How to improve the outcomes of invasive Listeriosis?

In a time when medicine in general is advancing quickly, some areas are lagging behind. One of them is Listeria monocytogenes, a foodborne infectious disease, for which mortality has remained steady around 30% the last two decades (1-3). So why does treating Listeria monocytogenes challenging and which new insights could help us to improve treatment in the future?

One of principal causes of foodborne diseases

I. Why treating Listeria monocytogenes remains challenging?

In adults, Listeria monocytogenes presents in two ways. On the one hand, it is one of principal causes of foodborne diseases. Traditionally, it is associated with eating dairy products but cases have been described after eating processed meat, fish and vegetables (4,5). On the other hand, there is invasive listeriosis, which in itself has three clinical forms:

• Pregnancy-associated and neonatal infections, which is a topic on its own

• Bacteremia or septicemic listeriosis

• Neurolisteriosis, in essence this is a meningoencephalitis (as also brain tissue is involved)

There are multiple reasons why treating Listeria monocytogenes is challenging:

a. Listeria monocytogenes is a rare disease and so far the best evidence comes from prospective cohort studies (2,3).

b. Although many antibiotics might work well against Listeria monocytogenes in vitro, probably several don’t reach optimal killing concentrations in vivo. This bacteria is after all often found inside the cells of the central nervous system, a place very hard to reach for antibiotics (1).

c. Invasive listeriosis occurs mainly in immunocompromised and older patients (4). This already implicates a more vulnerable population to treat.

d. Invasive listeriosis can present very non-specific. In some larger case series, only two third of cases were adequately treated empirically (2,5).

II. How to improve treatment of invasive Listeriosis?

1) When empirically coverage of Listeria is indicated.

The main antibiotic therapy of Listeria monocytogenes is amoxicillin, ampicillin and penicillin G. They cause cell death by binding to the penicillin-binding protein 3 (8). However, this protein forms an ineffective target for a frequently used antibiotic in sepsis and especially meningitis, namely the third generation cephalosporins. As a consequence, a third of patients aren’t receiving adequate treatment from the start.

If you look at the guidelines for meningitis, there are two positions. Some, such as ESCMID and NICE, recommend only adding empiric coverage for Listeria monocytogenes if risk factors are present for such infection like old age or immunocompromised state (7,9). Other guidelines recommend empiric treatment for everyone (2,10).

My conclusion: There are good arguments to also cover Listeria in the empirical treatment of meningitis.

• Giving antibiotics in meningitis is an emergency. In this type of situations, it is better to have one clear rule in place without exceptions, so that the whole team knows what to do.

  
  

• This should lead to a drastical improvement of the empiric coverage of neuro-listeriosis and thus reduce mortality of this type of infections.

  
  

• Nowadays, multiplex PCR and WBC count on cerebral spinal fluid are assessed in a few hours. This means that in most cases the diagnosis of Listeria meningo-encephalitis can be rapidly confirmed or rejected. Although every gift of antibiotic can potentially harm an individual level, on a population level the negative impact of a few gifts of aminopenicillins per patient will be minimal.

Note: for Listeria bacteremia, empiric treatment of everyone is overshooting. Luckily, Listeria is often at least partially covered by the administration of beta-lactams (except cephalosporins), vancomycin or aminoglycosides used in case of suspected sepsis.

2) Should patients with confirmed invasive Listeriosis be treated with combination therapy?

In the literature, different treatment regimens have been proposed, mostly based on in vitro data, such as adding cotrimoxazole or rifampicin to aminopenicillins. However, no treatment regimen has been discussed that much as adding aminoglycosides to aminopenicillins.

The facts about combination therapy with aminoglycosides:

• In vitro, adding aminoglycosides to aminopenicillins led to a faster killing of Listeria (11). However, aminoglycosides don’t penetrate well in the central nervous system and display only poor activity against intracellular bacteria.

• Administrating aminoglycosides for a longer duration is associated with important side effects, in particular nephrotoxicity. As a consequence, in recent years, there is a move away from combination therapy beta-lactam and aminoglycosides in other infections. For instance, the latest ESC guidelines no longer recommend adding aminoglycosides in treatment of staphylococcus native valve endocarditis (12).

  
  

• The results of some retrospective studies are all over the place. For instance, one showed increasing trend for early mortality (13) whereas another observed a reduction in the 90-day mortality if at least four days of gentamicin was given (14).

• In the MONALISA trial, the largest prospective cohort study, an association was observed between survival and combination therapy, especially if gentamicin was giving for more than 3 days (3).

Most guidelines are hesitant to recommend combination therapy with gentamicin. The ESCMID guidelines on meningitis, for instance, only mention that combination therapy with gentamicin could be considered as a treatment regimen (7). Interestingly, even guidelines released after the publication of the MONALISA trial recommend against combination therapy because of the fear of nephrotoxicity (9).

