Tag Archives: antimicrobial stewardship

“Are we too protective of new antibiotics?”

Antimicrobial Resistance, Antimicrobial Stewardship, Confessions of a Microbiologist, ,

By reserving new antibiotics for the sickest of the sick and for the most resistant of resistant organisms, are we essentially making them commercially non-viable?

To be honest I am not really surprised that pharmaceutical industries do not want to invest in development of new antibiotics. Such drugs will only be necessary for a small proportion of the population and unlike many other drugs (e.g. cardiac, arthritis drugs) will only be given for a short duration (i.e. 1-2 weeks).

And then, as antimicrobial stewards, we make matters even worse by insisting that these antibiotics need to be fiercely protected in order to prevent or at least delay the development of antimicrobial resistance.

The consequence of this is that any new antibiotic needs to be priced at ridiculous levels to even have a chance at being commercially viable. Hospitals and governments baulk at such prices and subsequently the new antibiotic becomes almost impossible to get hold of. Industry then has to charge even more to make a return, and thus, a vicious cycle is started.

Have a look at the list of new antibiotics from 2000-202 below:
  • 2000: Linezolid (Zyvox) — The first oxazolidinone, a new class effective against vancomycin-resistant enterococci (VRE) and MRSA.
  • 2003: Daptomycin (Cubicin) — The first lipopeptide approved for skin and skin structure infections.
  • 2005: Tigecycline (Tygacil) — First glycylcycline, a derivative of minocycline designed to overcome resistance.
  • 2010: Ceftaroline fosamil (Teflaro) — First cephalosporin with activity against MRSA.
  • 2011: Fidaxomicin (Dificid) — A macrocyclic antibiotic for Clostridioides difficile.
  • 2012: Bedaquiline (Sirturo) — First diarylquinoline for multi-drug resistant tuberculosis (MDR-TB).
  • 2014: Dalbavancin (Dalvance) & Oritavancin (Orbactiv) — Lipoglycopeptides for acute bacterial skin and skin structure infections (ABSSSI).
  • 2014: Tedizolid (Sivextro) — A second-generation oxazolidinone.
  • 2014: Ceftolozane/tazobactam (Zerbaxa) — Cephalosporin/β-lactamase inhibitor combination.
  • 2015: Ceftazidime/avibactam (Avycaz) — Novel β-lactamase inhibitor combination for serious Gram-negative infections.
  • 2017: Meropenem/vaborbactam (Vabomere) — Combination targeting carbapenem-resistant Enterobacteriaceae (CRE).
  • 2017: Delafloxacin (Baxdela) — An anionic fluoroquinolone with activity against MRSA.
  • 2017: Ozenoxacin (Ozanex) — Topical quinolone.
  • 2018: Plazomicin (Zemdri) — Next-generation aminoglycoside.
  • 2018: Eravacycline (Xerava) — Novel synthetic fluorocycline.
  • 2018: Omadacycline (Nuzyra) — Aminomethylcycline for pneumonia and skin infections.
  • 2018: Sarecycline (Seysara) — Tetracycline for acne.
  • 2019: Cefiderocol (Fetroja) — Siderophore cephalosporin for MDR Gram-negative infections.
  • 2019: Lefamulin (Xenleta) — First systemic pleuromutilin for community-acquired pneumonia (CABP).
  • 2019: Pretomanid — Nitroimidazole for extensively drug-resistant TB (XDR-TB)

Then work out how many antibiotics on this list are available for use at your local hospital? In my local hospital in New Zealand, I could comfortably count on one hand the number of antibiotics from the above list that are available for me as a clinical microbiologist to recommend without multiple barriers to prescribing. The majority are just not available in New Zealand at all…

I would argue that increasing the range of antibiotic classes that are available for use is much more important than restricting the use of new antibiotics.

I am not claiming that we shouldn’t have good antimicrobial stewardship, of course we should. Neither am I claiming that antimicrobial resistance to new antibiotics will not develop if we use them, of course it will. However, if we have more classes of antibiotics available, then one would expect classes that are used infrequently over a certain time period to recover a degree of susceptibility.

I think we need to be encouraging the use of new antibiotics so that they are sufficiently used to get an idea of their efficacy, and so that any developing resistance can be effectively monitored.

If we reserve new antibiotics only for when there are no other options available, then in a country like New Zealand, we might only be using them a few times each year.

We need to be somewhat less zealous in our antimicrobial stewardship efforts when it comes to new antibiotics. We need to work alongside industry, not against them in maximising the range of antibiotics that are available to us. However, the goal should be sustainable use, not reckless use…

I know solutions have been proposed to the above problem, essentially allowing industry to get a return on their investment regardless of how often the new antibiotic is actually used (i.e. de-linking). I remain unconvinced by such proposals as a long-term solution, as it relies on successive governments to both prioritise and fund such initiatives.

