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May 2015 FAQs

Questions

What evidence supports the efficacy of the new antibiotic, ceftazidime/avibactam (Avycaz)?

What should healthcare providers know about the recent measles outbreak in the United States?

What are the current recommendations for managing patients initiating non-VKA oral anticoagulants (NOACs) after receiving thrombolytic therapies for pulmonary embolism?

Answers

What evidence supports the efficacy of the new antibiotic, ceftazidime/avibactam (Avycaz)?

Introduction

Resistance to antibacterial drugs is a global problem that poses a great threat to patient health.1 In addition to antimicrobial stewardship efforts, the development of novel antibacterial drugs is necessary to address this problem and preserve the efficacy of currently available antibiotics. Several common pathogens, such as Staphylococcus aureus, Enterococcus faecium, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, andEnterobacter species, have developed resistance mechanisms that are particularly difficult to treat. Escherichia coli, K pneumoniae, P aeruginosa, A baumannii, and Enterobacter species are capable of expressing extended spectrum beta-lactamases (ESBLs), a resistance mechanism that can inactivate third- and fourth-generation cephalosporins.2 Recently, the development of avibactam, a novel beta-lactamase inhibitor, has introduced a new way to combat ESBL inactivation of ceftazidime in the form of a ceftazidime/avibactam (CAZ-AVI) combination product.

CAZ-AVI was given priority Food and Drug Administration (FDA) review due to its designation as a Qualified Infectious Disease Product (QIDP).3,4 In February 2015, CAZ-AVI was approved for the treatment of complicated intra-abdominal infections (cIAI) in combination with metronidazole, and for complicated urinary tract infections (cUTI), including pyelonephritis, in patients 18 years or older with infections caused by susceptible organisms. 3,5 Approval of avibactam in combination with ceftazidime was based on in vitro and animal studies, Phase I data, and 2 Phase II studies in humans.3 Preliminary data from 2 Phase III trials was also available during the FDA review process. Due to the expedited approval process, a limited use statement was added to the labeling to indicate that this drug is only intended for use when other therapeutic alternatives are not available. 3

Characteristics of ceftazidime/avibactam

Ceftazidime is a third-generation cephalosporin.2 Avibactam is a non-β-lactam beta-lactamase inhibitor with no direct antibacterial activity.3,6 The combination product is designed to expand the activity of ceftazidime in the presence of ESBL-producing gram-negative bacilli.2,6 Table 1 provides a summary of the spectrum of activity of CAZ-AVI.6

Table 1. Spectrum of activity of ceftazidime/avibactam.6

cIAI

cUTI

Escherichia coli

Klebsiella pneumoniae

Proteus mirabilis

Providencia stuartii

Enterobacter cloacae

Kelbsiella oxytoca

Pseudomonas aeruginosa

Escherichia coli

Klebsiella pneumoniae

Citrobacter koseri

Enterobacter aerogenes

Enterobacter cloacae

Citrobacter freundii

Proteus species

Pseudomonas aeruginosa

cIAI=complicated intra-abdominal infection; cUTI=complicated urinary tract infection.

CAZ-AVI appears to have linear kinetics and does not accumulate in healthy adults.6 It is <10% protein bound, and is eliminated mostly in the urine as unchanged drug. Time above the minimum inhibitory concentration (MIC) best correlates with efficacy of CAZ-AVI. The dose of CAZ-AVI is 2.5 g (ceftazidime 2 g/avibactam 0.5 g) intravenously (IV) every 8 hours for 5 to 14 days in cIAI, and 2.5 g IV every 8 hours for 7 to 14 days in cUTI and pyelonephritis. Manufacturer-recommended dosing for different levels of renal impairment appears to be based on population pharmacokinetic modeling data.3 Dosing in patients with hepatic impairment has not been established.6 Adverse effects of CAZ-AVI include hypersensitivity,Clostridium difficile diarrhea, and central nervous system (CNS) reactions including seizures, encephalopathy, coma, asterixis, and myoclonia. Central nervous system reactions have been reported with ceftazidime use, with the highest rates in patients with underlying renal impairment.

Published Phase II studies with ceftazidime/avibactam

Complicated intra-abdominal infection

Lucasti et al conducted a Phase II, prospective, randomized, multicenter, double-blind, active-controlled trial in patients with cIAI.7 Patients were included if cIAI required surgical intervention and antibiotics, and if the presumed diagnosis was confirmed with surgical intervention within 24 hours. Eligible patients had a perforation or abscess along the gastrointestinal tract, or secondary peritonitis that was not associated with cirrhosis or chronic ascites. Patients with abdominal wall abscess, bowel obstruction, antibiotics within 72 hours (unless unsuccessful or if the duration was <24 hours), concurrent infections that might interfere with the evaluation of response to study drugs, pathogens resistant to study drugs, creatinine clearance (CrCl) <50 mL/min, or other factors suggesting poor prognosis were excluded. Patients were randomized 1:1 to either ceftazidime 2 g/avibactam 0.5 g IV every 8 hours over 30 minutes plus metronidazole 500 mg IV every 8 hours over 1 hour, or meropenem 1 g IV every 8 hours (duration of infusion not specified) plus placebo IV every 8 hours over 1 hour for 5 to 14 days. Concomitant antibiotics were not permitted except for vancomycin, linezolid, and daptomycin for suspected or documented infections caused by methicillin resistant Staphylococcus aureus (MRSA) or Enterococcus species.

