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TITLE OF ARTICLE:Probiotics did not prevent antibior C difficile diarrhea inor C. difficile diarrhea inhospitalized older patients17 June 2014 | ACP Journal ClubPhysicians 160 • Number 12

ioticassociated

b | Volume © 2014 American College of

QUESTION:QUESTION:

Does a high-dose, multistrain pdiarrhea (AAD) and Clostridiumolder patients?

robiotic prevent antibiotic-associated difficile diarrhea (CDD) in hospitalized

METHODS:PATIENTS:2981 inpatients ≥ 65 y50% women) who received ≥ 1 opast 7 days or were about to stapast 7 days or were about to sta

EXCLUSION CRITERIA:Exclusioincluded diarrhea in the past 24 immunocompromise with need freactions to probioticsreactions to probiotics.

years of age (median age 77 y,oral or parenteral antibiotic in theart antibioticsart antibiotics

on criteriahours, CDD in the past 3 months,for isolation, or previous adverse

DESIGN:Randomized placebo-cpSETTING:Inpatient wards in 5 Nin the UK.RISK FACTORS:OUTCOME:AAD (diarrhea associwithout diarrheal pathogens identiwithout diarrheal pathogens identior alternative explanations), CDD identified on routine laboratory tes(SAEs). 2974 patients were needeCDD from 4% in the placebo grouin AAD from 20% in the placebo gin AAD from 20% in the placebo gallowing for 20% dropouts or loss

controlled trialNational Health Service hospitals

ated with antibiotic use andified on routine laboratory testsified on routine laboratory tests(AAD with C. difficile toxins

sts), and serious adverse eventsed to detect a 50% reduction inup (80% power, α = 0.05) andgroup (> 99% power α = 0 05)group (> 99% power, α = 0.05),

to follow-up.

• MAIN RESULTS:79% of patien• MAIN RESULTS:79% of patienused

• penicillins, and 24% used ceph• had diarrhea had stool samples• and placebo did not differ for AA• CDD at 12 weeks (Table), or SACDD at 12 weeks (Table), or SA• 4.4%, relative risk increase 24%

nts received antibiotics from ≥ 1 class: 72%nts received antibiotics from ≥ 1 class: 72%

halosporins. 59% of patients whos tested for pathogens. ProbioticsAD or SAEs at 8 weeks (Table),AEs resulting in death (5.4% vsAEs resulting in death (5.4% vs%, 95% CI −10 to 70).

TABLE&FIGURESTABLE&FIGURES:

CONCLUSION:In hospitalized older patients who probiotics did not prevent antibioticdifficile diarrhea compared ith pladifficile diarrhea compared with pla

were receiving antibiotics,c-associated or Clostridiumaceboacebo.

COMMENTARY:Allen and colleagues did a large mtrial evaluating the use of multistrAAD and CDD in older hospitalizeAAD and CDD in older hospitalizeThey concluded that probiotics arAAD in that population. Strengthsmethodology, large sample size, patients. C. difficile is the most codiarrhea in hospital settings and ldiarrhea in hospital settings and ldisproportionately affects older pedata are rare or underpowered to

multicenter, randomized placebocontrolledrain probiotics to prevented patients in the UK.ed patients in the UK.re unlikely to reduce CDD ors of the trial included rigorousand a specific focus on older

ommon cause of acute infectiouslong-term care facilities andlong-term care facilities andersons; however, randomized

o detect treatment differences.

The study results argue against rohospitalized patients receiving anCochrane review pooled data fromand found a reduction in CDD withand found a reduction in CDD withplacebo or no treatment (pooled r0.51) (1). In subgroup analysis, thremained in adults and inpatientsmade for age > 65 years. Howevedefinitions of CDD based on indivdefinitions of CDD based on indiv

outine use of probiotics in oldertibiotics. In contrast, a recent

m pediatric and adult patientsh probiotics compared withh probiotics compared withrelative risk 0.36, CI 0.26 tohe protective effect of probiotics, although no stratification waser, the review allowed for variedvidual included studies (1)vidual included studies (1).

