Infectious Disease

COVID – 19

RECOVERY trial: Dexamethasone in COVID-19

Article Name: Dexamethasone in Hospitalized Patients with Covid-19

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa2021436

Journal and year of publication: NEJM, 2021

Trial Design: Randomized clinical trial

Population: 6,425 patients
Key inclusion criteria:
– Hospitalized patients with clinically suspected or laboratory-confirmed SARS-CoV-2 infection
Key exclusion criteria:

Intervention Studied: Oral or intravenous dexamethasone (6 mg once daily) up to 10 days

Control: Usual care alone

Outcomes:
– Death (within 28 days): Dexamethasone: 22.9% vs Usual care: 25.7% (P<0.001)
– Subgroup analysis:
1. Death in those on Invasive mechanical ventilation: Dexamethasone: 29.3% vs Usual care: 41.4% – Rate ratio: 0.64 (95% CI: 0.51 to 0.81)
2. Death in those on oxygen without invasive mechanical ventilation: Dexamethasone: 23.3% vs Usual care: 26.2% – Rate ratio: 0.82 (95% CI: 0.72 to 0.94)
3. Death in those not needing respiratory support at randomization: Dexamethasone: 17.8% vs Usual care: 14.0% – Rate ratio: 1.19 (95% CI: 0.92 to 1.55)

The authors concluded that “In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.”

Citation: _{RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, Prudon B, Green C, Felton T, Chadwick D, Rege K, Fegan C, Chappell LC, Faust SN, Jaki T, Jeffery K, Montgomery A, Rowan K, Juszczak E, Baillie JK, Haynes R, Landray MJ. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 Feb 25;384(8):693-704. doi: 10.1056/NEJMoa2021436. Epub 2020 Jul 17. PMID: 32678530; PMCID: PMC7383595.}

ACTT-1 trial: Remdesivir in COVID-19

Article Name: Remdesivir for the Treatment of Covid-19 — Final Report

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa2007764

Journal and year of publication: NEJM, 2020

Trial Design: Randomized clinical trial

Population: 1,062 patients
Key inclusion criteria:
– Meet one of the criteria of lower respiratory tract infection at enrollment:
1. Radiographic infiltrates by imaging study
2. SpO2 ≤94% on RA, or requiring supplemental oxygen
3. Mechanical ventilation, or ECMO
– Laboratory-confirmed SARS-CoV-2 (+ve RT-PCR)
Key exclusion criteria:
– ALT, AST > 5x ULN, impaired renal function or need for hemodialysis or hemofiltration

Intervention Studied: Remdesivir

Control: Placebo

Outcomes:
– Median recovery time: Remdesivir: 10 days (95% CI: 9 to 11) vs Placebo: 15 days (95% CI: 13 to 18) (P<0.001)

The authors concluded that “Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection.”

Citation: _{Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S, Lopez de Castilla D, Finberg RW, Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA, Short WR, Touloumi G, Lye DC, Ohmagari N, Oh MD, Ruiz-Palacios GM, Benfield T, Fätkenheuer G, Kortepeter MG, Atmar RL, Creech CB, Lundgren J, Babiker AG, Pett S, Neaton JD, Burgess TH, Bonnett T, Green M, Makowski M, Osinusi A, Nayak S, Lane HC; ACTT-1 Study Group Members. Remdesivir for the Treatment of Covid-19 – Final Report. N Engl J Med. 2020 Nov 5;383(19):1813-1826. doi: 10.1056/NEJMoa2007764. Epub 2020 Oct 8. PMID: 32445440; PMCID: PMC7262788.}

Pfizer & BioNTech vaccine trial

Article Name: Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa2034577

Journal and year of publication: NEJM, 2020

Trial Design: Randomized clinical trial

Population: 43,548 patients
Key inclusion criteria:
– 16 years of age or older
– Healthy or had stable chronic medical conditions
Key exclusion criteria:
– Medical history of Covid-19
– Treatment with immunosuppressive therapy or diagnosed with an immunocompromising condition

Intervention Studied: 2 doses of BNT162b2 vaccine candidate (21 days apart)

Control: Placebo

Outcomes:
– Confirmed cases of covid (onset after at least 7 days after second dose): BNT162b2: 8 cases out of 21,720 vs Placebo: 162 cases out of 21,728. BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval: 90.3 to 97.6)

The authors concluded that “A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines.”