There were 101 patients in CAZ-AVI plus metronidazole group, and 102 patients in the meropenem group.7 The majority of patients in both groups were male, and the mean patient age was about 43 years. Approximately 47% of patients had primary infection at the site of the appendix, followed by approximately 26% of patients having primary infection at the site of stomach or duodenum. Polymicrobial infections were present in 41.2% of the CAZ-AVI plus metronidazole group and 35.5% of the meropenem group. E coli was the most common pathogen isolated in both groups and all isolates were susceptible to the study drugs. Median treatment durations were 6 days with CAZ-AVI plus metronidazole and 6.5 days with meropenem. The major clinical outcomes and results for the microbiologically evaluable (ME) population are described in Table 2. Results in the ME population were similar to results in the clinically evaluable population, the microbiological modified intent to treat population (mMITT), and the safety population. Among patients who received at least 1 dose of study drug, adverse events were reported in 64.4% of the CAZ-AVI plus metronidazole group, and 57.8% of the meropenem group. The most common adverse events were vomiting, fever, and hepatic transaminase elevation, with a generally similar frequency between treatment arms. Most adverse events were of mild/moderate intensity. Serious adverse events occurred in 8.9% and 10.8% of the CAZ-AVI plus metronidazole and meropenem groups, respectively; only 1 event (in the CAZ-AVI plus metronidazole group) was considered related to the study drug. One serious adverse event led to drug discontinuation in the CAZ-AVI plus metronidazole group. The patient reportedly had elevated liver function tests and septic shock.3,7 Three and 2 patients died in the CAZ-AVI plus metronidazole and meropenem groups, respectively.7

Table 2. Outcomes in the microbiologically evaluable cIAI population a.7

CAZ-AVI + metronidazole

(n=68)

Meropenem

(n=76)

Difference

(95% CI)

Clinical responseb, n (%)

Primary outcome

TOC visitc

Secondary outcome

End of IV therapy

62 (91.2)

66 (97.1)

71 (93.4)

74 (97.4)

-2.2% (-20.4% to 12.2%)

-0.3% (-17.1% to 15.4%)

Overall microbiological responsed, n (%)

62 (91.2%)

71 (93.4%)

-

Microbiological responsed among ceftazidime-intermediate or resistant Gram-negative isolates, n (%)

25/26 (96.2)

16/17 (94.1)

-

Abbreviations: CAZ-AVI=ceftazidime/avibactam; CI=confidence interval; cIAI=complicated intra-abdominal infection; IV=intravenous; TOC=test of cure.

Patients with confirmed cIAI who received 80% to 120% of the scheduled study drug, had sufficient information to determine clinical outcome at the TOC visit, and had ≥1 pathogen that was susceptible to both study interventions on initial culture.

Favorable clinical response was defined as complete resolution or significant improvement of signs and symptoms of infections and no requirement for additional antibiotics or surgery.

Test of cure visit occurred 2 weeks after the last dose of study drug.

Microbiological response was defined as eradication of the baseline pathogen at the TOC visit.

The investigators concluded that outcomes in the CAZ-AVI plus metronidazole group were comparable to those in the meropenem group with similar safety/tolerability findings.7 The microbiological response in ceftazidime non-susceptible (CAZ-NS) pathogens was promising. Although the number of patients with K pneumoniae (n=3 per group) and P aeruginosa (n=1 per group) were small, all patients with infections due to these organisms achieved microbiological response with both study regimens.

Complicated urinary tract infection

Vazquez et al conducted a Phase II, prospective, multicenter, double-blind, randomized, comparative study with CAZ-AVI.8 Patients with either acute pyelonephritis or cUTI due to a gram-negative organism that required parenteral therapy were eligible for inclusion. Patients infected with a uropathogen that was resistant to either study dug, who received more than one dose of a potentially effective systemic antibiotic within 48 hours prior to or after urine culture, had abnormalities of the genitourinary tract or a permanent indwelling catheter or instrumentation unless removed within 48 hours of study entry, or with CrCl <70 mL/min were excluded.6 Patients were randomized 1:1 to treatment with ceftazidime 500 mg/avibactam 125 mg IV every 8 hours over 30 minutes or imipenem/cilastatin 500 mg IV every 6 hours over 30 minutes.8 Patients who improved clinically after at least 4 days of study treatment could switch to ciprofloxacin 500 mg orally twice daily. The total treatment duration was 7 to 14 days. Criteria for clinical improvement were prespecified.

There were 69 patients randomized to the CAZ-AVI group, and 68 patients randomized to the imipenem-cilastatin group.8 The average age was approximately 47 years, and the majority of patients were female. The primary diagnosis was acute pyelonephritis in approximately 63% of patients in both groups. E coli was the most common pathogen isolated in both groups and all isolates were susceptible to imipenem-cilastatin; 20 E coli isolates were resistant to ceftazidime. The median duration of IV plus oral therapy was 11 days in the CAZ-AVI group and 12 days in the imipenem-cilastatin group. The major clinical outcomes and results for the ME population are summarized in Table 3. Microbiological response rates in the ME population were similar when patients were stratified by primary diagnosis and baseline pathogen. Results in the ME population were similar to results in the clinically evaluable population and the modified intent to treat population. Among patients who received at least 1 dose of study medication, adverse events were reported in 67.6% of the CAZ-AVI population and 76.1% of the imipenem-cilastatin population. The most common drug-related adverse events were headache and injection/infusion site reaction, which were both more frequent with imipenem-cilastatin. Drug-related abdominal pain and constipation were more common with CAZ-AVI. Serious adverse events occurred in 8.8% and 3% of the CAZ-AVI and imipenem-cilastatin groups, respectively. Serious adverse events related to the study drug included renal failure, diarrhea, and accidental overdose in the CAZ-AVI group (n=3 patients) and increased serum creatinine in the imipenem-cilastatin group (n=1 patient).

