Procalcitonin-guided antibiotics for respiratory tract infections (part 2)

Two weeks ago I posted a blog about an impeccable NEJM study on the effects of procalcitonin (PCT) on antibiotic use in patients with lower respiratory tract infection. I stated that this RCT was one of the first diagnostic studies in this disease area targeting the correct patients and ended by an invitation to identify the fatal flaw. Last week one of the PhD students (Valentijn Schweitzer, absent when the paper was discussed in our journal club) told me that searching a fatal flaw was not needed; as the RCT was unnecessary in the first place. Here is why. Continue reading


Procalcitonin-guided antibiotics for respiratory tract infections

Every day thousands of physicians worldwide are facing the dilemma whether “to treat or not to treat this coughing patient with antibiotics”. A test that safely discriminates a bacterial from a non-bacterial cause is the holy grail, and some feel that procalcitonin (PCT) is just that. Results from multiple – mostly European – studies and meta-analyses pushed them in that direction. Yet, we are not that often sure of the causative pathogen, and diagnostic research in the absence of a gold standard is tricky business. And now there is this marvelous study that perfectly addresses that uncertainty and questions all prior PCT evidence, and that was discussed in our PhD journal club. Continue reading

The antipathy against SDD explained

With the first paper on Selective Digestive Decontamination in ICU patients published in 1983, this year marks the 35th anniversary of one the fiercest controversies in intensive care medicine, infection prevention and clinical microbiology. To celebrate this, Intensive Care Medicine published 3 editorials called the “Antipathy against SDD is justified”: 1 arguing Pro, 1 Con and 1 wasn’t sure. If the contents of these editorials had been patients, a (good) physician would have called them “diagnostic”. SDD is where clinical epidemiology becomes psychology and sociology. Continue reading

Attacking the fecal veneer (part 2)

Last year (Jan 17, 2017) I blogged on an excellent pragmatic cluster-randomized crossover study in which 4 patient room cleaning strategies were tested for their effectiveness to reduce acquisition of bacterial carriage for the incoming patients. The authors’ conclusion was that “enhanced terminal room disinfection decreases the risk of pathogen acquisition”, which I interpreted as “Not for C. diff, may be for MRSA and yes for VRE.” Now the same group published the effects of these interventions on infection/colonization with these pathogens in ALL patients admitted to the hospital during the study period, see. Authors’ conclusion this time: “Enhanced terminal room disinfection with UV in a targeted subset of high-risk rooms led to a decrease in hospital-wide incidence of C difficile and VRE.” Really? Continue reading

Antibiotic resistance after the toilet is flushed

Last week Jon ended his reflection with a grade A recommendation to close the toilet lid before flushing, as the best way to minimize the potential impact of “toilet flushing plumes”. Even better: do not flush at all. This week we take it from there, in a discovery of what happens subsequently. Let’s take the loo with the highest likelihood of being soiled with antibiotic-resistant bacteria (ARB) and antimicrobial resistance genes (ARGs): the hospital loo. Elena Buelow, former Phd student in our group and now post-doc in Limoges, France, quantified how hospital sewage contributes to the quantity and diversity of ARGs in the general sewerage system. The work was published on-line today.
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Fosfomycin: the hottest drug in town!? News from ECCMID 2018

In our team Thijs ten Doesschate does a PhD in clinical epidemiology addressing some clinical aspects on fosfomycin; An old antibiotic, active against Enterobacteriaceae, and surfacing as promising alternative to beta-lactams and fluoroquinolones in times of antibiotic resistance. He is currently coordinating a multi-center double-blind placebo-controlled randomized trial to determine non-inferiority of fosfomycin (against ciprofloxaxin) in the step-down oral treatment of complicated Urinary Tract Infections (UTI). If non-inferior, we could reduce cipro usage. For himself (and now for us) he summarized fosfomycin news at ECCMID. Most presentations (O) and posters (P) can also be found on .

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Late-breaker on clinical trials: less is more, but not always.

This years’ late-breaker session on clinical trials at ECCMID had 8 presentations; 3 on shortening duration of treatment; 2 compared antibiotics; 2 phase PK/PD studies and 1 PK/PD study in kids. The room was packed (and not that big anyway), so you may be interested to read what I thought I heard (and saw).

Dafna Yahav presented 7 vs 14 days for GNB BSI (community- and hospital-acquitred), an open-label non-inferiority RCT in 3 centers (2 in Israel and 1 in Italy). They adopted a non-inferiority margin of 10%, and pursued a sample size of 2×300 patients. Patients with GNB BSI that were afebrile and haemodynamically stable before day 5, could be randomzied. The priary outcome was a composite of all cause mortality, clinical failure and readmission/extended stay at day 90. They had 306 patients in the 7 days group and 298 in 14 days, with a balanced baseline table; 25% of infections was hospital-acquired; 70% had UTI, 65% were E. coli. The primary endpoint was reached in 141/306 and 149/298 patients yielding an absolute Risk Difference (aRD) of -3.9% (95% CI -11.9-4%), with non-inferiority demonstrated. 7 days was associated with less antibiotic use and earlier recovery. Conclusion: safe to stop at day 7 in non-neutropenic, HD stable patients not having an uncontrolled source infection that had a GNB BSI.

