New antimicrobials, real world data and LTACs – an interview with Ellie Goldstein

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Long-term acute care hospitals (LTACs), which cater to chronically ill patients with multiple co-morbidities and prolonged stays, have been suggested to act as reservoirs for multi-drug resistant organisms (MDROs) – making them of particular interest for surveillance and monitoring.

At ASM Microbe, the annual meeting of the American Society for Microbiology (7–11 June, GA, USA), we spoke to infectious diseases specialist, Ellie Goldstein (Santa Monica, CA, USA), about his recent publication on this issue and the challenges facing drug-resistant infections.

First, could you introduce yourself and tell us a bit about your background?

My name is Ellie Goldstein, I’m an infectious disease physician and I do many different things; I’m a Clinical Professor of Medicine at the University of California, Los Angeles, I’m Director of the RM Alden Research Laboratory (Santa Monica, CA, USA), which is an anaerobic research lab, I am in clinical practice and I’m involved in antimicrobial stewardship.

With regards to antimicrobial resistance, why are Gram-negative infections an area of particular concern?

One of my functions is as chair of Infection Prevention and Antimicrobial Stewardship at an LTAC – these are particular to the USA and patients go to these facilities when they’re too sick to go to nursing homes but not sick enough to stay in an acute care hospitals. These patients – who often have multiple comorbidities, are on ventilators, have decubiti, renal failure and are pre-exposed to antibiotics – are really the ‘poster child’ patients for these MDRO Gram-negative infections.

In our LTAC, we’ve noticed that many of patients are infected with resistant isolates; for example, if they have a staphylococcus infection it’ll be MRSA, or if it’s Gram-negative it might be an ESBL or a carbapenem-resistant Enterobacteriaceae (CRE). These resistant infections are a particular concern with regards to stewardship, guiding appropriate antibiotic use and infection prevention. Our observations are consistent with the global pattern – resistance to Gram-negative rods have been labelled an urgent threat by the Centers for Disease Control and Prevention (CDC; GA, USA). Proper therapy of these MDROs are problematic.

You recently published a paper on the comparative ‘real world’ in vitro activity of two new antimicrobials – why do you think ‘real world’ data is important?

What we find is that much of the work done on antimicrobials susceptibility testing is done by laboratories that collect selected resistant isolates, from universities with special care units, or come from the selected studies that lead to licensure. These take into account various groups of patients but they can’t give any information on what’s happening in a local institution who face community real life problems. So, while we can make generalizations from these studies, when new drugs are released it’s important that we study what is happening at a single institution with a wide catchment referral base and evaluate how this can help physicians guide specific therapies for these patients.

LTACs are a particularly important place to evaluate new antibiotics because LTAC patients often move between different healthcare facilities and carry their resistant organisms with them.  Approximately 50% of short-term acute care hospital patients who have CREs are ultimately discharged to LTACs – so LTACs are thought to be reservoirs for resistance. By carrying out this study we hoped to understand how we could best guide therapy for our patients.

You mentioned these LTAC patients move around often, is that a problem for the spread and transmission of these isolates?

Yes, the movement between facilities actually has many issues. One of the problems is inter-facility communication.  During transitions of care, where one facility communicates with another about a patient, often there is no established routine method of communicating resulting in no data transfer at all. This means the receiving facility could be taking patients who might have unsuspected resistant isolates. If this is the case and then there are any lapses in hygiene or there’s a need to cohort patients, the facility will be unprepared to take appropriate measures to deter intra- and inter-facility spread of MDROs. There are a number of studies that have  tracked patients within a  in a system – one study even suggests acute care hospitals could predict what MDRO  isolates were going to occur and their resistance pattern just by knowing what nursing home or LTAC a patient came from. The goal is that we all talk and, communication from one facility to another when a patient is transferred. This is important as otherwise these MDRO carrier patients can lead to mini-outbreaks of resistant isolates.

Why is it important to look at susceptibility rates on an ongoing basis?

It’s challenging to reliably predict what the resistance pattern and therefore susceptibility tests are necessary. I attended a session at ASM Microbe on whole-genome sequencing and how this might predict what will happen in terms of resistance; however, most facilities do not have access to this technology and are still using phenotypic identification and antimicrobial susceptibility testing.

Moreover, real-time, real-world experience becomes important because most studies are focused on one aspect of resistance may be biased. Therefore looking in-depth at susceptibility rates in one institution – a sentinel type of institution – with a large diverse referral bases and broad catchment area allows physicians to treat their patients appropriately.

Finally, empiric therapy might be possible if we knew whether a patient had resistant isolates, had multiple risk factors, or came from institutions where certain resistance patterns were prevalent. Antimicrobial susceptibility testing in the real world is therefore an exceedingly important device for physicians to use to guide empirical as well as specific therapy.

What’s the importance of surveillance on a global scale?

Global surveillance gives you broad patterns – it’s like predicting is the stock market going to go up or down based on the price of oil or technology, but that doesn’t help you with your own individual assets. Globally, resistance patterns can give you an idea of the general issues but you also need your local data. For example, if a person travelled to a country that has a high prevalence of CREs and/or ESBLs and that person came back home sick, you’d expect that they’d have an increased risk of a resistant infection. So the global perspectives can be applied to the individual patient that you’re treating, but local data is also important.

Finally, what do you consider to be the greatest challenges hindering the treatment of multidrug-resistant infections?

The major challenge of treating drug-resistant infections is having antibiotics that are appropriate and active against those organisms. For CREs, two Gram-negative drugs have been recently licensed in the USA. One is ceftolozane-tazobactam, which in our study showed very good Pseudomonas aeruginosa activity – 88% of our ceftazidime-resistant Pseudomonas were susceptible to ceftolozane-tazobactam, while in our CRE isolates ceftazidime-avibactam had good activity. However, for resistant Pseudomonas isolates, only 72% were susceptible to ceftazidime-avibactam. We also found there were no ceftolozane-tazobactam resistant isolates that were susceptible to ceftazidime-avibactam – so the two drugs have really different niches.

These findings highlight these two drugs are different and not interchangeable. Antimicrobials really need to be applied specifically for specific patients and specific pathogens.

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