Table 3. Outcomes in the microbiologically evaluable cUTI population a.8

CAZ-AVI

(n=27)

Imipenem-cilastatin

(n=35)

Difference

(95% CI)

Microbiological responseb n (%)

Primary outcome

TOC visitc

Secondary outcomes

End of IV therapy

Late follow-upd

19 (70.4)

25/26 (96.2)

15/26 (57.7)

25 (71.4)

34/34 (100)

18/30 (60.0)

-1.1% (-27.2% to 25.0%)

-

-

Microbiological responseb at the TOC visit among ceftazidime-resistant uropathogense, n (%)

6/7 (85.7)

9/11 (81.8)

-

Abbreviations: CAZ-AVI=ceftazidime/avibactam; CI=confidence interval; cUTI=complicated urinary tract infection; IV=intravenous; TOC=test of cure.

Patients with no major protocol violations, positive urine culture on enrollment with at least 1 uropathogen susceptible to study antibiotics, a complete assessment at the TOC visit, and either received at least 7 days of study medication or failed treatment after completing at least 48 hours of IV therapy.

Favorable microbiological response was defined as eradication of all uropathogens.

Test of cure visit occurred 5 to 9 days after the last dose of study drug.

Late follow-up occurred 4 to 6 weeks post-therapy.

Total 17 E coli isolates (n=7 CAZ-AVI, n=10 imipenem-cilastatin) and 1 E cloacae isolate (imipenem-cilastatin).

The authors concluded that CAZ-AVI may have similar efficacy to imipenem-cilastatin for treatment of cUTI in adults with good safety/tolerability. 8 Patients with CAZ-NS pathogens had a favorable microbiological response with both study medications.

Strengths and limitations

The comparator treatments used in both studies are highly efficacious and commonly used in clinical practice for these infection types.9-11 Clinical and microbiological endpoints are meaningful to patients and providers, and efficacy was measured at multiple time points after the end of treatment to increase certainty that the infections had truly resolved. Culture data was available for many patients, which contributes information about the activity of CAZ-AVI against various pathogens, particularly those that are ceftazidime-intermediate or resistant. The number of patients included in the studies was small, which may limit external validity and raises concern for the possibility of Type II error.

The dose of CAZ-AVI in the cUTI study and the infusion duration in both studies are different from the FDA-approved dosing for CAZ-AVI.6-8 This generates questions regarding how the labeled 2-hour infusion time was determined.6 The results of these studies cannot be applied to patients with renal impairment, which limits external validity.7,8 Another limitation is the absence of K pneumoniae in the cUTI study because this pathogen accounts for 8% to 12% of uropathogens in America and Europe.8 Adjustments to therapy based on culture and sensitivity data were not part of the methodology of either study.7,8 In clinical practice, clinicians should narrow therapy if appropriate based on culture and sensitivity information.9-11

Unpublished Phase III studies with ceftazidime/avibactam

Preliminary information from a Phase III, randomized, multicenter, double-blind, noninferiority study in patients with cIAI was also available to the FDA during the approval process.3,12 The preliminary results in an mMITT population for patients with CrCl >50 mL/min demonstrated clinical cure at a test of cure visit in 85% (322/379) of patients in the CAZ-AVI 2 g/500 mg every 8 hours plus metronidazole 500 mg every 8 hours group, and in 86% (321/373) of patients in the meropenem 1 g every 8 hours group.3,6 These results were not consistent in patients with CrCl between 30 and 50 mL/min; clinical cure was seen in 45% (14/31) of patients and 74% (26/35) of patients in the CAZ-AVI plus metronidazole and meropenem groups, respectively. In the population with renal impairment (CrCl 30 to 50 mL/min), mortality was higher in the CAZ-AVI plus metronidazole group compared to meropenem (8/31 [25.8%] vs 3/35 [8.6%], respectively). Mortality among patients with no or mild renal impairment was 1.0% in both groups.6 The difference in deaths between groups in patients with renal impairment was attributed to a lack of response when death occurred prior to outcome assessment; however, it is possible that patients with renal impairment in this study may have been underexposed to study drug.3

Additionally, interim data from a pooled analysis study of CAZ-NS pathogens was available prior to approval.3,12 This is an ongoing Phase III, international, multicenter, randomized, open-label study in adults with cUTI and cIAI caused by CAZ-NS Gram-negative pathogens.3Patients were randomized to ceftazidime 2 g/avibactam 500 mg IV every 8 hours over 2 hours or best available therapy, consisting of a carbapenem alone or in combination with colistin or ciprofloxacin. At the interim analysis, clinical cure rates in patients with CAZ-NS pathogens were higher with CAZ-AVI than with the comparators but the observed differences were not statistically significant. There were numerically higher (but statistically similar) clinical cure rates with comparators than CAZ-AVI among ceftazidime-susceptible strains.