Citation: _{Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, Perez JL, Pérez Marc G, Moreira ED, Zerbini C, Bailey R, Swanson KA, Roychoudhury S, Koury K, Li P, Kalina WV, Cooper D, Frenck RW Jr, Hammitt LL, Türeci Ö, Nell H, Schaefer A, Ünal S, Tresnan DB, Mather S, Dormitzer PR, Şahin U, Jansen KU, Gruber WC; C4591001 Clinical Trial Group. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020 Dec 31;383(27):2603-2615. doi: 10.1056/NEJMoa2034577. Epub 2020 Dec 10. PMID: 33301246; PMCID: PMC7745181.}

COVE trial: Moderna vaccine for COVID-19

Article Name: Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa2034577

Journal and year of publication: NEJM, 2020

Trial Design: Randomized clinical trial

Intervention Studied: 2 doses of BNT162b2 vaccine candidate (21 days apart)

Control: Placebo

HIV

INSIGHT-START trial: Early initiation of anti-retroviral therapy for HIV

Article Name: Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1506816

Journal and year of publication: NEJM, 2015

Trial Design: Randomized clinical trial

Population: 4,685 patients
Key inclusion criteria:
– HIV-positive patients of 18 years of age or older
– Not initiated antiretroviral therapy
– No history of AIDS
– Two CD4+ counts > 500 cells/mm³
Key exclusion criteria:
– Pregnant or breast-feeding at screening

Intervention Studied: Start antiretroviral therapy immediately (immediate-initiation group)

Control: Defer it until the CD4+ count decreased to 350 cells/mm³OR until the development of AIDS OR another condition that dictated the use of antiretroviral therapy (deferred-initiation group)

Outcomes:
– Primary end point occurrence (serious AIDS-related event, serious non–AIDS-related event, or death from any cause): Immediate-initiation group: 1.8% (0.60 events per 100 person-years) vs Deferred-initiation group: 4.1% (1.38 events per 100 person-years) (P<0.001)
– Adverse events of grade 4: Similar in both groups

The authors concluded that “The initiation of antiretroviral therapy in HIV-positive adults with a CD4+ count of more than 500 cells per cubic millimeter provided net benefits over starting such therapy in patients after the CD4+ count had declined to 350 cells per cubic millimeter.”

Citation: _{INSIGHT START Study Group, Lundgren JD, Babiker AG, Gordin F, Emery S, Grund B, Sharma S, Avihingsanon A, Cooper DA, Fätkenheuer G, Llibre JM, Molina JM, Munderi P, Schechter M, Wood R, Klingman KL, Collins S, Lane HC, Phillips AN, Neaton JD. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl J Med. 2015 Aug 27;373(9):795-807. doi: 10.1056/NEJMoa1506816. Epub 2015 Jul 20. PMID: 26192873; PMCID: PMC4569751.}

SINGLE trial: Dolutegravir + Abacavir-Lamivudine for HIV

Article Name: Dolutegravir plus Abacavir–Lamivudine for the Treatment of HIV-1 Infection

URL: https://www.nejm.org/doi/full/10.1056/nejmoa1215541

Journal and year of publication: NEJM, 2013

Trial Design: Randomized clinical trial

Population: 833 patients
Key inclusion criteria:
– 18 years of age or older with HIV-1 infection and didn’t receive ART
– Plasma HIV-1 RNA level of at least 1000 copies/mL without genotypic evidence of viral resistance at screening
Key exclusion criteria:
– Moderate or severe hepatic impairment
– Estimated Cr clearance <50 ml/min

Intervention Studied: Dolutegravir + abacavir–lamivudine (DTG–ABC–3TC group)

