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Journal club

Dr AMIR HOSEINSALEHI

Clindamycin did not differ fromtrimethoprim–sulfamethoxazole forcuring uncomplicated skin infections

Reference: Miller LG, Daum RS, Creech CB, et al; DMID 07-0051 Team. Clinda-mycin versus trimethoprim-sulfamethoxazole for uncomplicatedskin infections. N Engl J Med. 2015;372:1093-103.

Date of presentation: ١٧/١١/٩۵Presented By: dr SALEHI

Question

In outpatients with uncomplicated skin infections, what is theefficacy of clindamycin compared with trimethoprim–sulfamethoxazole(TMP-SMX)?

MethodsDesign: Randomized controlled trial. ClinicalTrials.gov NCT00730028.Allocation: {Concealed}Blinding: Blinded (patients, clinicians, data collectors, out-come assessors, and safety committee).Follow-up period: 40 days.Setting: Urgent care clinics, emergency departments (EDs), andaffiliated clinics at 4 sites in the USA.

Patients: 524 patients aged 6 months to 85 years (mean age27 y)with uncomplicated skin infec-tions (≥ 24 h with≥2 of erythema, swelling orinduration, local warmth, purulent drainage, and tenderness to pain orpalpa-tion) categorized as cellulitis, abscess > 5.0 cm in diameter (drainablecollection of pus, size propor-tionally smaller in children), or both.

Exclusion criteria: superficial skin infections, human or animal bites, highfever,immunosuppressive medication use or immune-compromisingconditions, surgical-site or prosthetic-device infection, or anti-bacterialtreatment with antistaphylococcal activity.

Intervention:Clindamycin, 300 mg, 3 times/dorTMP-SMX, 160 mg of TMP and 800 mg of SMX, 2 times/d, plusplacebo tablets at midday, for 10 days.Pediatric doses were ad-justed by body weight. All abscesses wereincised and drained.Patient follow-up: 89% were evaluated at 7 to 10 days aftertreatment.

Outcomes:Primary outcome was clinical cure at 7 to 10 days after completion oftreatment.Secondary outcomes included adverse events and clinical cure at 1month overall and in sub-groups (adults and children; cellulitis,abscess, and mixed cellulitis and abscess). 524 patients wererequired to detect a 10%between-group difference (85% vs 95%) in cure rates, with apower of 80% ( = 0.05) and an assumed 20% attrition rate.

Main results

31% of patients had abscesses, 53% had cellulitis, and 16% had

both.

Clindamycin did not differ from TMP-SMX for cure of skininfection or adverse events at 7 to 10 days or at 1 month.

Results did not vary by patient subgroups.

Table & figure

Conclusion

In patients with uncomplicated skin infections, clindamycindid not differ from trimethoprim–sulfamethoxazole for curerates or adverse events.

clinicians who treat skin infections have long wished for arandomized trial to guide antibiotic selection.

The large trial by Miller and col-leagues was well-designed andshowed that clindamycin and TMP-SMX are excellent foroutpatient skin infections;

it found no differences between treatments or in subgroupanalyses, or in adverse events.

Commentary

The National Institute of Allergy and Infectious Diseasesfunded a multicenter trial comparing TMP-SMX, placebo,clindamycin, cephalexin, or a combination thereof for differentskin infections seen in the ED (Stop-MRSA [methicillin-resistantStaphylococcus aureus] trial) .This trial found no difference in failure rates between

clindamycin and TMP-SMX for infected wounds, or betweencephalexin alone and cephalexin plus TMP-SMX for cellulitis.However, for abscesses, TMP-SMX had a lower fail-ure ratethan placebo!Given that treatment failure occurred in only 14% of patientswith abscesses treated with placebo and the NNT for TMP-SMXvs placebo was 14, perhaps close follow-up instead ofantibiotics is possible for selected patients.

Commentary

How can these findings be applied most effectively? In mostsettings, patient or provider preference is fine. Certainly, the 2older generic drugs clindamycin and TMP-SMX are useful andinterchangeable—at least for healthy outpatients.