Conclusions

Several Phase III studies with CAZ-AVI have been completed, and 1 study is currently ongoing.3,12 The results of these Phase III studies will continue to elucidate the efficacy and safety of CAZ-AVI in the treatment of cIAI, cUTI, nosocomial pneumonia, ventilator associated pneumonia, and in CAZ-NS organisms. Based on the Phase II studies in cIAI and cUTI, CAZ-AVI appears effective and safe in patients with normal renal function.7,8 There is concern about appropriate dosing of CAZ-AVI in patients with any degree of renal impairment, as the preliminary Phase III data in patients with cIAI showed a lower clinical cure rate and increased death in the CAZ-AVI plus metronidazole group compared to the studied carbapenems.3,6The FDA-approved dose for CrCl 31 to 50 mL/min was increased by 33% compared to the dose used in the Phase III cIAI study due to the possibility of patients in that study being underexposed to the medication; however, it is not clear whether the higher dose in the product labeling has been clinically evaluated. If use of CAZ-AVI is warranted before the Phase III studies are published, it should be used within the scope of the FDA-labeled indications when the infecting organisms are strongly suspected to be susceptible.

References

1. The 10 x ’20 initiative: pursuing a global commitment to develop 10 new antibacterial drugs by 2020. Clin Infect Dis. 2010;50(8):1081-1083.

2. Craig WA, Andes DR. Cephalosporins. In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 8th ed. Philadelphia, PA: Elsevier Saunders; 2015. https://www.clinicalkey.com/#!/content/book/3-s2.0-B978145574801300326X . Accessed March 5, 2015.

3. Briefing Package NDA 206494; Ceftazidime-Avibactam; Applicant: Cerexa, Inc. US Food and Drug Administration.http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM425458.pdf . Updated December 5, 2014. Accessed March 6, 2015.

4. US Food and Drug Administration. New FDA task force will support innovation in antibacterial drug development.http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm320643.htm . Updated September 24, 2012. Accessed March 4, 2015.

5. US Food and Drug Administration. FDA approves new antibacterial drug Avycaz.http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm435629.htm. Updated February 25, 2015. Accessed March 4, 2015.

6. Avycaz [package insert]. Cincinnati, OH: Forest Pharmaceuticals, Inc.; 2015.

7. Lucasti C, Popescu I, Ramesh MK, Lipka J, Sable C. Comparative study of the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infections in hospitalized adults: results of a randomized, double-blind, Phase II trial. J Antimicrob Chemother. 2013;68(5):1183-1192.

8. Vazquez JA, Gonzalez Patzan LD, Stricklin D, et al. Efficacy and safety of ceftazidime-avibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator-blinded, randomized study. Curr Med Res Opin. 2012;28(12):1921-1931.

9. Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(2):133-164.

10. Hooton TM, Bradley SF, Cardenas DD, et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(5):625-663.

11. Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society of Microbiology and Infectious Diseases. Clin Infect Dis. 2011;52(5):e103-e120.

12. US National Institutes of Health. Clinicaltrials.gov website.https://clinicaltrials.gov/ct2/results?term=ceftazidime+AND+avibactam&Search=Search . Updated March 9, 2015. Accessed March 9, 2015.

Prepared by:

Alexandra Riskus, PharmD Candidate

May 2015

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What should healthcare providers know about the recent measles outbreak in the United States?

Current Measles Outbreak

On January 5, 2015, the California Department of Public Health (CDPH) was notified about an 11-year-old patient hospitalized with a rash onset on December 28, 2014 suspected to have measles.1 The patient’s only notable travel history was a recent trip to a Disney theme park. That same day, the CDPH received reports of 4 additional suspected measles cases from patients who had visited the theme park December 17 to 20, 2014. It is suspected that the recent outbreak of measles in the United States originated from this California amusement park. From January 1 to February 27, 2015, 170 people from 18 states were reported to have measles. Seventy-four percent of all cases have been linked to the California theme park.

History of the Measles Virus

Measles is a very contagious virus spread by coughing or sneezing with a secondary attack rate of >90% and a reproduction rate estimated between 12 to 18, meaning the average person with measles can infect up to 12 to 18 susceptible contacts.2,3 Before the measles vaccine, 500,000 cases of measles, 48,000 hospitalizations, 4,000 cases of encephalitis and 500 measles-related deaths were reported annually in the United States.2,4 The first live attenuated measles vaccine was licensed in 1963, and measles was declared eliminated from the United States in 2000.5,6 Global reductions in measles morbidity and mortality are considered significant public health achievements, and it is estimated that the measles vaccine saved 12.7 million lives during 2000 to 2008.The World Health Organization (WHO) has declared that measles eradication is feasible and is targeted for elimination in 5 WHO regions by 2020. Despite this, measles outbreaks continue to occur. In 2014, the United States experienced 23 measles outbreaks including a large outbreak of 383 cases.6 Last year had the greatest number of cases than any year in the last 2 decades. 5 The 2 major reasons for the resurgence of measles in the United States can be attributed to the transmission of the virus from other countries where measles is still endemic to the United States and an increase in the number of parents who refuse to vaccinate their children. The majority of current measles cases are in people who are not vaccinated against the virus.6

Pathophysiology

The measles virus is a single-stranded, enveloped ribonucleic (RNA) virus of the paramyxovirus family.6-8 Measles is transmitted by respiratory droplets over short distances.8The measles virus has a survival time of <2 hours in the air or on surfaces.The incubation period for measles is 10 days to the onset of fever and 14 days to the onset of rash. People are contagious 1 day before the onset of symptoms and up to 4 days after the rash appears.9In the days preceding the rash is when the concentrations of the measles virus in the blood and bodily fluids are the highest and when symptoms of cough and sneezing are most severe.8 This highlights how contagious the virus is even before the onset of recognizable disease features. During incubation, the virus replicates in the epithelial cells of the respiratory tract before spreading to regional lymph nodes and ultimately the blood and other organs.

