Transcript Results
Updates in
Infectious Diseases
Sandra A. Kemmerly, MD, MACP, FIDSA
26 June, 2015
Disclosure of Financial Relationship
•
Sandra Kemmerly, Has no relationships with any entity
producing, marketing, re-selling, or distributing health care
goods or services consumed by, or used on, patients
Objective:
• Select clinical infectious diseases papers of
interest to general internists and family
physicians.
Amoxicillin for acute rhinosinusitis.
A randomized controlled trial.
Garbutt JM, Banister C, Spitznagel E, Piccirillo JF
.
JAMA 2012;307:685-692
Background:
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1 in 5 antibiotic prescriptions
for US adults is for treatment of sinusitis.
Antibiotic resistance increasing, want to limit use to those for
whom it will provide help.
Trials of antibiotics for sinusitis have had conflicting results.
‒ Those requiring confirmatory tests like sinus x-rays tended to show
antibiotic benefit
‒ Those using clinical diagnostic criteria tend to show no or minimal
benefit
‒ CDC expert panel’s evidence-based guidelines recommended clinical
criteria for diagnosis and antibiotics only for those with moderately
severe or severe symptoms. Use narrow spectrum antibiotic
Methods:
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Randomized, placebo-controlled trial in 166 adults with
uncomplicated, acute rhinosinusitis from 10 community
primary-care office practices.
Diagnosis: maxillary pain or tenderness, purulent nasal
secretions, and rhinosinusitis symptoms for 7 days or
more; but not more than 28 days.
Amoxicillin 500mg tid vs. placebo for 10 days.
All got week supply of symptomatic treatments for pain,
fever, cough and nasal congestion.
Primary outcome: quality of life after 3 days of treatment
assessed by Sinonasal Outcome Test-16 (SNOT-16).
Results:
• No significant difference between antibiotic and
placebo:
• At day 3*, same (37% Abx better vs 34% placebo).
At day 7, antibiotic group better (74% vs 56%).
At day 10, same (78% vs 80%).
* Primary outcome
Take home message:
• First trial of antibiotics for sinusitis to assess
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improvement in disease-specific quality of life as
primary outcome (what patients want).
In both groups, sinus symptoms improved over
time with no difference at 10 days.
No differences in work days missed, satisfaction
with treatment, rate of relapse, or amount of
additional medical care.
Don’t give antibiotic to usual patient with acute
sinusitis.
Most prescribed antibiotics for adults US:
Product Name
Total Spending in
2009
Number of
Prescriptions
Azithromycin
$4,234,950.16
292,797
$14.46
Amoxicillin
$920,529.32
184,921
$4.98
Cephalexin
$577,347.89
113,861
$5.07
Ciprofloxacin
$392,565.25
107,295
$3.66
Amoxicillin-Clavulanate
$2,131,969.68
88,257
$24.16
TrimethoprimSulfamethoxazole
$384,944.21
87,423
$4.40
Doxycycline
$532,470.62
75,536
$7.05
Levofloxacin
$6,566,226.78
59,525
$110.31
Clindamycin
$498,133.18
53,473
$9.32
Penicillin V
$246,756.42
42,614
$5.79
Top Antibiotic Drugs, Adults, BCBSM, 2009
Price per
Course
Azithromycin and the risk of
cardiovascular death.
Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM.
N Engl J Med 2012;366:1881-1890
Background:
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The macrolide antibiotics erythromycin and clarithromycin
can increase the risk of serious ventricular arrhythmias and
are associated with an increased risk of sudden death.
Azithromycin, a widely-used macrolide, has been thought to
be free of cardiac toxicity; adverse event reports gathered by
the FDA suggest otherwise.
Authors’ hypothesis: patients who took azithromycin would
have an increased risk of sudden death when compared with
persons who didn’t take antibiotics and with patients who
took other selected antibiotics.
Methods:
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Retrospective cohort study of azithromycin use and
mortality.
Included persons aged 30-74 enrolled in Tennessee
Medicaid Program who got azithromycin between 1992 and
2006 and who had no life-threatening noncardiovascular
illness.
Also included matched control periods during which there
was no use of study antibiotics (four control periods for
each azithromycin prescription).
Also included control groups who took amoxicillin (including
amox-clav), ciprofloxacin, and levofloxacin.