Future studies should include patients with such disorders asdiabetes, renal failure, and immune suppression, who wereexcluded from Stop-MRSA and the trial by Miller andcolleagues.There may yet be information to be learned in these specificpatient populations, and having options other than vancomycinor newer agents with broad gram-positive coverage would beappealing..

Commentary

Weekly dalbavancin was noninferior todaily vancomycin for acute bacterial skininfection in adults

Reference: Boucher HW, Wilcox M, Talbot GH, et al. Once-weekly dalbavancin versusdaily conventional therapy for skin infection. N Engl J Med.2014;370:2169-79.

Question

In adults with acute bacterial skin and skin-structureinfection (SSSI), is weekly dalbavancin noninferior todaily vancomycin?

Design:2 replicate, randomized, controlled, noninferiority trials (DISCOVER-1 andDISCOVER-2). ClinicalTrials.govNCT01339091 and NCT01431339.

Blinding: Blinded* (patients, clinicians, data collectors,outcome assessors, data analysts, and safety committee).

Setting:140 investigative sites in the USA, Canada, Europe,South Africa, and Asia.

Follow-up period: 14 days.

Methods Patients:573 adults in DISCOVER-1 (mean age 49 )and 739 adults in DISCOVER-2 (mean age 50

y).who had acute bacterial SSSI :

cellulitis, major abscess, or wound infectionwith• ≥ 75 cm2 of erythema• would probably need ≥ 3d of IV antibiotics• had ≥ 1 systemic sign of infection (t>38°, WBC>12000, or > 10% band) in past 24• ≥2 of (purulent drainage or discharge, fluctuance, localized warmth,

tenderness, swelling or induration in addition to erythema.

Exclusion criterion was:antibiotic therapy in the past 14 days.

Intervention:IV dalbavancin, 1 g on day 1 and 500 mg on day 8, plus placeboinfusion everyorIV vancomycin, 1 g or 15 mg/kg every 12 ≥ 3 days, with an optionto switch to oral linezolid, 600 mg every 12, to complete 10 to 14days of inpatient or outpatient therapy.

Outcomes:Primary outcome was early clinical response at 48 to 72 hours(cessation of spread of erythema associated with infection and t ≤ 37.6° for 3consecutive readings 6 h apart).Patient follow-up: 90% in each trial.

Main results

Dalbavancin did not differ from vancomycin for early clinicalresponse; dalbavancin was noninferior to vancomycin .

Table & figure

Conclusion

In adults with acute bacterial skin and skin-structureinfection, dalbavancin was noninferior to vancomycin.

Boucher and colleagues found that IV dalbavancin was noninferior toIV vancomycin followed by oral linezolid for acute bacterial SSSI.

These results are similar to those of Jauregui and colleagues but arebased on a more robust study design.

The DISCOVER trials conformed to new (FDA) guidelines for designingnoninferiority trials for SSSIs.

Commentary

In the USA, > 500 000 patients are hospitalized annually witha primary diagnosis of SSSI.After FDA clearance, dalbavancin will add to our treatmentoptions for such infections.Its long-term bioavailability could reduce hospitalizations andlength of stay, potentially reducing in-hospital infections andcosts.These outcomes should be formally assessed for dalbavancin tobecome a first-line treatment option.

Commentary

Long-acting antibiotics pose some practical issues:

• Administration of additional drug doses need for referral out-patient infectious disease clinics.

• hospitalized patients who are discharged on dalbavancin. For the drug tobe cost-effective from a hospital perspective, a reimbursement model isneeded to account for the overall reduction in outpatient expenses.

Dalbavancin increases our options for gram-positive SSSI infections, butthese issues should be addressed.

Metoclopramide during pregnancydid not increase risk for majorcongenital malformations or fetaldeath

Reference: Pasternak B, Svanström H, Mølgaard-Nielsen D, Melbye M, Hviid A. Metoclopramide inpregnancy and risk of major congenital malformations and fetal death. JAMA. 2013;310:1601-11..

Question

Does use of metoclopramide duringpregnancy increase risk for majorcongenital malformations or fetal death?

Design:Retrospective population-based cohort study withindividual-level linkage of several national registers.