Allen and colleagues used a highand bifidobacteria because multisto prevent transmission and reinfadministration may be needed toadministration may be needed towith nosocomial infections usuallcompleted the 21-d course). It is be the same in the USA, where Cantibiotic exposure may be differe

h-dose preparation of lactobacillistrain schemes may be preferredfections. Moreover, prolonged

document benefit as patients document benefit, as patientsy receive short courses (53%unclear whether results would

C. difficile epidemiology andent.

• Rigorous methodology and the sg gy• study add value to the findings a• in older patients. However, the r

f f• future use of probiotics in other • multifaceted approach that inclu• restriction of proton-pump inhibitrestriction of proton pump inhibit• with C. difficile infection

sample size of Allen and colleagues’p gagainst indiscriminate use of probioticsresults do not preclude

fhigh-risk groups or as part of ades antibiotic stewardship andtors, which have been associatedtors, which have been associated

17 November 2009 | ACP Journal C5

lub | Volume 151 • Number 

QUESTION:QUESTION:What is the safety of proton-pumpearly pregnancy in terms of fetal o

p inhibitors (PPIs) taken duringoutcome?

METHODS:PATIENTS:Included studies examthe first trimester of pregnancy, exposed to PPIs, and describedexposed to PPIs, and described

EXCLUSION CRITERIA:

mined exposure to PPIs during at least included a comparison group not

d fetal outcomes.d fetal outcomes.

DESIGN:4 prospective cohort stucohort studies (n = 133 039) werSETTING:canada

RISK FACTOR:PPI

Outcomes werecongenital malformations, spontadeliverydelivery.

udies (n = 1901) and 3 retrospectivere included

aneous abortion, and preterm

Main resultsUse of PPIs during the first trimewith increased risk for congenitab ti t d li (T babortion, or preterm delivery (Tab

associated with increased risk fo

ester of pregnancy was not associatedl malformations, spontaneousbl ) O l tble). Omeprazole was not

or congenital malformations.

CONCLUSION:CONCLUSION:Use of proton-pump inhibitors dupregnancy was not associated wmalformations, spontaneous abo

ring the first trimester ofwith increased risk for congenitalortion, or preterm delivery.

COMMENTARY:

Approximately 50% of pregnant w

treat reflux outside of, but not dur

have shown that therapeutic dose

Administration category C) increa

excessive doses have teratogenic

esomeprazole) have low risk for t

Therefore, a “step-up” regimen us

receptor antagonists, and PPIs is

women have reflux. PPIs are widely used to

ing, pregnancy because animal experiments

es of omeprazole (US Food and Drug

ase embryonic and fetal mortality and that

c effects (1). Other PPIs (lansoprazole and

oxicity (category B) in human studies (2).

sing conservative measures, antacids, H2-

preferred for treating reflux during pregnancy

The meta analysis by Gill and colThe meta-analysis by Gill and colhave major teratogenic effects; thstudies included were not heterogcongenital anomalies were similaodds ratios included 1 in all studiereassuring further studies are nereassuring, further studies are newomen exposed to PPIs was smapublication bias, although this findgsmall number of studies. Data froprovided 43% of exposed participb t t l t d babstract supplemented by person

lleagues shows that PPIs do notlleagues shows that PPIs do nothe 7 prospective and retrospectivegeneous. The relative risks forar across studies, and 95% CIs fores. Although these findings are

eeded because the number ofeeded because the number ofall. Funnel plots did not revealding could be a result of theg

om the largest study, whichpants, were obtained from an

l i tinal communication.

It is difficult to exclude ascertainmIt is difficult to exclude ascertainmcongenital anomalies are identifieeven imaging are required to deteof these outcomes to dose and dubecause only 1 study, in which woan average 2 to 3 weeks providedan average 2 to 3 weeks, provided

ment bias Because only two thirds of majorment bias. Because only two thirds of majored at birth, longer follow-up andect other anomalies. The relationuration of therapy is unknownomen were exposed to PPIs ford this informationd this information.

Women who have reflux before prWomen who have reflux before prfor a longer duration during pregnatherapy predispose to other side ebone fractures (3). Individual studiall, risk factors for the outcomes oshould consider using PPIs for mashould consider using PPIs for main pregnant women who have not established safety.

regnancy often require treatment with PPIsregnancy often require treatment with PPIsancy. Higher doses or prolonged

effects of PPIs, such asies controlled for some, but notf interest. In summary, clinicians

anaging reflux symptomsanaging reflux symptomsresponded to agents with more

TITLE OF ARTICLE:New oral anticoagulants increaseGI bleeding in venous thrombosis

18 February 2014 | ACP Journal Physician

es and ACS

Club | Volume © 2014 American College of

QuestionDo new oral anticoagulants (NOAg (clinically relevant bleeding?