My conclusion: The adverse events of aminoglycosides are well known; meanwhile their added value in case of Listeria monocytogenes remains unclear. However, in all positive cohort studies, it seems that their beneficial effect is only present early in the treatment of invasive listeriosis (3, 14). So depending on what you believe, one prudent approach could be to give gentamicin for 4 days while monitoring trough levels and immediately stopping if renal function deteriorates.

3) Should patients with neurolisteriosis receive dexamethasone?

Luckily, this question seems to be settling right now. Traditionally, it was recommended to stop dexamethasone, once the diagnosis of neurolisteriosis was established (8). This recommendation was further reinforced after the publication of the French MONALISA trial, which observed an association between adjunctive dexamethasone and increased mortality (3). However, in 2023, the results of a Dutch prospective study were released which showed the opposite. In this study, adjunctive dexamethasone was associated with an improved outcome in patients with neurolisteriosis (2).

There are several good reasons to attach more value to the Dutch study than the MONALISA trial.

a. Other retrospective cohort studies also didn’t show any harm of adding dexamethasone (4, 15).

b. In randomized controlled trials, adjunctive dexamethasone was shown to improve outcomes for all patients with ding dexamethasone to the first gift of antibiotics was shown to case of bacterial meningitis (so not specifically for Listeria monocytogenes) (2).

c. In the French trial, only 13% of patients received adjunctive dexamethasone whereas in the Dutch study this was 58%. This probably indicates a selection bias in the French study, leading to administration of dexamethasone in the more severely ill.

d. In the Dutch study, majority of dexamethasone was started together with the first gift of antibiotics. This moment is unclear for the MONALISA trial.

My conclusion: Every patient with neurolisteriosis should receive the full 4-day course of adjunctive dexamethasone.

References:

1. Hof H. An update on the medical management of listeriosis. Expert Opin Pharmacother. 2004 Aug;5(8):1727-35.

2. Brouwer MC, van de Beek D. Adjunctive dexamethasone treatment in adults with listeria monocytogenes meningitis: a prospective nationwide cohort study. EClinicalMedicine. 2023 Mar 24;58:101922. 

3. Charlier C, Perrodeau É, et al. Clinical features and prognostic factors of listeriosis: the MONALISA national prospective cohort study. Lancet Infect Dis. 2017 May;17(5):510-519. 

4. Koopmans MM, Brouwer MC, Vázquez-Boland JA, van de Beek D. Human Listeriosis. Clin Microbiol Rev. 2023 Mar 23;36(1):e0006019. 

5. Kiss R, Marosi B, et al. Clinical and microbiological characteristics and follow-up of invasive Listeria monocytogenes infection among hospitalized patients: real-world experience of 16 years from Hungary. BMC Microbiol. 2024 Sep 6;24(1):325. 

6. Carter E, McGill F. The management of acute meningitis: an update. Clin Med (Lond). 2022 Sep;22(5):396-400. 

7. van de Beek D, Cabellos C, et al. ESCMID guideline: diagnosis and treatment of acute bacterial meningitis. Clin Microbiol Infect. 2016 May;22 Suppl 3:S37-62. 

8. Pagliano P, Arslan F, Ascione T. Epidemiology and treatment of the commonest form of listeriosis: meningitis and bacteraemia. Infez Med. 2017 Sep 1;25(3):210-216. 

9. Meningitis (bacterial) and meningococcal disease: recognition, diagnosis and management: Evidence review A1. London: National Institute for Health and Care Excellence (NICE); 2024 Mar. 

10. Klein M, Abdel-Hadi C, et al. German guidelines on community-acquired acute bacterial meningitis in adults. Neurol Res Pract. 2023 Aug 31;5(1):44. 

11. Azimi PH, Koranyi K, Lindsey KD. Listeria monocytogens: synergistic effects of ampicillin and gentamicin. Am J Clin Pathol. 1979 Dec;72(6):974-7. 

12. Delgado V, Ajmone Marsan N, et al. 2023 ESC Guidelines for the management of endocarditis. Eur Heart J. 2023 Oct 14;44(39):3948-4042. 

13. Mitjà O, Pigrau C, et al. Predictors of mortality and impact of aminoglycosides on outcome in listeriosis in a retrospective cohort study. J Antimicrob Chemother. 2009 Aug;64(2):416-23. 

14. Sutter JP, Kocheise L, et al. Gentamicin combination treatment is associated with lower mortality in patients with invasive listeriosis: a retrospective analysis. Infection. 2024 Aug;52(4):1601-1606.

15. Koopmans MM, Brouwer MC, et al. Listeria monocytogenes sequence type 6 and increased rate of unfavorable outcome in meningitis: epidemiologic cohort study. Clin Infect Dis. 2013 Jul;57(2):247-53.