Results:
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Cohort: 347,795 persons with azithromycin prescriptions.
‒ 1,391,180 matched control periods with no antibiotic
‒ 1,348,672 amoxicillin prescriptions
‒ 264,626 ciprofloxacin prescriptions
‒ 193,906 levofloxacin prescriptions
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Azithromycin users mostly women (77.5%)
Mean cardiovascular risk scores:
‒ Azithromycin 9.3
‒ Amoxicillin
9.5
‒ Ciprofloxacin 10.3
‒ Levofloxacin 10.6
Results:
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Most azithromycin use for ENT infections and bronchitis;
same for amoxicillin (62 and 63% of prescriptions).
Sudden cardiac deaths during five-day course of treatment:
‒ Azithro:
65 per 1 million courses (n=22)
‒ No abx:
24 per 1 million periods (n=33)
‒ Amoxicillin: 22 per 1 million courses (n=29)
Cumulative Incidence of Cardiovascular Death among Patients Who Took Azithromycin and
Persons Who Did Not Take Study Antibiotics during a 10-Day Period.
Ray WA et al. N Engl J Med 2012;366:1881-1890
Cumulative Incidence of Cardiovascular Death for Patients
Who Took Azithromycin or Amoxicillin during a 10-Day Period.
Ray WA et al. N Engl J Med 2012;366:1881-1890
Results:
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Azithromycin patients had an estimated 47 additional
cardiovascular deaths per 1 million 5-day courses of
therapy.
As compared with amoxicillin, those who got ciprofloxacin
had no increased risk of cardiovascular death; there was a
nonsignificant trend toward increased cardiovascular death
risk for levofloxacin.
Death risk for azithromycin varied according to baseline risk
for cardiovascular disease.
‒ Those in the highest decile of risk, had 245 additional cardiovascular
deaths per 1 million courses.
Excess Risk of Cardiovascular Death with Azithromycin as Compared with Amoxicillin,
According to Decile of Cardiovascular Risk Score.
Ray WA et al. N Engl J Med 2012;366:1881-1890
Take home message:
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A short course of azithromycin was associated with an
increase in cardiovascular deaths.
Although the risk was small, it was greater than with
amoxicillin.
The increased risk for cardiovascular death didn’t persist
after the course of therapy ended.
Physicians should think twice about prescribing
azithromycin for patients with cardiovascular disease
and should first ask whether the patient needs an
antibiotic at all.
Azithromycin for Prevention of Exacerbations of COPD
N Engl J Med 2011; 365:689-698
Conclusions:
Among selected subjects with COPD, azithromycin
taken daily for 1 year, when added to usual treatment,
decreased the frequency of exacerbations and
improved quality of life but caused hearing decrements
in a small percentage of subjects.
Based on the previous study, one
wonders how many deaths there might
be in this group!!!
CBS News/ March 12, 2013, 1:59 PM
FDA warns azithromycin
"Z-pack“ antibiotics could
lead to deadly heart rhythms
for some.
Early surgery versus conventional
treatment for infective endocarditis.
Kang D-H, Kim Y-J, Kim S-H, Sun BJ,
Kim D-H, Yun S-C, Song J-M, Choo SJ, Chung C-H, Song JK, Lee J-W, Sohn D-W.
N Engl J Med 2012;366:2466-2473
Background:
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Guidelines advocate early surgery for patients
with infective endocarditis and heart failure.
Indications for surgery to prevent embolism are not
clearly defined and debate continues.
ACC-AHA* 2006: early surgery as Class IIa
recommendation in those with recurrent emboli and
persistent vegetation.
European Society of Cardiology: early surgery as
Class IIb recommendation for those with isolated,
large vegetations (>15mm).
*American College of Cardiology-American Heart Association
Background:
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There has been no randomized trial to make clear the
indications for surgery and timing of surgery.
Designed this study to compare surgery with conventional
treatment in those with left-sided endocarditis and a high risk
of embolism.
Hypothesis was that early surgery would reduce
death or embolic events.
the rate of
Methods:
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Prospective, randomized trial at two centers.
All had blood cultures and TTE within 24 hours of
hospitalization.
Enrolled consecutive patients 18-80 years old with native valve
endocarditis defined by modified Duke criteria and severe mitral
or aortic valve disease and a vegetation >10mm.
