The colour of the global crisis of antibiotic resistance is red (if te Gram stain is your reference). In rich countries we have ESBL-producing Enterobacterales (mainly E. coli), but the real problem are carbapenemase-producing strains (Klebsiella, Pseudomonas and Acinetobacter) that are already endemic in lower and middle-income countries. The unanswered question is “where did these resistant bacteria come from”? Animals or bathrooms? Continue reading
“33000 people die every year due to infections with antibiotic-resistant bacteria” this is what ECDC released on Nov 6, 2018, on their website. “Superbugs kill 33,000 in Europe every year” said CNN and the same wording was used (in Dutch) by our Telegraaf. Naturally, the headings were based on the ECDC study published that day in Lancet ID, which happened to be the most downloaded paper ever of the journal. But was this really what was published? Valentijn Schweitzer and I got lost in translation when trying to answer that question. Continue reading
Just before Christmas a follow-up on that what bothers us most: patients dying because of antibiotic resistance. I previously tried, see here, to disentangle from the ECDC study (33.000 deaths per year in Europe) how they got to 206 AMR casualties in the Netherlands and ended with a recommendation to not “focus too much on the absolute numbers as they may not be very precise.” With Valentijn Schweitzer I spent some more time in the 200 pages supplement, only to find out – in the end – that the Americans do these kind of studies much better. Continue reading
I attended a thought-provoking session at the recent Healthcare Infection Society (HIS) conference in Liverpool on reducing GNBSI (you can download some of the speaker abstracts here). It seems that the hefty majority of E. coli BSIs are rooted in issues outwith the walls of acute hospitals. So the question is, who’s going to tackle these issues to prevent GNBSI? Who’s going to go for GNBSI (sorry, couldn’t resist another pop-culture reference to the ‘80s – who could forget ‘Going for Gold’ with Henry Kelly).
“In case of an emergency check your own pulse first”, that’s one of the rules of the House of God. More than 33.000 deaths due to AMR in Europe per year, as reported yesterday, definitely is an emergency. Therefore, I tried to disentangle what that means for my small country that so vividly tried to keep these superbugs out of the country. Continue reading
This weeks’ publication of the highly controversial results of the MERINO trial in JAMA caused quite a stir on social media. The paper has been viewed >50,000 times and the unexpected outcome has been challenged by many. But what was the conclusion in JAMA? “Among patients with E. coli or K. pneumoniae bloodstream infection (BSI) and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a non-inferior 30-day mortality.” Not and in the same sentence, a doubled denial, is confusing. More important, as formulated, the study was inconclusive, which nobody seems to accept. We dived into the depths of the reporting and then tried to explain it. Continue reading
Today, the Journal of Hospital Infection have published an article from our research group about E. coli BSI sources. The key message is that the sources of E. coli BSIs at a large teaching hospital differ considerably from the national average, with a large proportion related to febrile neutropaenia (18%) and diverse gastrointestinal sources (15%). This calls into question the ‘preventable’ proportion of these cases – and adds something to the discussion as to whether the national ambition to halve GNBSI by 2021 is feasible.
I’ve been mulling over the issue of sinks in clinical areas a lot recently and a paper published today in the Journal of Hospital Infection has really crystallised my thoughts. Sinks are everywhere; often extra ones are installed in the quest for high hand hygiene compliance however are we really thinking about the risks that these may cause apart from the traditional ones posed by Pseudomonas and Legionella? Do we even really reflect upon what they are used for? Continue reading
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.