Control: Efavirenz–tenofovir disoproxil fumarate (DF)–emtricitabine (EFV–TDF–FTC group)

Outcomes:
– Participants with HIV-1 RNA level <50 copies/mL (At week 48): DTG–ABC–3TC: 88% vs EFV–TDF–FTC:81% (P=0.003)
– Median time to viral suppression: DTG–ABC–3TC: 28 days vs EFV–TDF–FTC: 84 days (P<0.001)
– Discontinuation due to adverse events: DTG–ABC–3TC: 2% of patients vs EFV–TDF–FTC: 10% of patients

The authors concluded that “Dolutegravir plus abacavir–lamivudine had a better safety profile and was more effective through 48 weeks than the regimen with efavirenz–tenofovir DF–emtricitabine.“

Citation: _{Walmsley SL, Antela A, Clumeck N, Duiculescu D, Eberhard A, Gutiérrez F, Hocqueloux L, Maggiolo F, Sandkovsky U, Granier C, Pappa K, Wynne B, Min S, Nichols G; SINGLE Investigators. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013 Nov 7;369(19):1807-18. doi: 10.1056/NEJMoa1215541. PMID: 24195548.}

Biktarvy for HIV

Article Name: Coformulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection (GS-US-380–1490): a randomised, double-blind, multicentre, phase 3, non-inferiority trial

URL: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32340-1/fulltext

Journal and year of publication: The Lancet 2017

Trial Design: Randomized clinical trial

Population: 657 patients
Key inclusion criteria:
– Aged ≥18 years with previously untreated HIV-1 infection
– Plasma HIV-1 RNA levels of at least 500 copies/mL
– eGFR at least 30 mL/min
Key exclusion criteria:

Intervention Studied: Bictegravir, emtricitabine, and tenofovir alafenamide fixed-dose combination (bictegravir group)

Control: Dolutegravir + emtricitabine and tenofovir alafenamide (dolutegravir group)

Outcomes:
– Achieving an HIV-1 RNA <50 copies/mL (at week 48): Bictegravir group: 89% vs Dolutegravir group: 93% (p=0.12, Non-inferiority of bictegravir regimen to dolutegravir regimen)
– Similar Incidence and severity of adverse events in both groups

The authors concluded that “At 48 weeks, virological suppression with the bictegravir regimen was achieved and was non-inferior to the dolutegravir regimen in previously untreated adults. There was no emergent resistance to either regimen. The fixed-dose combination of bictegravir, emtricitabine, and tenofovir alafenamide was safe and well tolerated compared with the dolutegravir regimen.“

Citation: _{Sax PE, Pozniak A, Montes ML, Koenig E, DeJesus E, Stellbrink HJ, Antinori A, Workowski K, Slim J, Reynes J, Garner W, Custodio J, White K, SenGupta D, Cheng A, Quirk E. Coformulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection (GS-US-380-1490): a randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet. 2017 Nov 4;390(10107):2073-2082. doi: 10.1016/S0140-6736(17)32340-1. Epub 2017 Aug 31. PMID: 28867499.}

iPrEx trial: PREP for HIV prophylaxis

Article Name: Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1011205

Journal and year of publication: NEJM, 2010

Trial Design: Randomized clinical trial

Population: 2,499 patients
Key inclusion criteria:
– Male sex at birth aged 18 or older with HIV-seronegative status
– Evidence of high risk for acquisition of HIV infection
Key exclusion criteria:
– Serious illness
– Active illness like DM on Meds, TB, and cancer require further therapy

Intervention Studied: Emtricitabine and tenofovir disoproxil fumarate (FTC–TDF)

Control: Placebo

Outcomes:
– Acquiring HIV: FTC–TDF: 36 vs Placebo: 64 (P=0.005)

The authors concluded that “Oral FTC–TDF provided protection against the acquisition of HIV infection among the subjects. Detectable blood levels strongly correlated with the prophylactic effect.”