Cs) increase risk for gastrointestinal (GI) or ) g ( )

METHODS:METHODS:43 RCTs (n = 151 578, mean or mmen, follow-up range 3 wk to 31 m21 used NOACs in orthopedic sur7 in acute deep venous thrombosiacute coronary syndrome (ACS) aacute coronary syndrome (ACS), aRCTs evaluated rivaroxaban, 12 aand 1 betrixaban. All RCTs excludrisk for GI bleeding. 31 RCTs had 30 were reported as double-blind

d 23 t d l t f ll (and 23 reported loss to follow-up (

median age range 56 to 73 y, 17% to 82%mo) met the inclusion criteria:rgery, 8 in atrial fibrillation (AF),is or pulmonary embolism, 5 in theand 2 in medically ill patients 16and 2 in medically ill patients. 16

apixaban, 10 dabigatran, 4 edoxaban,ed patients with increasedadequate allocation concealment,and all 43 blinded outcome assessors,(0% t 2 5%)(0% to 2.5%).

Included studies compared NOAC

edoxaban, or betrixaban) with stan

vitamin K antagonist, antiplatelet th

the target population for the drug a

Outcomes were GI bleeding or clin

s (rivaroxaban, apixaban, dabigatran,

ndard care (low-molecularweight heparin,

herapy, no additional therapy, or placebo) in

and reported bleeding as a safety outcome.

nically relevant major or nonmajor bleeding.

Main resultsResults of meta-analysis of NOACsettings are reported in the Tablerivaroxaban increased risk for GIrivaroxaban increased risk for GI relative risk increase [RRI] 47%, 9relevant bleeding (16 RCTs, 12%compared with standard care, anGI bleeding (3 RCTs, 3.3% vs 2.1NOAC t i t d ithNOACs were not associated with

Cs vs standard care in different. In subgroup analyses by drug,bleeding (5 RCTs 2 1% vs 1 4%bleeding (5 RCTs, 2.1% vs 1.4%,95% CI 21 to 80) and clinically

% vs 9.7%, RRI 27%, CI 4 to 54)d dabigatran increased risk for

1%, RRI 56%, CI 28 to 89); otherh i d i k f bl dih increased risk for bleeding.

Conclusion

In patients with deep venous thro

acute coronary syndrome, new or

gastrointestinal bleeding compare

mbosis or pulmonary embolism, or the

ral anticoagulants increase risk for

ed with standard care.

CommentaryCommentary

NOACs have been reported to be

th i d itherapies and are more convenien

that these agents are associated

compared with standard therapiescompared with standard therapies

questions whether the greater con

e at least as effective and safe as standard

t (1) H l t d ll tnt (1). Holster and colleagues now report

with an increased risk for GI bleeding

s and an accompanying editorials, and an accompanying editorial

nvenience of NOACs is worth the risk (2).

The meta-analysis by Holster andincrease GI bleeding compared wwith ACS and venous thromboemAF We urge cautious interpretatioAF. We urge cautious interpretatioindividual trials, the effects of NOAthe NOAC and control used, as rein the pooled estimates. The largewas in ACS trials, where NOACs a background of dual antiplateleta background of dual-antiplatelet the results of placebo-controlled tfrom active-controlled trials.

d colleagues shows that NOACswith standard therapies in patientsmbolism, but not in those withon of these data First in theon of these data. First, in theACs differed by indication andeflected by substantial heterogeneityest increase in GI bleedingwere compared with placebo ontherapy We question whethertherapy. We question whether

trials should be pooled with those

Individual trials, each involving

> 10 000 patients with AF, have s

twice daily, and rivaroxaban, 20 m

with creatinine clearance 30 to 4

increase GI bleeding compared w

questions about the results of the

AF. Second, despite increases in

associated with excess clinically because increases in GI bleedingsites.

shown that dabigatran, 150 mg

mg daily (15 mg daily in patients

49 mL/min), but not apixaban,

with warfarin (3-5), which raises

e meta-analysis in patients with

n GI bleeding, NOACS are not

relevant bleeding in the activecontrolled trialsg were offset by decreases in bleeding at othe

What are the implications of thesWhat are the implications of thesThe data by Holster and colleaguNOACs can increase the risk fordifferences between drugs. ClinicGI bleeding when making treatmthe context of NOAC effects on athe context of NOAC effects on a

se results for clinical practice?se results for clinical practice?ues are a timely reminder thatr bleeding but also highlightcians should consider risk for

ment recommendations, but inall patient-important outcomesall patient-important outcomes.