I also know that some (possibly most!) of my colleagues will not agree with me on this particular topic. But when we sit on antimicrobial stewardship committees, we need to consider the whole picture, and not try and protect the sanctity of the new antibiotic at all costs…

Michael

“Carbapenem Conundrums”

Antimicrobial Resistance, Antimicrobial Stewardship, The Science of Microbiology,

Last week, while on-call I recommended a carbapenem for three different patients within the space of 30 minutes. Yes, it happens sometimes! Most empiric antibiotic choices do not require the inclusion of a carbapenem, but key factors to consider are ESBL history, travel or hospitalisation in areas with high ESBL endemicity, and how sick the patient is.

It is interesting to look at the psychology of carbapenem prescribing. Some doctors prescribe carbapenems because they are afraid of giving treatment to their patients that might not cover all resistance profiles. Others are afraid of prescribing carbapenems because they are traditionally the top line treatment and scared of criticism from antimicrobial stewards like myself!

But if you have to use a carbapenem, which one should you use?

The main choice in New Zealand is generally between meropenem and ertapenem. Imipenem-cilastatin is rarely used now in New Zealand, mainly due to its seizure risk. (There is a little evidence that it is the optimal carbapenem for disseminated nocardiosis and a few other isoteric indications) Other carbapenems outside these three have limited availability in NZ hospitals, or at least the ones I work in. This may be different elsewhere in the world.

Choosing between meropenem and ertapenem:

Here are most of the key factors I take into account when choosing between the two

Organism coverage-If I need to empirically cover Pseudomonas or Enterococci or Acinetobacter spp., then meropenem is a better option than ertapenem due to its broader coverage.

CNS penetration-Meropenem is a better option than ertapenem due to better CNS penetration. I had a patient with E.coli meningitis recently who required meropenem until the susceptibilities were known.

Hypo-albuminaemia– Ertapenem is highly protein bound compared to meropenem, so in hypo-albuminaemic states, the free fraction of ertapenem is increased, and it is chucked out through the kidneys leading to a decreased half-life. Therefore, meropenem is preferred in hypo-albuminemia. I use 25 g/l as an arbitrary cut-off.

Dosing frequency– If reduced dosing frequency is preferred due to patient compliance/outpatient therapy etc, then once daily ertapenem is preferable to three times a day meropenem.

Penetration into biliary tissue-Ertapenem has poor penetration into biliary tissue compared to meropenem, so I prefer meropenem for biliary infections.

Duration of treatment- Meropenem is more stable than ertapenem against resistance mechanisms such as upregulation of efflux pumps or porin channel loss. These mechanisms can become an issue with prolonged treatment and should be taken into account when choosing between the two.

Although the above points might suggest otherwise, I actually recommend more ertapenem than meropenem. Ertapenem is absolutely fine for most straightforward cases of urosepsis where empiric ESBL coverage is required.

One other point. If you do need to utilise a carbapenem, then regular review and timely de-escalation based on the patient’s condition and/or susceptibility results is important to optimise antimicrobial stewardship.

Michael

“Reporting susceptibilities on UTIs, not urinary isolates…”

Antimicrobial Resistance, Antimicrobial Stewardship, , , ,

Urines arrive at diagnostic microbiology laboratories in considerable numbers. My own lab in New Zealand processes a couple of thousand urines a week. A significant proportion of these will have positive cultures. Therefore, the potential for the laboratory to promote good antimicrobial stewardship with respect to urinary tract infection is considerable.

My mantra on this is as follows: “The microbiology lab should never release antibiotic susceptibilities on a positive culture from a urine sample unless there is reasonable evidence accompanying the request that the patient has a UTI.”

The fact that the urine sample has turned up at the microbiology lab is insufficient evidence per se that the patient has a UTI. Urines get sent to microbiology laboratories for all sorts of spurious reasons, see below for a few examples:

  • Urines often get sent “automatically” from acute receiving wards as part of a blanket laboratory screen, where the patient may have a diverse spectrum of symptoms such as chest pain, shortness of breath, collapse, etc.
  • Urines can get sent from Long Term Care Facilities when someone decides to dipstick all their patients and send the urine samples with positive dipsticks to the lab for culture. Yes, it happens, and a lot more often than you might think!
  • Urine from indwelling catheters can get sent when the patient has a blocked catheter, or the catheter bag is cloudy.
  • Urines from patients attending outpatient clinics should also raise a flag. With the exception of urology clinics, patients who attend a pre-planned elective clinic appointment generally do not have an acute UTI. The same principle can apply for patients who are in hospital wards for other reasons.
  • Urines where the clinicians are looking for other tests, i.e. albumin/creatinine ratio, and due to laboratory processes the urine ends up getting cultured as well…

So, my argument is that if a urine sample turns up at the laboratory without any clinical details or with inappropriate clinical details, the lab is under no obligation whatsoever to release antibiotic susceptibilities on any organisms grown. 

The best approach of course is not to process the sample at all unless relevant clinical details are received. I would regard all of the following clinical details as being unacceptable to justify proceeding to urine culture:

  • No clinical details
  • Cloudy urine
  • Concentrated urine
  • Dark urine
  • Smelly urine
  • Urine dipstick urinalysis results only
  • Routine/monitoring/screening urine
  • Fatigue
  • Increased CRP
  • Lots of other non-specific symptoms!

The easy option for the lab of course is just to accept the sample, report the organisms, and the accompanying susceptibilities. However, this is almost certainly not the best way…

Michael