Setting: Denmark

Methods Patients:1 222 503 singleton pregnancies (mean maternal age 29 y).Pregnancies exposed to metoclopramide were matched 1:4 based onage, calendar year, and propensity scores (and, for fetal deathanalyses, first day of metoclopramide exposure) with pregnanciesthat were not exposed to metoclopramide during the exposurewindow.

Fetuses/infants with < 6 completed weeks of gestation, missing orimplausible gestational ages, chromosomal aberrations, geneticsyndromes, malformations with known causes, viral infectionspossibly associated with malformations, or whose mothers hadcancer within 6 months before pregnancy or filled prescriptions formetoclopramide in the month before pregnancy were excluded

Risk factors:Filled prescriptions for maternal use of metoclopramide duringpregnancy.Outcomes:Primary outcomes included Major congenital malformations,spontaneous abortion,and stillbirth.Secondary outcomes included preterm birth (< 37w), lowbirthweight (< 2500 g), and small for gestational age (lowest 10thpercentile of gestational age specific birthweight).

Main results

45 002 fetuses were exposed to a median of 40 doses ofmetoclopramide, beginning at a median of 57 gestational days.

Results show that metoclopramide use during any exposurewindow during pregnancy did not increase risk for correspondingadverse outcomes.

First-trimester metoclopramide use was not associated with anyof 20 specific malformations

Table & figure

Conclusion

Use of metoclopramide during pregnancy did not increase risk formajor congenital malformations or fetal death.

• Metoclopramide is prescribed in pregnancy mostcommonly for nausea and vomiting of pregnancy(NVP).

•• NVP affects up to 90%of pregnancies, with symptoms

beginning in the first trimester in 99% of cases• Management of NVP can be overly conservative• Inadequate symptom control may lead to hyperemesisgravidarum, for which inpatient treatment is usuallyrequired.

Commentary

• The study by Pasternak and colleagues showed that exposure tometoclopramide (occurring in 3% to 4% of the study population)during early pregnancy seems to be safe.• The study methodology was appropriate and included statistical

adjustment to control for potential confounders.• The large sample size allowed for specific powered evaluation of 20 of

the most common malformations. The study ruled out an absoluteincrease of > 0.5 cases of malformations per 1000 exposed infants.

Commentary

Not addressed in this study was whether metoclopramide use at highdoses and for periods > 3 months may be associated with tardivedyskinesia.

Overall, the study provides further reassurance on the short-term use ofmetoclopramide in early pregnancy.

Commentary

In adults, quitting smoking abruptlyimproved abstinence more than quittinggradually

Reference: Lindson-Hawley N, Banting M, West R, et al. Gradual versus abruptsmoking cessation: a randomized, controlled noninferiority trial.Ann Intern Med. 2016;164:585-92..

Question

In adult smokers, what is the efficacy of abrupt smokingcessation compared with gradual cessation?

Design:Randomized controlled noninferiority trial ISRCTN22526020.

Blinding: Unblinded Setting:31 primary care practices in England, UK.

Methods Patients:697 adult smokers (mean age 49 y, 50% men, 94%white)who were addicted to tobacco (≥ 15 cigarettes or /d or end expiratorycarbon monoxide [CO] concentration ≥ 15 ppm) and were willing to quitsmoking 2 weeks after enrollment.

Exclusion criteria includedcurrent use of cessation treatment or contraindications to nicotinereplacement therapy (NRT).

Intervention:Abrupt (n = 355) or gradual (n = 342) smoking cessation.Before the quit date, the abrupt cessation group received nicotinepatches, 21 mg/d, but were asked to continue smoking as usual for 2weeks and not to reduce smoking between the baselineappointment and quit date.2 weeks before quit day, the gradual cessation group chose 1 of 3structured reduction programs;• received nicotine patches, 21 mg/d• a choice of short-acting NRT products• created reduction schedules with a nurseall with the aim of reducing smoking by 50% in the first week and75% by quit day.After quit day, both groups received withdrawal-oriented behavioralcounseling, nicotine patches, and choice of short-acting NRT.