Citation: _{Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, Goicochea P, Casapía M, Guanira-Carranza JV, Ramirez-Cardich ME, Montoya-Herrera O, Fernández T, Veloso VG, Buchbinder SP, Chariyalertsak S, Schechter M, Bekker LG, Mayer KH, Kallás EG, Amico KR, Mulligan K, Bushman LR, Hance RJ, Ganoza C, Defechereux P, Postle B, Wang F, McConnell JJ, Zheng JH, Lee J, Rooney JF, Jaffe HS, Martinez AI, Burns DN, Glidden DV; iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010 Dec 30;363(27):2587-99. doi: 10.1056/NEJMoa1011205. Epub 2010 Nov 23. PMID: 21091279; PMCID: PMC3079639.}

Hepatitis B/C

ION-1 trial: Ledipasvir + sofosbuvir for HCV

Article Name: Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection

URL: https://www.nejm.org/doi/full/10.1056/nejmoa1402454

Journal and year of publication: NEJM, 2014

Trial Design: Randomized clinical trial

Population: 865 patients
Key inclusion criteria:
– Previously untreated patients with chronic HCV genotype 1 infection.
– HCV RNA ≥ 10,000 IU/mL at Screening
Key exclusion criteria:
– Current or prior history of GI condition that may affect absorption of drugs
– Current or prior history of clinical hepatic decompensation
– Chronic liver disease of a non-HCV etiology

Intervention Studied:
1) Ledipasvir and sofosbuvir for 12 weeks
2) Ledipasvir–sofosbuvir plus ribavirin for 12 weeks
3) Ledipasvir–sofosbuvir for 24 weeks
4) Ledipasvir–sofosbuvir plus ribavirin for 24 weeks

Control: See above

Outcomes:
– Percentage of patients meeting the criterion for a sustained virologic response:
– 12 weeks of (ledipasvir + sofosbuvir): 99% (95% CI:96 to 100)
– 12 weeks of (ledipasvir + sofosbuvir + ribavirin): 97% (95% CI:94 to 99)
– 24 weeks of (ledipasvir + sofosbuvir): 98% (95% CI:95 to 99)
– 24 weeks of (ledipasvir + sofosbuvir + ribavirin): 99% (95% CI:97 to 100)

The authors concluded that “Once-daily ledipasvir–sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection.”

Citation: _{Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, Romero-Gomez M, Zarski JP, Agarwal K, Buggisch P, Foster GR, Bräu N, Buti M, Jacobson IM, Subramanian GM, Ding X, Mo H, Yang JC, Pang PS, Symonds WT, McHutchison JG, Muir AJ, Mangia A, Marcellin P; ION-1 Investigators. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014 May 15;370(20):1889-98. doi: 10.1056/NEJMoa1402454. Epub 2014 Apr 11. PMID: 24725239.}

VALENCE trial: Sofosbuvir + Ribavirin for HCV

Article Name: Sofosbuvir and Ribavirin in HCV Genotypes 2 and 3

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1316145

Journal and year of publication: NEJM, 2014

Trial Design: Randomized clinical trial (Study was unblinded, study findings were redefined to be descriptive)

Population: 419 patients
Key inclusion criteria:
– Chronic infection with HCV genotype 2 or 3
– Serum HCV RNA levels of 10,000 IU per milliliter or higher
Key exclusion criteria:

Intervention Studied: Sofosbuvir–ribavirin (Genotype 2: 12 weeks, Genotype 3: 24 weeks)

Control: Placebo (terminated later)

Outcomes:
– Percentage of patients meeting the criterion for a sustained virologic response:
– Patients with HCV genotype 2: 93% (95% CI: 85 to 98)
– Patients with HCV genotype 3: 85% (95% CI: 80 to 89)

The authors concluded that “Therapy with sofosbuvir–ribavirin for 12 weeks in patients with HCV genotype 2 infection and for 24 weeks in patients with HCV genotype 3 infection resulted in high rates of sustained virologic response.”