Excluded those with: moderate-severe CHF, heart block, aortic
abscess, penetrating lesions requiring urgent surgery, fungal
endocarditis, coexisting major embolic stroke, right-sided
vegetations, prosthetic valve or referral from another institution
more than seven days after diagnosis of endocarditis.
Methods:
• Surgery done within 48 hours after randomization.
• Conventional group: surgery only if complications
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requiring urgent surgery developed during medical
treatment or if symptoms persisted after end of
antibiotics.
Followed in hospital; then 4 weeks, 6 weeks, 3
months, 6 months and one year; then six month
intervals until Sept 2011.
Primary end point: composite of hospital death or
clinical embolic events within 6 weeks of
randomization. (didn’t count skin lesions or
metastatic abscesses as embolic events).
Results:
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37 in surgery group; 39 conventional
Mean age 47; 67% men
Mitral valve in 45; aortic in 22; both in 9.
Severe regurgitation: 97% surgery; 92% conventional.
Organisms:
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viridans streptococci……… 33%
Other streptococci………… 31%
Staphylococcus aureus….. 13%
Enterococcus……………….. 3%
Other………………………….3%
Culture negative……………18%
Results:
• Primary end point of in-hospital death or emboli
within the first 6 weeks after randomization:
‒ Surgery: 1 patient
‒ Conventional: 9 patients (P=0.03)
‒ At 6 weeks, rate of embolism 0% in surgery group and
21% in conventional treatment group (P=0.005).
Kang D et al. N Engl J Med 2012;366:2466-2473.
Cumulative Probabilities of Death and of the Composite End Point at 6 Months,
According to Treatment Group.
• No difference in all cause
mortality at 6 months.
• Composite end point of
death from any cause, embolic
events, recurrence of
endocarditis, or repeat
hospitalization due to CHF
was: 3% in early surgery
group and 28% in
conventional treatment
group (P=0.02).
Kang D et al. N Engl J Med 2012;366:2466-2473.
Editorial:
“..implication of this study for early surgery
is profound..”
“..endocarditis is a dangerous condition and
the benefits of timely surgical intervention in
patients with large vegetations and severe
valvular dysfunction, even if they do not have
congestive heart failure, outweigh the additional
risk of surgery in patients with active infection.”
Gordon SM, Pettersson GB. NEJM 2012;366:2519-2521.
Take home message:
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Early surgery in patients with left-sided endocarditis,
severe valve dysfunction and a large vegetation (but
without heart failure) reduced systemic embolization
(the second most common cause of endocarditis
death).
Limitations: only applies to a subset of endocarditis
patients. Less S. aureus than in most series. Don’t
know how long from symptoms to randomization.
Early surgery seems appropriate in the subset
examined in this study. I would recommend it.
The role of asymptomatic bacteriuria in
young women with recurrent urinary
tract infections: to treat or not to treat?
Cai T, Mazzoli S, Mondaini N, Meacci F, Nesi G, D’Elia C, Malossini G, Boddi V, Bartoletti R.
Clin Infect Dis 2012;55:771-777
Background:
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Asymptomatic bacteriuria (AB) is the presence of bacteria
in the urine without signs or symptoms of a UTI
(independent of pyuria).
AB is associated with adverse outcomes in pregnant
women, and treatment of AB in this group decreases risk of
pyelonephritis.
Been assumed that AB defines a population at risk, and
that elimination of bacteriuria will minimize risk for
symptomatic illness. But, the role of treatment of AB in
young women with recurrent UTIs has not been evaluated.
Methods:
• Evaluated the impact of AB treatment on UTI
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rates in young women with recurrent UTIs.
Screened women attending an STD center for
recurrent UTIs.
Selected sexually active women 18-40; Hx of UTI
in previous year but at least one month prior to
enrollment; currently asymptomatic; had
significant bacteriuria (105 CFUs/ml of single
uropathogen) in 2 consecutive voided midstream
urines.
Methods:
• Randomly assigned to:
‒ Group A = not treated (treated if got UTI)
‒ Group B = treated (based on susceptibility)
• Follow-up with cultures at 3, 6 and 12 months.
• Principal outcome: recurrence free rate at end of
study period.