TITLE OF ARTICLETITLE OF ARTICLE:

In acute calculous cholecystitis, a

after cholecystectomy did not red

Infection

16 December 2014 | ACP Journa16 December 2014 | ACP Journa

Physicians 161 • Number 12

antibiotics

uce

al Club | Volume © 2014 American College ofal Club | Volume © 2014 American College of

QuestionQuestion

In patients having cholecystecto

postoperative antibiotics reducepostoperative antibiotics reduce

antibiotics?

omy for acute calculous cholecystitis, do

infection compared with no postoperativeinfection compared with no postoperative

MethodsMethods

Patients: 414 patients ≥ 18 years

d itt d t thwere admitted to the emergency

(grade II) acute calculous cholec

amoxicillin plus clavulanic acid 2amoxicillin plus clavulanic acid, 2

Exclusion criteria included acalcu

common bile duct stones found dcommon bile duct stones found d

acute pancreatitis, cirrhosis, susp

s of age (mean age 55 y, 51% women) who

d t t ith ild ( d I) d tdepartment with mild (grade I) or moderate

cystitis requiring cholecystectomy and receive

2 g 3 times/d before and once during surgery2 g, 3 times/d before and once during surgery

ulous cholecystitis, symptoms for > 5 days,

during surgery, cholangitis, biliary peritonitis,during surgery, cholangitis, biliary peritonitis,

pected biliary cancer, or allergy to β-lactam.

• Design: Randomized controlledg

• Setting: 17 medical centers {in

RISK FACTOR• RISK FACTOR:

• Outcomes: Primary outcome w

or a distant site based on clinica

confirmed with bacteriology.

d trial (The FRENCH Study).( y)

France}*.

was postoperative infection at the surgical site

al, biochemical, and morphologic features and

Main resultsMain results

Postoperative antibiotics did not r

cholecystectomy compared with ncholecystectomy compared with n

reduce infection 4 weeks after

no postoperative antibioticsno postoperative antibiotics

Conclusion

In patients having cholecystecto

postoperative antibiotics did notpostoperative antibiotics did not

my for acute calculous cholecystitis,

reduce infectionreduce infection.

Commentary

The 2013 Tokyo Guidelines recom

cholecystectomy for patients withy y p

cholecystitis (1). Duration of treat

depends on illness severity. This

because there are few data to gu

patients.

mmend antibiotic therapy after

h mild to moderate acute calculous

tment varies from 24 hours to 7 days and

recommendation represents expert opinion

uide postoperative antibiotic therapy in these

The trial by Regimbeau and colleaantibiotics on infection. However, effect is subject to some uncertainanalysis the 95% confidence inteanalysis, the 95% confidence inte5% reduction in risk for infection (would prescribe antibiotics) as weincreased risk for infection (in whiTo bolster validity in open-label triassessment should be blinded Alassessment should be blinded. Alunclear in this study, and blinded the outcomes.

agues found no effect of postoperativeas in all trials, the true

nty. In the intention-to-treatrval includes the possibility of arval includes the possibility of ain which case many clinicians

ell as the possibility of a 9%ch case many would not).als, randomization and outcomelocation concealment waslocation concealment wasassessors verified only 10% of

Clinicians should continue to follo

concert with clinical judgment and

case (e g whether infection is cocase (e.g., whether infection is co

bacteremia is present). Antibiotic

providers, and the potential for anp , p

infection should always be consid

ow current guidelines (1) ing ( )

d consideration of individual aspects of each

ontrolled with surgery and whetherontrolled with surgery and whether

stewardship is the responsibility of all

ntibiotic resistance and Clostridium difficile

dered.