Citation: _{Zeuzem S, Dusheiko GM, Salupere R, Mangia A, Flisiak R, Hyland RH, Illeperuma A, Svarovskaia E, Brainard DM, Symonds WT, Subramanian GM, McHutchison JG, Weiland O, Reesink HW, Ferenci P, Hézode C, Esteban R; VALENCE Investigators. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med. 2014 May 22;370(21):1993-2001. doi: 10.1056/NEJMoa1316145. Epub 2014 May 4. PMID: 24795201.}

BEHOLD trial: Entecavir + Lamivudine for HCV

Article Name: A Comparison of Entecavir and Lamivudine for HBeAg-Positive Chronic Hepatitis B

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa051285

Journal and year of publication: NEJM, 2006

Trial Design: Randomized clinical trial

Population: 715 patients
Key inclusion criteria:
– 16 years of age or older with HBeAg-positive chronic hepatitis B and compensated liver function.
– Detectable hepatitis B surface antigen (HBsAg) for at least 24 weeks before
– HBV DNA level of at least 3 MEq per/mL
– ALT level 1.3 to 10.0 times ULN
Key exclusion criteria:
– Coinfection with hepatitis C, hepatitis D, or HIV
– Presence of other forms of liver disease

Intervention Studied: Entecavir

Control: Lamivudine

Outcomes:
– Histologic improvement (after 48 weeks): Entecavir: 72% of patients vs Lamivudine: 62% of patients (P=0.009)
– Achieving undetectable HBV DNA levels as per PCR: Entecavir: 67% of patients vs Lamivudine: 36% of patients (P<0.001)

The authors concluded that “Among patients with HBeAg-positive chronic hepatitis B, the rates of histologic, virologic, and biochemical improvement are significantly higher with entecavir than with lamivudine. The safety profile of the two agents is similar, and there is no evidence of viral resistance to entecavir.”

Citation: _{Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, Lok AS, Han KH, Goodman Z, Zhu J, Cross A, DeHertogh D, Wilber R, Colonno R, Apelian D; BEHoLD AI463022 Study Group. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006 Mar 9;354(10):1001-10. doi: 10.1056/NEJMoa051285. PMID: 16525137.}

Clostridium difficile

Vancomycin and metronidazole for C. diff

Article Name: A Comparison of Vancomycin and Metronidazole for the Treatment of Clostridium difficile–Associated Diarrhea, Stratified by Disease Severity

URL: https://academic.oup.com/cid/article/45/3/302/358373

Journal and year of publication: Clinical Infectious Disease, 2007

Trial Design: Randomized clinical trial

Population: 172 patients
Key inclusion criteria:
– Diarrhea (defined as ⩾3 nonformed stools in 24 h)
– C. difficile toxin A demonstrated in the stool within 48 h after study entry OR pseudomembranous colitis found on endoscopic examination
Key exclusion criteria:
– Prior failure of CDAD to respond to either study drug
– Treatment with vancomycin or metronidazole in the past 14 days

Intervention Studied: Oral Vancomycin + Placebo

Control: Oral Metronidazole + Placebo

Outcomes:
– Percentage of patients achieving clinical cure:
– Patients with mild CDAD: Metronidazole: 90% vs Vancomycin: 98% (P = 0.36)
– Patients with severe CDAD: Metronidazole: 76% vs Vancomycin: 97% (P = 0.02)

The authors concluded that “Our findings suggest that metronidazole and vancomycin are equally effective for the treatment of mild CDAD, but vancomycin is superior for treating patients with severe CDAD.”