Clinical Presentation

Presentation begins with a prodrome lasting 2 to 4 days characterized by fever (as high as 105°F), which increases in stepwise fashion, followed by malaise, cough, coryza, and conjunctivitis.6,7 Koplik spots is a term used to describe a characteristic rash present on mucous membranes. The rash is described as punctate blue-white spots on the buccal mucosa. Koplik spots occur 1 to 2 days before the measles rash and lasts 1 to 2 days afterwards. The characteristic maculopapular rash caused by measles lasts 5 to 6 days.6 The rash spreads from head to trunk to the lower extremities and then fades in the order of appearance.6,7 Patients who are immunocompromised may not develop the rash.In uncomplicated measles, recovery begins soon after the appearance of the rash.9

Complications

Complications can occur in up to 40% of patients and the risk for developing a complication increases in extremes of age and malnutrition.8 Case-fatality is highest in infants and young children. The most commonly reported complication of measles is diarrhea.7 Pneumonia is reported in 6% of cases and accounts for the majority of measles-associated deaths.7,8 The rarer, but serious, complications of measles involve the central nervous system (CNS). Acute encephalitis occurs 6 days after rash onset and is characterized by fever, headache, vomiting, stiff neck, meningeal irritation, drowsiness, convulsions, and coma.Encephalitis occurs in approximately 0.1% of cases and the case-fatality rate is 15%. 7,8 Subacute sclerosing panencephalitis (SSPE) is a condition caused by persistent measles viral infection. It occurs in about 1 in 100,000 patients and is characterized by seizures, progressive deterioration of cognitive and motor function, and eventually death. Measles infection during pregnancy results in an increased risk of premature labor, spontaneous abortion, and low-birth weight infants. Measles in immunocompromised patients may be more severe and prolonged.

Diagnosis

Measles should be suspected in patients presenting with hallmark symptoms of measles- like fever and generalized rash, especially if the patient has recently traveled outside of the United States or was exposed to a person with a febrile rash illness.6

The WHO clinical case definition for measles is a person with fever and maculopapular rash and cough, coryza or conjunctivitis.More commonly, serology is collected in suspected cases of measles. Specifically, serum immunoglobulin M (IgM) and immunoglobulin G (IgG) and samples of throat or nasopharyngeal swabs and blood should be collected for polymerase chain reaction (PCR) RNA testing.The Centers for Disease Control and Prevention (CDC) website contains a detailed protocol for the collection of specimens for viral isolation at: http://www.cdc.gov/measles/lab-tools/rt-pcr.html.

Treatment

Vitamin A is effective for the treatment of measles and can reduce morbidity and mortality.8WHO recommends Vitamin A 200,000 international units once daily for 2 consecutive days to all children >1 year of age who have measles. Lower doses are recommended for younger children: 100,000 international units once daily for ages 6 to 12 months and 50,000 international units per day for children younger than 6 months.

There is no antiviral therapy available for measles. Ribavirin, interferon alpha, and other antiviral drugs have been used for severe measles including infections of the CNS.

Prevention

The best way to prevent measles is with the measles vaccine.8 The measles vaccine is administered as a combination measles-mumps-rubella (MMR) vaccine.7 There is also a combination measles-mumps-rubella-varicella (MMRV) vaccine available to children >12 months to 12 years of age. There is no single-antigen measles vaccine available.

The MMR vaccine is approximately 95% effective at preventing measles.7 Approximately 2 to 5% of children who receive only 1 dose of MMR vaccine fail to respond. Causes of vaccine failure include development of passive antibody in the recipient, a damaged vaccine, incorrect records or other reasons. Most patients who do not respond to the first dose of MMR vaccine will respond to the second dose. Studies have shown serologic evidence of measles immunity is evident in >99% of people who receive 2 doses of the vaccine. This is reflected in the current measles vaccination schedule which requires 2 doses of the MMR vaccine, separated by at least 4 weeks, for all children 12 months of age and older. Although the second MMR dose may be administered as soon as 4 weeks after the initial dose, it is routinely given at 4 to 6 years of age before the child enters the school system. At 11 or 12 years of age, the patient’s vaccine status should be verified and the vaccine administered to those who have not yet received the recommended 2 doses.

The Food and Drug Administration (FDA) has approved a quadrivalent measles-mumps-rubella-varicella (MMRV) to be used in children 12 months to 12 years of age.Between 12 and 47 months, the first dose should be the separate MMR and varicella vaccines (unless the parent specifically requests the MMRV). Past 48 months of age, MMRV is preferred as the first dose. The second dose of MMR and varicella vaccine (separate) can be administered anytime between 15 months and 12 years of age.

It is recommended that during routine vaccination screening, healthcare professionals give strong recommendations for full immunization and remind their patients that refusal to get vaccinated not only affects them as individuals, but also their communities as a whole.The recommendations for measles vaccination for all patient groups are outlined in Table 1 below.

Table 1. Current Recommendations for Measles Vaccination6

Children

Routine immunization starting with the first dose at 12 to 15 months and the second dose at 4 to 6 years or at least 28 days after the first dose.

College Students

If no evidence of measles immunity, 2 doses of MMR vaccine with the second dose administered no earlier than 28 days after the first.

Adults

Born during or after 1957 without evidence of immunity against measles should get at least 1 dose of MMR vaccine.