Results:
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Group A (not treated): 330 women
Group B (treated):
369 women
Development of symptomatic UTIs
‒ At 3 months: 3.5% group A; 8.8% group B
‒ At 6 months: 7.6% group A; 29.7% group B
‒ At 1 year: 14.7% group A; 73.1% group B
Treatment of AB due to E. faecalis was associated with
development of multi-drug resistant E. coli.
Probability of being recurrence-free
Cai T et al. Clin Infect Dis. 2012;55:771-777
Caution:
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The study population was one that attended an STD clinic
and had a history of multiple antibiotic courses for
recurrent UTIs. (most had more than 3 UTIs/year).
There was no control group of healthy young women.
Nevertheless…..
Take home message:
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In healthy, sexually active young women with recurrent
urinary tract infections, the treatment of asymptomatic
bacteriuria increases the risk of subsequent infection and
is associated with the development of resistant
organisms.
Don’t look for or treat asymptomatic bacteriuria in young
women with recurrent UTIs.
Antiretroviral prophylaxis for HIV
prevention in heterosexual men and
women.
Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, Tappero JW et al. for the Partners
PrEP Study Team.
N Engl J Med 2012;367:399-410
Background:
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To impact the global HIV epidemic effective primary
prevention strategies are critical.
Antiretroviral prophylaxis is a potential HIV prevention
strategy for uninfected persons given either as
postexposure prophylaxis after high-risk occupational or
nonoccupational exposure or as preexposure prophylaxis
for those who have ongoing HIV exposure such as an
HIV-seronegative person in a partnership with someone
already infected (serodiscordant couple).
Methods:
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Randomized trial of antiretrovirals for preexposure
prophylaxis among HIV-1 discordant couples in Kenya
and Uganda. At enrollment, seropositive partner not
eligible for treatment, according to national guidelines.
Median CD4 495 (375-662).
Seronegative partner (male in 62% of couples) assigned
one of three regimens:
‒ Daily tenofovir (N=1584)
‒ Tenofovir plus emtricitabine (N=1579)
‒ Placebo (N=1584)
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Followed monthly up to 36 months.
Results:
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82 HIV infections occurred:
‒ 17 in tenofovir group
‒ 13 in tenofovir-emtricitabine group
‒ 52 in placebo group
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Relative reduction of HIV infection in treatment groups
67%-75% (P<0.001).
Protective effects not significantly different in two
treatment arms.
Eight of those treated were found to have been infected at
baseline; antiretroviral resistance developed in two.
Cumulative Probability of HIV infection in the Modified Intention-to-Treat Analysis
Baeten JM et al. N Engl J Med 2012;367:399-410.
Results:
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Better results than some other similar studies. Why???
Comprehensive package of HIV prevention services:
counseling before and after testing, risk reduction
counseling, screening and treatment for STIs, free condoms
with training, referral for male circumcision and
postexposure prophylaxis.
Monthly visits with HIV testing, dispensing of 30 days of
meds, adherence counseling, collection of prior months
unused meds, pregnancy testing.
97% of study medication was taken.
Condom use increased.
Take home message:
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In heterosexual, HIV discordant couples, oral prophylaxis
with both daily tenofovir or tenofovir combined with
emtricitabine protect against HIV transmission in both
women and men.
Preexposure prophylaxis can reduce HIV acquisition in
heterosexual persons.
High adherence is essential!!!
Synergy between medication, risk-reduction counseling,
methods to increase adherence.
New Germs
Lober, circ 1980s
21st century
MERS
Ebola
Chikungunya virus
SARS
West Nile Virus
Metapneumovirus
Bird Flu
Monkey Pox
Novel H1N1
Dengue
XDR Tb
Lorber B. Ann Intern Med 1996; 125:844-851.
Chikungunya (CDC Bulletin May 14, 2015)
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What is the current situation?
In December 2013, French Guiana reported
locally transmitted cases for the first time in South
America. Local transmission means that mosquitoes
in the area have been infected with chikungunya and
are spreading it to people.
Local transmission of chikungunya is now being
reported in other countries in the South America. As
of February 23, 2015, the following South American
countries have reported cases of chikungunya:
Chikungunya Virus
Chikungunya Transmission South America
• Bolivia
• Brazil
• Colombia
• Ecuador
• French Guiana
• Guyana
• Paraguay
• Peru
• Suriname
• Venezuela
CDC Bulletin May 14, 2015
“New truths become evident
when new tools become available”
Rosalyn Yalow
Nobel Laureate
1977