Citation: _{Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007 Aug 1;45(3):302-7. doi: 10.1086/519265. Epub 2007 Jun 19. PMID: 17599306.}

Fidaxomicin for C. diff

Article Name: Fidaxomicin versus Vancomycin for Clostridium difficile Infection

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa0910812

Journal and year of publication: NEJM, 2011

Trial Design: Randomized clinical trial

Population: 629 patients
Key inclusion criteria:
– Diagnosis of C. difficile infection: Diarrhea + difficile toxin A, B, or both
Key exclusion criteria:
– Life-threatening or fulminant C. difficile infection, or toxic megacolon.
– History of UC or Crohn’s disease

Intervention Studied: Fidaxomicin

Control: Vancomycin

Outcomes:
– Rates of clinical cure: (Fidaxomicin was noninferior): Fidaxomicin: 88.2% vs Vancomycin: 85.8%
– Recurrence of infection:
As per modified intention-to-treat analysis: Fidaxomicin: 15.4% vs Vancomycin: 25.3% (P=0.005)

The authors concluded that “The rates of clinical cure after treatment with fidaxomicin were noninferior to those after treatment with vancomycin. Fidaxomicin was associated with a significantly lower rate of recurrence of C. difficile infection associated with non–North American Pulsed Field type 1 strains.”

Citation: _{Louie TJ, Miller MA, Mullane KM, Weiss K, Lentnek A, Golan Y, Gorbach S, Sears P, Shue YK; OPT-80-003 Clinical Study Group. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011 Feb 3;364(5):422-31. doi: 10.1056/NEJMoa0910812. PMID: 21288078.}

Fecal transplant for C. diff

Article Name: Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1205037

Journal and year of publication: NEJM, 2013

Trial Design: Randomized clinical trial

Population: 43 patients
Key inclusion criteria:
– Relapse of C. difficile infection
Key exclusion criteria:
– Prolonged compromised immunity
– Use of antibiotics other than for treatment of C. difficile infection at baseline
– Admission to ICU or need for vasopressor medication

Intervention Studied:
1) Vancomycin regimen, followed by bowel lavage and subsequent infusion of a solution of donor feces through a nasoduodenal tube
2) Standard vancomycin regimen.
3) Standard vancomycin regimen with bowel lavage

Control: See above

Outcomes:
– Resolution of c.difficile infection:
Infusion group: 13 of 16 of patients (81%) after the first trial vs Vancomycin alone: 4 of 13 patients (31%) vs Vancomycin + bowel lavage: 3 of 13 patients (23%) (P<0.001 for both comparisons with the infusion group)

The authors concluded that “The infusion of donor feces was significantly more effective for the treatment of recurrent C. difficile infection than the use of vancomycin.“

Citation: _{van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG, Speelman P, Dijkgraaf MG, Keller JJ. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013 Jan 31;368(5):407-15. doi: 10.1056/NEJMoa1205037. Epub 2013 Jan 16. PMID: 23323867.}

Infective Endocarditis

POET trial: Oral vs IV antibiotics for endocarditis

Article Name: Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis

URL: https://www.nejm.org/doi/10.1056/NEJMoa1808312

Journal and year of publication: NEJM, 2019

Trial Design: Randomized clinical trial

Population: 400 patients
Key inclusion criteria:
– Adults, in stable condition, receiving IV antibiotic for endocarditis of the left of the heart (native or prosthetic valves), who fulfilled the modified Duke criteria
– Positive blood cultures for streptococcus, Enterococcus faecalis, Staphylococcus aureus, or coagulase-negative staphylococci.
– No signs of abscess formation or valve abnormalities that would require surgery on TEE
Key exclusion criteria:
– Body mass index > 40
– Concomitant infection requiring IV antibiotic therapy

Intervention Studied: Switch to oral antibiotic treatment (after at least 10 days of IV antibiotics)

Control: Continue intravenous treatment

Outcomes:
– Primary composite outcome occurrence (all-cause mortality, unplanned cardiac surgery, embolic events, or relapse of bacteremia with the primary pathogen, from the time of randomization until 6 months after antibiotic treatment was completed): IV treated group: 24 patients (12.1%) vs Orally treated group: 18 patients (9.0%) (P=0.40, met noninferiority criteria)

The authors concluded that “In patients with endocarditis on the left side of the heart who were in stable condition, changing to oral antibiotic treatment was noninferior to continued intravenous antibiotic treatment.”