International Travelers

1. Infants 6 to 11 months of age should receive 1 dose of MMR vaccine.

2. Children 12 months of age or older should have documentation of 2 doses of MMR vaccine (first dose at age 12 months or older; second dose no earlier than 28 days after the first).

3. Teenagers or adults born during or after 1957 without evidence of immunity should have documentation of 2 doses of MMR vaccine (second dose administered no earlier than 28 days after the first dose)

Healthcare personnel

Should have documented evidence of immunity.

Post-exposure Prophylaxis

Patients exposed to measles and who cannot show that they have evidence of immunity qualify for post-exposure prophylaxis (PEP).Two options for PEP are the MMR vaccine administered within 72 hours of exposure and immunoglobulin (IG) administered within 6 days of exposure.

MMR Vaccine as PEP

The MMR vaccine should be administered within 72 hours of initial measles exposure. If the vaccine is not administered within this window, it should still be offered at any interval following exposure to the disease in order to protect from future exposure.6 Administering the measles vaccine in infants as young as 6 months may be used as an outbreak control measure, but the patient will need to complete revaccination at 12 to 15 months and again at 4 to 6 years of age.

IG as PEP

Immunoglobulin is indicated in people who are at risk for severe illness and complications from measles (e.g., infants <12 months, pregnant women without immunity, immunocompromised). For infants <12 months with a known exposure to measles, intramuscular immunoglobulin (IMIG) is preferred. For infants 6 to 11 months, the MMR vaccine can be given instead of IG if administered 72 hours of exposure.6 Intravenous immunoglobulin (IVIG) is indicated in pregnant women who have been exposed to measles but do not have evidence of measles immunity since pregnant women might be at higher risk for severe measles and complications. Immunocompromised patients should be administered IVIG as well regardless of their immunologic or vaccination status because these patients may not be protected by the MMR vaccine.

Immunoglobulin should not be used to control outbreaks, but rather to reduce risk of infection and complications in patients receiving it.6 The recommended dose of IMIG is 0.5 mL/kg (maximum dose of 15 mL) and the recommended dose of IVIG is 400 mg/kg.

Summary

Measles is a very contagious acute viral respiratory illness with characteristic clinical features like the development of a prodrome, Koplik spots, and a characteristic maculopopular rash.6-8While some may recover from measles, up to 40% of patients may develop complications, which may be life-threatening. Infants and children have the highest case-fatality rate from measles complications.

Before the invention and licensing of the first measles vaccine in 1963, measles infections were almost universal among children.Since 1963, there have been strong efforts made to increase vaccination coverage among children. As a result of these efforts, measles was declared eliminated from the United States in 2000, and a record annual low of 37 cases was reported in 2004. In recent years, however, there has been a rise in the number of reported measles cases including the recent outbreak of measles, which originated in a California theme park. The CDC believes these outbreaks are caused by an increase in the import of measles into the United States by Americans who travel to regions that are experiencing outbreaks of their own and the spread of measles inside of the United States within regions of low vaccination rates.

The lack of apparent measles disease to the average person may give a false sense of the threat of measles, and this is largely attributable to the success of the current United States vaccination program.5 In order to prevent the reestablishment of measles as an endemic disease, all healthcare providers have a responsibility to ensure vaccination of their patients. Target groups include those traveling to other countries with active outbreaks and parents of pre-school aged children. Efforts need to be made to educate patients who may be hesitant to vaccinate themselves or their children on the safety and effectiveness of the measles vaccine and the risks to the individual and the community as a whole associated with unvaccinated patients.

References

1. Zipprich J, Winter K, Hacker J, Xia D, Watt J, Harriman K. Measles outbreak - California, December 2014-february 2015. MMWR Morb Mortal Wkly Rep. 2015;64(6):153-154.

2. Whitaker JA, Poland GA. Measles and mumps outbreaks in the United States: Think globally, vaccinate locally. Vaccine. 2014;32(37):4703-4704.

3. Jin J. Measles in the United States. [published online ahead of print February 16, 2015].JAMA. doi:10.1001/jama.2015.1555.

4. Orenstein WA, Papania MJ, Wharton ME. Measles elimination in the United States. J Infect Dis. 2004;189(Suppl 1):S1-3.

5. Orenstein W, Seib K. Mounting a good offense against measles. N Engl J Med. 2014;371(18):1661-1663.

6. Measles (Rubeola). Centers for Disease Control and Prevention.http://www.cdc.gov/measles/index.html . Updated March 23, 2015. Accessed March 24, 2015.

7. Centers for Disease Control and Prevention. Measles. In: Atkinson W, Wolfe S, Hambrosky J, eds.Epidemiology and Prevention of Vaccine-Preventable Diseases. 12th ed. Washington, DC: Public Health Foundation; 2012. http://www.cdc.gov/vaccines/pubs/pinkbook/meas.html. Accessed March 24, 2015.

8. Moss WJ, Griffin DE. Measles. Lancet. 2012;379(9811):153-164.

9. Macfadden DR, Gold WL. Measles. CMAJ. 2014;186(6):450.

Prepared by:

Alexandra Goncharenko, PharmD

PGY1 Pharmacy Practice Resident

College of Pharmacy

University of Illinois at Chicago

May 2015

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What are the current recommendations for managing patients initiating non-VKA oral anticoagulants (NOACs) after receiving thrombolytic therapies for pulmonary embolism?

