is This a Game Changer?

Simply stated, vancomycin requires a high trough level. Thus, the new recommendations for serious infectionsinvolving S aureus include dosing to reach trough concentrations of 15-20 µg/mL, which, based on tests of more than 400 for strains with MIC ≤ 1 mg/L, should achieve the target AUC/MIC. However, this will not be achieved if the MIC is 2 mg/L, leading to the paradoxical suggestion that strains with a MIC of 2 mg/L (which account for 20%-30% of MRSA in many hospitals[38]) are sensitive by lab definition. Strains with this sensitivity should not be treated with vancomycin.[37,39]

The toxicity of vancomycin has always been controversial. In 1960, the initial form of vancomycin was brown in color and often referred to as "Mississippi mud."[40] Vancomycin was subsequently purified by the manufacturer and not believed to be nephrotoxic in animals or man. A statement in the new guidelines warns that "vancomycin nephrotoxicity should be considered if the serum creatinine concentration increases by 0.5 mg/dL or more than 50% above baseline."[35] Of note, in the same issue of Clinical Infectious Diseases is a sophisticated analysis of the vancomycin concentration-time profile, indicating that the target serum level of 15-20 mg/L resulted in nephrotoxicity in 20% of patients![41]

Another potentially important report[42] suggested that the available generic products of vancomycin often failed to show in vivo activity in a mouse model of a MRSA thigh infection. The implication is that generic forms of the drug may vary in potency and toxicity possibly as a result of variations in purity. Most pharmacies purchase vancomycin on the basis of price and not purity.

What Does This Mean to the Practitioner?

One of our oldest and most revered antibiotics is under the microscope with respect to adequacy for its main target -- MRSA. The recent developments include an entirely new dose recommendation and the paradoxical message that an MIC of 2 mg/L will mean that the lab will report sensitivity but we should use an alternative drug. The need for an alternative agent for serious infections involving MRSA with an MIC of 2 mg/L was shown clinically in a study of ventilator-associated pneumonia where mortality was directly correlated with the MRSA MIC.[43]

Furthermore, although the assumption is that generic forms of vancomycin are therapeutically equivalent, pharmacy decisions driven by cost may result in a suboptimal product. The poor clinical outcomes associated with MRSA infections involving strains with relatively high vancomycin MICs may simply reflect increased virulence,[44] but concerns for potency of generic vancomycin are under review. Vancomycin has been used for 60 years, it is the most frequently ordered antibiotic in US hospitals, and we still do not seem to know much about it.

Pandemic Influenza

Following the first major report of the 2009-2010[45] pandemic influenza, influenza will never be the same. The report included a detailed account of 18 relatively young patients from a total of 98 patients with laboratory-confirmed influenza who were hospitalized at the National Tertiary Hospital for Respiratory Illnesses in Mexico City. Of these 18 patients, 12 required mechanical ventilation and 7 died. Subsequent events led to a massive scientific attack on influenza, substantial changes in our understanding of the disease, policies in dealing with influenza epidemics, changes in public health policy, and new recommendations for management.

Why Is This a Game Changer?

  • This epidemic was humbling; it was declared a pandemic, but no one seemed to be able to define "pandemic."[46] Perhaps more important is that no one saw it coming. The expectation of a pandemic was correct, but it was supposed to come from Asia where we have the surveillance system set up. It was expected to involve a new strain of influenza (such as H5N1) and to be highly lethal. Instead it came from Mexico, involved the oldest strain of influenza (H1N1), and had low mortality.
  • We rapidly learned that our vaccine production supply was not very efficient and this led to an ambitious attempt to improve the product and reduce the time required for delivery using alternative systems.[46]
  • Urgency for diagnostic testing coincided with the surge in technology for point-of-care testing and molecular diagnostics, and both were applied to influenza with fervor. The point-of-care test proved to be quite successful in specificity but was relatively poor in sensitivity; in fact, clinical judgment seemed to be superior to the available point-of-care test.[47] Molecular PCR testing requires 1-2 hours and, compared with culture, actually emerged as the gold standard for diagnosis. The main disadvantages are the need for laboratory technicians and cost.
  • The attention on this pandemic prompted multiple historic reviews of previous pandemics including the 1918-1919 pandemic that exceeded all others in terms of global morbidity and mortality. Influenza pundits engaged in a continuous debate over the major cause of death in that pandemic; was it bacterial superinfection (which would be less problematic in the antibiotic era), or was it simply viral pneumonia? Ambitious gumshoe detective work with historic reports and autopsy studies determined that the major cause of death was bacterial infection with the following pathogens: S pneumoniae, N meningitidis, H influenzae type B, S aureus, and group A streptococci.[48] Translated to the 2011 experience, the major bacterial superinfecting pathogens were S pneumoniae, group A streptococci, and S aureus, which proved prophetic in the subsequent CDC review.[49]
  • A raging debate arose over the requirements for masks by healthcare workers. The CDC and Institute of Medicine recommended the N95 mask.[50] This was bad news because the N95 masks required fitting, were relatively expensive, were in short supply, and were uncomfortable to wear because of difficulty breathing through them. The definitive study was finally conducted showing that surgical masks were equally good, and this made the N95 masks almost totally antiquated except for special procedures such as bronchoscopy.[51]
  • The issue of mandatory healthcare worker vaccination came to a head during the 2009 influenza pandemic. The review of the record indicated successful vaccination in only about 62% of healthcare workers in the United States.[52] However, the momentum for mandatory use of the vaccine came from proven benefit, vaccine safety, ethical principles, and legal precedent.[53,54]
  • Influenza vaccine recommendations from the CDC had a history of increasing inclusions, on the basis of risk, that seemed to continually expand the targeted population until the 2009 pandemic when the Advisory Committee on Immunization Practices finally went all the way and recommended the vaccine for all persons over the age of 6 months.[55]
What Does This Mean to the Practitioner?

Oseltamivir and zanamivir remain the only anti-influenza drugs that are generally recommended, and oseltamivir seems to have the decided edge because of its oral delivery system. We have all learned that the window of opportunity for impact on disease course is during the first 48 hours, but the more recent guidelines, based largely on the 2009 pandemic experience, are much more aggressive. Although early treatment is urged, patients who are seriously ill with influenza or at high risk for serious illness (chronic heart, lung, renal, neurologic, or liver disease) should be treated on the basis of clinical observation. The recommendation is to use this agent regardless of the duration of symptoms.[56]

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