Citation: _{Iversen K, Ihlemann N, Gill SU, Madsen T, Elming H, Jensen KT, Bruun NE, Høfsten DE, Fursted K, Christensen JJ, Schultz M, Klein CF, Fosbøll EL, Rosenvinge F, Schønheyder HC, Køber L, Torp-Pedersen C, Helweg-Larsen J, Tønder N, Moser C, Bundgaard H. Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis. N Engl J Med. 2019 Jan 31;380(5):415-424. doi: 10.1056/NEJMoa1808312. Epub 2018 Aug 28. PMID: 30152252.}

EASE trial: Early surgery for infective endocarditis

Article Name: Early Surgery versus Conventional Treatment for Infective Endocarditis

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1112843

Journal and year of publication: NEJM, 2012

Trial Design: Randomized clinical trial

Population: 76 patients with infective endocarditis
Key inclusion criteria:
– Diagnosis of Infective endocarditis according to the modified Duke criteria
– Severe mitral valve or aortic valve disease and vegetation with a diameter greater than 10 mm
Key exclusion criteria:
– Moderate-to-severe congestive heart failure
– Infective endocarditis complicated by heart block
– Annular or aortic abscess
– Destructive penetrating lesions requiring urgent surgery
– Fungal endocarditis
– Infective endocarditis involving a prosthetic valve
– Right-sided vegetations

Intervention Studied:
Early surgery

Control:
Medical therapy

Outcomes:
– Primary endpoint occurrence (in-hospital death and embolic events that occurred within 6 weeks after randomization): 3% in the early-surgery group vs 23% in the conventional-treatment group (P=0.03)
– The rate of the composite endpoint of death from any cause, embolic events, or recurrence of infective endocarditis at 6 months: 3% in the early-surgery group vs 28% in the conventional-treatment group (P=0.02)

The authors concluded that “As compared with conventional treatment, early surgery in patients with infective endocarditis and large vegetations significantly reduced the composite end point of death from any cause and embolic events by effectively decreasing the risk of systemic embolism.”

Citation: _{Kang DH, Kim YJ, Kim SH, Sun BJ, Kim DH, Yun SC, Song JM, Choo SJ, Chung CH, Song JK, Lee JW, Sohn DW. Early surgery versus conventional treatment for infective endocarditis. N Engl J Med. 2012 Jun 28;366(26):2466-73. doi: 10.1056/NEJMoa1112843. PMID: 22738096.}

Others

Early treatment for sepsis

Article Name: Time to Treatment and Mortality during Mandated Emergency Care for Sepsis

URL: https://www.nejm.org/doi/10.1056/NEJMoa1703058

Journal and year of publication: NEJM, 2017

Trial Design: Retrospective cohort study

Population: 49,331 patients
Key inclusion criteria:
– Community-acquired severe sepsis or septic shock
Key exclusion criteria:

Intervention Studied: Implementation of sepsis bundle

Control: N/a

Outcomes:
– RIsk adjusted in-hospital mortality:
– Longer time to bundle completion was associated with higher risk
Odds ratio: 1.04 per hour (95% CI: 1.02 to 1.05), P<0.001
– Longer time to administration of antibiotics was associated with higher risk
Odds ratio: 1.04 per hour (95% CI: 1.03 to 1.06), P<0.001
– No association with longer time to completion of fluid bolus (within 12 hours)
Odds ratio: 1.01 per hour (95% CI: 0.99 to 1.02), P=0.21

The authors concluded that “More rapid completion of a 3-hour bundle of sepsis care and rapid administration of antibiotics, but not rapid completion of an initial bolus of intravenous fluids, were associated with lower risk-adjusted in-hospital mortality.”