Introduction

Non-vitamin K antagonist oral anticoagulants (NOACs) have been available since 2010, when the Food and Drug Administration (FDA) approved dabigatran etixelate, a direct thrombin inhibitor and the first oral, non-warfarin anticoagulant on the United States market.1 Five years later, NOACs have gained popularity because they lack the strict dietary restrictions, numerous drug interactions, frequent laboratory monitoring, and dose adjustments associated with warfarin therapy. Despite their growing utilization for indications such as atrial fibrillation and peripheral deep vein thrombosis (DVT) prophylaxis, their role has yet to become fully defined in the treatment of pulmonary embolism (PE).

Rivaroxaban and apixaban, both oral factor Xa inhibitors, are FDA-approved for standalone treatment of symptomatic (but not massive) PE in hemodynamically stable patients.2 In contrast, the other NOACs, dabigatran, and the recently approved edoxaban, require 5 to 10 days of lead-in therapy with parenteral anticoagulation.3,4 None of these agents have been adequately studied in combination with thrombolytic therapy in the setting of massive or submassive PE. Moreover, the trials that led the FDA to grant indications for treatment of symptomatic PE to these NOACs specifically excluded patients who had received thrombolytic therapy.5–8

Current Evidence

To date, there is little experience with concomitant use of thrombolytic therapy and NOACs for the management of massive or submassive PE. A literature search yielded a scant 2 case reports from physicians in Korea who treated patients with full-dose thrombolysis and rivaroxaban for the treatment of massive PE.9 The remaining body of evidence consists of 1 single-arm, single-center study, and 1 retrospective study conducted by the same investigators at the same medical center.10,11

Case Reports

The first case report is of a 61-year-old woman on hormone replacement who was admitted with extensive bilateral PE accompanied by right lower extremity deep vein thrombosis (DVT) and right heart strain.9 Per hospital protocol, the patient received a bolus of 10,000 units of unfractionated heparin (UFH) followed by an infusion of 1,250 units/hour to achieve an activated partial thromboplastin time (aPTT) of approximately 80 seconds. The UFH infusion was then turned off and the patient received 100 mg of alteplase infused over 2 hours. Heparin was not resumed after completion of alteplase and the patient was treated with rivaroxaban 15 mg twice daily after the aPTT decreased to below 80 seconds. She was discharged after 4 days. After 3 weeks, the rivaroxaban dose was reduced to 20 mg daily.

The second patient, a 73-year-old woman who had an intracranial hemorrhage (ICH) 2 years prior, presented similarly with bilateral PE, a right femoral DVT, and right sided heart strain.9Due to her history of ICH she was managed conservatively with UFH alone following the same hospital protocol and then was transitioned to rivaroxaban 15 mg twice daily. After 3 days, however, the patient again became dyspneic and hypoxic, so rivaroxaban was discontinued and the UFH infusion was resumed. A repeat CT scan was obtained due to marginal improvement and showed largely unchanged thrombus burden. To avoid right ventricular failure, physicians elected to treat her with full dose thrombolytic therapy despite her history of ICH. The patient received 100 mg of alteplase infused over 2 hours and her symptoms resolved without bleeding complications. Thereafter, warfarin was initiated as secondary prophylaxis. Both patients recovered with no reports of major bleeding.

Studies

Investigators at a single center in Arizona have studied the combination of thrombolytic therapy and NOACs in greater depth. They have developed the idea of “safe dose thrombolysis” (SDT) for the treatment of submassive PE which utilizes half of the usual dose of alteplase (0.5 mg/kg with a maximum dose of 50 mg) rather than the flat dose of 100 mg that is most commonly used for the management of massive PE.12 These investigators hypothesize that SDT is safe and effective because the lungs are the only organs that receive 100% of cardiac output; therefore, they receive virtually full exposure to whatever dose of alteplase the patient receives. Thus, a lower dose of tPA should be sufficient to manage thrombus burden in submassive PE.

The 2013 Moderate Pulmonary Embolism Treated with Thrombolysis (MOPETT) trial served as proof of concept for SDT.12 In this single-center, randomized, open-label, active-comparator trial, investigators randomized 121 patients with submassive PE to receive anticoagulation with low molecular weight heparin (LMWH) or UFH plus SDT or anticoagulation alone and showed that SDT was superior in terms of relieving pulmonary hypertension, reducing cardiac strain, and reducing hospital length of stay, but did not make a statistically significant difference in mortality or recurrence of PE. No patients in the trial experienced bleeding of any kind.

The same group of investigators went on to assess the efficacy and safety of SDT in combination with the NOACs rivaroxaban and apixaban for the treatment of submassive PE.10,11 Their treatment protocol involves a modified dose of UFH and SDT with alteplase infused over 2 hours. The UFH infusion is continued for 24 hours (goal activated partial thromboplastin time (aPTT) of 60 to 100 seconds) then turned off. Two hours later patients are started on once-daily rivaroxaban or twice-daily apixaban. The investigators’ dosing schemes for UFH, NOAC, and SDT are outlined in the table below. 
 

Table. Pharmacologic agents for treatment of pulmonary embolism. 10,11

Drug

SDT Protocol Dosing and Administration

Alteplase

0.5 mg/kg (maximum of 50 mg)

10 mg as IV push over 1 minute with remainder infused over 2 hours

UFH

70 units/kg bolus (maximum bolus of 6,000 units)

Then 10 units/kg/hour (maximum 1,000 units/hour) during alteplase infusion and for 3 hours after infusion is completed

Increase as needed to achieve aPTT 60-100 seconds for remainder of 24 hours from start of infusion

Rivaroxaban

CrCL > 30 mL/min and body weight ≥ 50 kg: 20 mg PO daily

CrCL 15-30 mL/min or weight < 50 kg: 15mg PO daily

Apixaban

Body weight ≥ 50 kg: 5mg PO twice daily

Body weight < 50 kg: 2.5mg PO twice daily

Abbreviations: aPTT, activated partial thromboplastin time; CrCL, creatinine clearance; IV, intravenously; PO, by mouth; UFH, unfractionated heparin.

