“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

“Sometimes you just have to admit that you were wrong”

Confessions of a Microbiologist, The Science of Microbiology, , ,

Many microbiology laboratories, including my own, have in place a CSF leucocyte count cut-off of 5 × 10⁶/L as a criterion for performing multiplex PCR in the investigation of meningoencephalitis. This diagnostic stewardship policy has attempted to focus testing on those most likely to have CNS infection, and to reduce unnecessary testing. However, growing evidence indicates that this approach is not appropriate when there is clinical suspicion of encephalitis…

Take this hypothetical case study…

A 58-year-old man, Mr J Bloggs, presents with fever, headache, confusion and a vague history of what could be a focal seizure. MRI was unremarkable. A lumbar puncture is performed within eight hours of presentation. The CSF shows a white cell count of 4 × 10⁶/L, normal glucose, and mildly elevated protein. Under existing laboratory policy, the CSF multiplex PCR panel is not performed because the leucocyte count is below 5 × 10⁶/L. Empirical acyclovir therapy is discontinued on the basis of the normal CSF leucocyte count. However, the diagnosis remained uncertain and persistent symptoms prompted a repeat CSF several days later. HSV-1 DNA is detected by PCR on the second CSF sample.

CSF analysis is excellent for detecting meningeal inflammation, as occurs in meningitis, but it is less reliable for parenchymal infection, which characterises encephalitis. In encephalitic processes, inflammation may be largely confined to the brain parenchyma, without a corresponding CSF pleocytosis, especially early in the disease. Leucocyte thresholds designed for meningitis are therefore poorly suited to encephalitis and potentially risk giving false reassurance.

Recent evidence has demonstrated that a substantial proportion of patients with encephalitis have normal CSF leucocyte counts. The most compelling data to date come from a recent large retrospective study by Habis et al., involving 597 adult patients with encephalitis. They found that 25.3% had no CSF pleocytosis (<5 × 10⁶/L). Among those with infectious encephalitis, 19% lacked pleocytosis, and notably, 23.7% of HSV-1 encephalitis cases had normal CSF cell counts at presentation. Patients without pleocytosis were also less likely to receive empiric acyclovir, showing how laboratory thresholds influence clinical care. These findings strongly challenge the validity of using a fixed leucocyte cut-off to determine whether PCR testing should be performed, as it would exclude roughly one in four encephalitis patients, including many with HSV infection.

In addition, and as also shown by Habis et al., patients without pleocytosis are less likely to receive prompt antiviral therapy. This matters because early treatment, particularly for HSV encephalitis, improves outcomes. Diagnostic stewardship should promote timely, appropriate testing, not create barriers based on outdated assumptions…

Laboratory protocols should always be responsive to new data. When high-quality evidence emerges that challenges existing practice, policies must be reviewed and revised. While a 5 × 10⁶/L CSF leucocyte threshold may remain reasonable in the investigation of suspected meningitis, it is no longer valid in the setting of suspected encephalitis, where pleocytosis may be absent in a substantial proportion of cases. Stewardship frameworks should incorporate these distinctions, and most importantly, allow flexibility in order to optimise patient safety.

Laboratory practice must evolve with emerging data to ensure that diagnostic stewardship supports, rather than hinders, accurate and timely diagnosis. I am a diagnostic stewardship enthusiast, but I am the first to admit that we don’t get it right all the time.

Michael

p.s. Check out this great editorial on this topic!

References

“Too much information”

The Art of Microbiology, ,

Can the microbiology lab give too much information to the clinicians?

Take the following hypothetical example regarding reporting of enteric type organisms:

Patient X presents with acute appendicitis with perforation. They are taken to theatre for appendicectomy and peritoneal washout, and started on IV cefuroxime and metronidazole. The sample of peritoneal fluid is returned from the microbiology lab as being “mixed enteric flora”. the patient recovers well, and they are discharged after 3 days on oral co-amoxiclav to complete a 1 week course of antibiotics.

Patient Y presents with acute appendicitis with perforation. They are taken to theatre for appendicectomy and peritoneal washout, and started on IV cefuroxime and metronidazole. However, in this patient, the microbiology lab decides to work up the individual organisms in the peritoneal fluid sample. The report states that the patient has grown an ESBL E.coli, an Enterococcus faecium, a Pseudomonas aeruginosa and a Candida albicans. Even though the patient is recovering well, the clinician feels obliged to cover the organisms that the micro lab has grown and reported, and changes the antibiotic therapy to meropenem, vancomycin and fluconazole. The patient unfortunately develops a bout of Clostridium difficile diarrhoea (!), extending their hospital stay by a week.

Microbiology labs can get very nervous about reporting “mixed enteric flora” from sterile site samples. They really shouldn’t be.

Here are a few pointers as to when it may be reasonable for the microbiology laboratory to report “mixed enteric flora”

  • Non-sterile site samples:- almost always
  • When several organism types are present- the number of different microorganism types present in a sample is inversely proportional to the value the lab can provide to the clinician
  • When no specific organism is dominant over the others
  • When source control has been achieved-this is important as in the hypothetical example above.
  • Drain samples- generally of low value unless the drain has just been inserted
  • When the clinical microbiologist has liaised with clinical team and clear that patient is doing well on current therapy- Treat the patient, not the result.

Such an approach saves the lab time and money, and may also be beneficial to the patient, as demonstrated above. Sometimes in our efforts to do the right thing, we end up trying just a bit too hard…

Michael