Outcomes:Primary outcome was abstinence from smoking at 4 weeks, validated byexhaled CO concentration < 10 ppm.Secondary outcomes included validated abstinence at 6months.

Participant follow-up: 84% at 6 months

Main results

Smoking abstinence was higher with abrupt cessation than withgradual cessation at 4 weeks and 6 months.

Table & figure

Conclusion

In adult smokers, abrupt smoking cessation increased abstinenceat 4 weeks and 6 months compared with gradual smokingreduction before a quit day.

• The well-designed and executed trial by Lindson-Hawley and colleaguescompared gradual smoking cessation with abrupt smoking cessation.the method generally recommended by clinicians .

• The results showed that quitting abruptly increased abstinence.• The exclusion criteria were minimal and allowed for participants with

severe medical or psychiatric conditions, including substance abuse.• The population was overwhelmingly white (94%) andhad a postsecondary school education (51%), which limits general-izability to other races/ethnicities and less-educated individuals.

• The results may also not be applicable to light smokers (< 15 ciga-rettes/d) or those who are less motivated to quit.

Commentary

• Since the abrupt cessation group had higher abstinence rates than thegradual cessation group at 4 weeks and 6 months,practicing cliniciansshould counsel their patients to quit abruptly.

• An important finding from this study was that participants whopreferred gradual cessation at baseline were less likely to be abstinentregardless of group allocation, which suggests that they may have beenmore ambivalent to quitting.

Commentary

For each patient who smokes, clinicians should1) assess interest inquitting2) encourage interested patients to set a quit date3) assist them by offering medications4) provide brief counseling or connect them with a local or regional quit

line.5) Counseling should focus on expected problems with quitting (e.g.,

difficulties patients faced with previous attempts and preparation forthe quit attempt

This trial adds to the literature by guiding clinicians to recommend abruptcessation over tapering.

Case 1A n 81-year-old woman with cerebrovascular disease presented to the emergency department

with a 1-week history of vomiting. Findings on abdominal examination were notable for normal

bowel sounds and the absence of tenderness, rebound, or guarding. A chest radiograph showed a large

air–liquid shadow in the inferior retrocardiac position (Panels A and B, arrows), which suggested a large paraesophageal

hernia. A computed tomographic scan showed a large retrocardiac mass containing air and liquid (Panels C

and D, red arrows) that was consistent with herniation of the stomach into the chest. Thickening of the gastric wall

suggested edema (Panel D, white arrow) and compression of the first portion of the duodenum, which caused gastric

distention. Hiatal hernias are defined as protrusion of the stomach through the diaphragm into the chest. The

degree of displacement can produce obstructive symptoms, as occurred in this patient, and may increase the risk of

volvulus. Owing to her generally poor health status, the patient was treated conservatively, with gastric suction

performed through a nasogastric tube followed by initiation and advancement of her oral diet, first with clear liquids,

then soft foods, and finally solid foods. The vomiting resolved, and the patient was asymptomatic at the time of

discharge.

caes2A 72-year-old woman with poorly controlled hyperlipidemia

and diabetes presented to the emergency department with a 5-day history of

lower abdominal pain. She also had fever and reported nausea and vomiting.

Physical examination revealed lower abdominal tenderness. Blood tests revealed

leukocytosis associated with a left shift (neutrophil count of 11,800 per cubic millimeter)

and elevation of the levels of C-reactive protein (24.0 mg per deciliter) and

glucose (735 mg per deciliter [41 mmol per liter]). A plain radiograph of the kidneys,

ureters, and bladder showed air surrounding the bladder (Panel A, arrows).

An abdominal computed tomographic scan revealed an area of gas dissecting the

bladder wall, bilateral hydronephrosis, and intramural gas with a cobblestone or

beaded-necklace appearance (Panel B, arrows), findings consistent with emphysematous

cystitis. The patient was treated with broad-spectrum antimicrobial agents

and placement of a Foley catheter. Subsequently, a urine culture was positive for

Escherichia coli; the patient was treated with antibiotics and recovered uneventfully.

Emphysematous cystitis is a urinary tract infection that is associated with gas

formation and is commonly caused by E. coli and Klebsiella pneumoniae.

THANK U