Thus far these investigators have treated a total of 159 patients with both moderate (136 patients according to their severity rating system) and severe (23 patients) PE with SDT plus NOACs. Of these 159 patients, 124 were treated with rivaroxaban and 35 were treated with apixaban.11 Patients with poor renal function, those on hemodialysis, and those who had recent surgical procedures or bleeding tendencies received apixaban. With this protocol, investigators reported no in-hospital mortality, in-hospital VTE recurrence, in-hospital bleeding events of any severity, and a mean hospital length of stay of 1.8 ± 0.3 days. All patients were continued on NOAC therapy for a minimum of 1 month and all were started on aspirin 81mg daily. The investigators report that in patients treated with their SDT and NOAC protocol, reductions in pulmonary artery systolic pressure and relief of right heart strain are sustained through at least 6 months of follow up.10,11

Discussion

While the results from the above studies are impressive, it is important to note that these investigators’ definitions of PE severity differed from that of the American Heart Association (AHA)—according to the AHA criteria, 146 patients had submassive and 13 patients had massive PE.11 These results have also been met with skepticism by some readers because of the reportedly complete absence of bleeding incidents of any severity. It is widely accepted that treatment with UFH alone carries a 1% to 2% risk of bleeding events and although these investigators employed a modified UFH infusion protocol it seems that they have been extremely lucky to have experienced no bleeding at all in patients receiving both UFH and thrombolytic therapy.13 Skepticism aside, these data are from a single center and a single group of investigators. More information from other centers and other patient populations is needed before SDT protocols gain wider acceptance.

Neither the AHA nor the American College of Chest Physicians (ACCP) guidelines provide guidance regarding the combination of NOACs and thrombolytic therapy for PE.3,4 Their recommendation for the management of PE remains parenteral anticoagulation (UFH infusion, LMWH, or fondaparinux) with concomitant initiation of warfarin and continuation of parenteral anticoagulation until the INR is stable at 2 to 3 for at least 24 hours. The use of thrombolytic agents is currently only recommended for the management of massive or high risk PE in hemodynamically unstable patients.3,4 However, the guidelines do identify the eventual replacement of warfarin with NOACs in the treatment of PE and techniques for subsequent management of these patients as one of the greatest unmet needs in anticoagulation therapy.4

It is clear that further study of the combination of thrombolytics and NOACs is necessary, especially as the NOACs are increasingly favored over warfarin due to their convenience and lack of laboratory monitoring. No guidelines currently exist for how to manage these patients. It has been suggested that practitioners can slowly incorporate them into the management of PE treated with thrombolysis by anticoagulating patients with UFH or LMWH for several days following thrombolysis, and then starting a NOAC in lieu of LMWH-bridged warfarin.14 There is much more evidence to support warfarin use in these situations and until more information on the use of NOACs in patients who have received thrombolytic agents is available, it is likely that warfarin will remain the standard of care for these patients.

References

1. FDA approves Pradaxa to prevent stroke in people with atrial fibrillation. FDA News Release. 2010. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm230241.htm. Published October 19, 2010. Accessed March 20, 2015.

2. FDA-approved oral anticoagulants. Michigan Anticoagulation Quality Improvement Initiative. http://www.anticoagulationtoolkit.org/sites/default/files/toolkit_pdfs/anticoagselection.pdf. Accessed March 20, 2015.

3. Kearon C. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2_suppl):e419S-e494S.

4. Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association.Circulation. 2011;123(16):1788-1830.

5. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342-2352.

6. Hokusai-VTE Investigators, Büller HR, Décousus H, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406-1415.

7. EINSTEIN–PE Investigators, Büller HR, Prins MH, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-1297.

8. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799-808.

9. Kim H-J, Koo S-M, Ham N-S, Kim K-U, Uh S-T, Kim Y-K. Effect of rivaroxaban on fibrinolytic therapy in massive pulmonary embolism: two cases. Tuberc Respir Dis. 2014;76(3):127-130.

10. Sharifi M, Bay C, Schwartz F, Skrocki L. Safe-dose thrombolysis plus rivaroxaban for moderate and severe pulmonary embolism: drip, drug, and discharge. Clin Cardiol. 2014;37(2):78-82.

11. Sharifi M, Vajo Z, Freeman W, Bay C, Sharifi M, Schwartz F. Transforming and simplifying the treatment of pulmonary embolism: “Safe Dose” thrombolysis plus new oral anticoagulants. [Epub ahead of print]. Lung. 2015. http://link.springer.com/10.1007/s00408-015-9702-1. Accessed March 16, 2015.

12. Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol. 2013;111(2):273-277.

13. Crowther MA, Warkentin TE. Bleeding risk and the management of bleeding complications in patients undergoing anticoagulant therapy: focus on new anticoagulant agents. Blood. 2008;111(10):4871-4879.

14. Cohen AT, Dobromirski M, Gurwith MMP. Managing pulmonary embolism from presentation to extended treatment. Thromb Res. 2014;133(2):139-148.

Prepared by

Kristin Kaneshiro

PGY1 Pharmacy Practice Resident

College of Pharmacy

University of Illinois at Chicago

May 2015

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