Duncan Cranendonk presented the DANCE trial comparing 6 days to 12 days of antibiotic treatment for severe cellulitis; all started with flucloxacillin (Dutch study, no MRSA) and were randomized at day 5-6 to placebo or continuation of antibiotics. The primary endpoint was clinical cure at  day 14. In all, 151 patients were randomized; 74 to 6 days 77 to 12 days, and 69 and 71 were evaluable in the modified Intention To Treat (mITT). The groups were well balanced, and the clinical cure rate was about 50% in both groups, with and aRD of 1.4% (95% CI 14.8-17.5%). So, the the non-inferiority margin of 10% was crossed. Moreover, relapses occurred more frequently in the 6-day group. Thus: non-inferiority not demonstrated (which may have resulted from not reaching the pursued enrollment) and more relapses….. So, keep on finalzing your 12-day course of antibiotics, is their message.

Aurelien Dinh presented the effectivenes of 3 days (vs 8 days) of beta-lactam antibiotics for hospitalized community-acquired pneumonia (CAP): a randomized non-inferiority double-blind trial. Fresh from the press, with last data from last Friday. The study domain included patients with “non-ICU CAP” treated with either amoxi-clav or 3rd generation cephalosporin and clinically stable at day 3. Dual therapy was not allowed (only 1 dose of macrolide or quinolone was). Randomization occurred at day 3, to placebo or oral amoxi clav. The primary endpoint was clinial cure (absence of fever, absence/improvement of clinica symptims, no new antibiotics ater day 3) at day 15. In the ITT they had 152 (8 days) and 156 patients (3 days), well balanced, median PSI 81-84, 4% had bacteremia, and 5% had a positive urinary pneumococcal antigen test. The primary endpoint was reached in 69.9% of patients in the 3-day group and in 61.2% in the 8-day group, yielding a 95% CI ranging from -1.09% to 20.55%, clearly demonstrating non-inferiority. One attendee in the audience not suffering from the oxygen-deficit had calculated that on average each participating hospital had included 3 patients per year, and whatt that meant for generalizibility.

Patrick Harris presented the MERINO trial in which piperacillin-tazobactam was compared to meropenem for definite treatment of BSI caused by 3rdG-Ceph-non-susceptible GNB (mainly E. coli). The primary endpoint was day-30 mortality. Patients needed to be enrolled within 72 hours after the index blood culture and had to receive at least 5 days of antibiotics. In all 391 patients were randomized and 378 evaluable; 85% of infections caused by E. coli, 45% community-were acquired. The study was suspened ath 3rd preplanned interim-analysis as it was highly unlikely that non-inferiority could be demonstrated, For day-30 mortality the aRD was 8.6% (95% CI 3.4-14.5), yielding a number needed to harm of 12! All secondary endpoinits favored meropenem. So, what started as a trial to reduce carbapenem use, provided undisputable evidence to do the opposite.

Finally, Angela Huttner presented a study from the AIDA project, which aimed to preserve old antibiotics for the future. in this open-label/analyst-blinded RCT, non-pregnant women aged ≥18 years with symptoms of lower UTI, a positive urine dipstick and no known colonization or previous infection with uropathogens resistant to the study antibiotics were included in Switzerland, Poland, and Israel. Women were randomized to either nitrofurantoine (5 days) (n=255) or a single-dose of fosfomycin (3 gram) (n=258). The primary outcome was clinical response at 28 days after therapy completion, defined as cure (complete resolution of symptoms and signs of UTI), failure (need for additional or change in antibiotic treatment due to UTI, or discontinuation due to lack of efficacy), or indeterminate (persistence of symptoms without objective evidence of infection). Both clinical and microbiological cure at day 28 was achieved more frequently in patients receiving nitrofurantoin (70% vs 58%; p=0.016; 74% vs 63%; p=0.037), as was hypothesized by the investigators. For those patients with E. coli infection the difference was even larger (aRD of 28%). So, the old drug (fosfo when used as a single-dose treatment) was worse than what is currently used in most countries for this indication. The study was published online in JAMA during the late-breaker session.

Five excellent investigator-initiated studies, that may all change our treatment guidelines. Unfortunately, short, old and less broad-spectrum is not always the better choice. Hope that many young scientists get inspired and will not be stopped by upcoming new EU regulations for clinical trials, see.