Citation: _{Seymour CW, Gesten F, Prescott HC, Friedrich ME, Iwashyna TJ, Phillips GS, Lemeshow S, Osborn T, Terry KM, Levy MM. Time to Treatment and Mortality during Mandated Emergency Care for Sepsis. N Engl J Med. 2017 Jun 8;376(23):2235-2244. doi: 10.1056/NEJMoa1703058. Epub 2017 May 21. PMID: 28528569; PMCID: PMC5538258.}

Dexamethasone for bacterial meningitis

Article Name: Dexamethasone in Adults with Bacterial Meningitis

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa021334

Journal and year of publication: NEJM, 2002

Trial Design: Randomized controlled study

Population: 301 patients
Key inclusion criteria:
– 17 years of age or older with suspected meningitis
Key exclusion criteria:
– Cerebrospinal shunt
– Treated with oral or parenteral antibiotics in the previous 48 hours
– History of active TB or fungal infection

Intervention Studied: Dexamethasone

Control: Placebo

Outcomes:
– Treatment with dexamethasone was associated with:
– Reduction of risk of an unfavorable outcome: Relative risk: 0.59 (95% CI: 0.37 to 0.94); P=0.03
– Reduction in mortality: Relative risk of death: 0.48 (95% CI: 0.24 to 0.96); P=0.04

The authors concluded that “Early treatment with dexamethasone improves the outcome in adults with acute bacterial meningitis and does not increase the risk of gastrointestinal bleeding.”

Citation: _{de Gans J, van de Beek D; European Dexamethasone in Adulthood Bacterial Meningitis Study Investigators. Dexamethasone in adults with bacterial meningitis. N Engl J Med. 2002 Nov 14;347(20):1549-56. doi: 10.1056/NEJMoa021334. PMID: 12432041.}

PneumA trial: Duration of antibiotics for VAP

Article Name: Comparison of 8 vs 15 Days of Antibiotic Therapy for Ventilator-Associated Pneumonia in Adults

URL: https://jamanetwork.com/journals/jama/fullarticle/197644

Journal and year of publication: JAMA, 2003

Trial Design: Randomized controlled study

Population: 401 patients
Key inclusion criteria:
– In ICU, intubated on mechanical ventilation for at least 48 hours
– Suspicion of VAP
– Positive quantitative cultures of distal pulmonary secretion samples
Key exclusion criteria:
– Neutropenia
– Acquired immunodeficiency syndrome, received immunosuppressants or long-term corticosteroid therapy
– Concomitant extrapulmonary infection requiring prolonged (>8 days) antimicrobial treatment

Intervention Studied: 8 days course of antibiotics

Control: 15 days course of antibiotics

Outcomes:
– Mortality: (no significant difference):
8 days course: 18.8% vs 15 days course: 17.2%
Difference: 1.6% (90% CI: −3.7% to 6.9%)

– Recurrent infections: (no significant difference)
8 days course: 28.9% vs 15 days course: 26.0%
Difference: 2.9% (90% CI: −3.2% to 9.1%)

– Mean (SD) antibiotic-free days:
8 days course: 13.1 days [±7.4] vs 15 days course: 8.7 days [±5.2]
P<.001

The authors concluded that “Among patients who had received appropriate initial empirical therapy, with the possible exception of those developing nonfermenting gram-negative bacillus infections, comparable clinical effectiveness against VAP was obtained with the 8- and 15-day treatment regimens. The 8-day group had less antibiotic use.”

Citation: _{Chastre J, Wolff M, Fagon JY, Chevret S, Thomas F, Wermert D, Clementi E, Gonzalez J, Jusserand D, Asfar P, Perrin D, Fieux F, Aubas S; PneumA Trial Group. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA. 2003 Nov 19;290(19):2588-98. doi: 10.1001/jama.290.19.2588. PMID: 14625336.}

Do you think there are some important trials we should add to our site? Please contact us at landmarktrials@gmail.com with the trial name, link, and why you think it is a landmark paper!

Disclaimer: Please note that articles mentioned on this site are the property of their respective journals. The information from these articles was presented on this site under the Fair Use legal doctrine (Section 107 of the Copyright Act) as the data shared was limited in quantity, factual in nature, already published, and for the purpose of relaying and teaching socially beneficial medical knowledge. The work was attributed to the journals that published them with citations and links provided.

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