Adjunctive antibiotic therapy with clindamycin or linezolid in patients with group A streptococcus (GAS) meningitis

To the Editor,

We recently studied with interest the viewpoint by Cortés-Penfield and Ryder discusses the adjunctive antimicrobial of choice in Group A streptococcus (GAS) infections published in Clinical Infectious Diseases [1]. The authors compared the pros and cons of adjunctive linezolid or clindamycin therapy – together with benzylpenicillin – in GAS infections, and concluded, “Clindamycin may still be the adjunctive treatment of choice for invasive GAS infections in areas where GAS susceptibility to clindamycin is known to remain high.” However, the authors have not considered the pharmacokinetics of clindamycin in central nervous system (CNS) infections, which is different from other tissues. Here, we aim to summarize information about the adjunctive antimicrobial of choice in patients with GAS meningitis. We have contacted the Clinical Infectious Diseases Editorial Office and they recommended us to submit the Letter to a different journal.

GAS or Streptococcus pyogenes is a Gram-positive beta-hemolytic bacterium that causes a wide range of invasive and non-invasive infections. Invasive GAS infections, including GAS meningitis, have increased almost epidemically during the last years in European countries and in the USA [2–4]. Hitherto, GAS meningitis has been uncommon, representing only 5% to 8% of the invasive GAS infections [5,6]; nonetheless, a recent study from the Netherlands reported that the incidence of GAS meningitis in 2022 was higher than the average yearly incidence from 1982 to 2021 [2]. Considering outcomes, GAS meningitis is a severe infection with more than 20% mortality and 50% neurological sequels in case of survival [7–10].

GAS can produce virulence factors such as pyogenic exotoxins mediating severe infections [11]. The standard treatment with benzylpenicillin is therefore usually combined with clindamycin which is a protein synthesis inhibitor. Therefore, besides the antibiotic properties, adjunctive clindamycin reduces exotoxin production and thus improves the outcome [11,12].

Clindamycin is a lincosamide antibiotic and shows high binding to serum proteins (up to 94%) [13]. The protein binding influences the antibacterial activity of clindamycin since only the free fraction (non-binding) clindamycin is active against microorganisms [13]. Clindamycin mainly binds to a serum protein called alpha-1-acid glycoprotein (AAG) [14]. AAG is an acute-phase reactant, and in patients with bacterial meningitis, AAG increases in serum and CSF [15]. Furthermore, it has been shown that clindamycin levels in CSF are negatively correlated with CSF protein concentration [16]. Therefore, considering the protein binding, the antibacterial activity of clindamycin in CSF might be decreased in patients with GAS meningitis [14].

Clindamycin diffuses poorly over the meningeal membranes [16,17]. An animal experiment in rhesus monkeys showed that the penetration of clindamycin into the brain tissue is erratic, and the CSF concentrations are dose-dependent [17]. Four or five doses of clindamycin (20 mg/kg) were administered intramuscularly to the animals, and within four hours after the last injection, clindamycin was measured in the CSF and brain tissue specimens. Clindamycin levels were measurable in 50% of CSF specimens only, but not in the brain tissue specimens when administered at 20 mg/kg. In animals receiving 30 mg/kg clindamycin, the drug was measurable in CSF and brain tissue specimens but not with concentrations surpassing the MICs of typical Gram-positive meningitis pathogens in all samples [17]. The study highlighted that despite clindamycin penetrating CSF, it could not pass the blood-brain barrier in lower doses, predisposing the patient to recurrent brain infections [17]. In a human study, patients with HIV and cerebral toxoplasmosis were treated with a single dose of 1200 mg clindamycin phosphate administered intravenously. CSF specimens were collected 1.5 and 2.5 h after drug infusion. Clindamycin levels in CSF were time-dependent [16], and the study supported the use of high-dose clindamycin in treating cerebral toxoplasmosis [16]. It should be noted that the recommended or conventional adjunctive clindamycin in treating adult patients with GAS infections is 600 mg to 900 mg per dose. Since high-dose clindamycin is required for treating CNS infections, clindamycin is not among the first-line recommended antibiotics for bacterial CNS infections [18,19].

Linezolid is an oxazolidinone antimicrobial and protein synthesis inhibitor that can be used as an alternative adjunctive antibiotic to clindamycin in treating GAS infections [20,21]. Linezolid has low protein binding and penetrates well into CSF and brain tissue [22]. After intravenous administration of the conventional dose of 600 mg every 12 h, linezolid achieves up to 80% of the serum concentrations in CSF [18,22–24]. Linezolid has been used successfully to treat CNS infections with Gram-positive bacteria [25,26]. However, we could not find any published article reporting adjunctive linezolid in patients with GAS meningitis.

Linezolid has the same problem as clindamycin that the bacteriostatic activity leads to bacterial growth inhibition which antagonizes the growth dependent cell-wall activity of penicillin [20]. In combination with either clindamycin or linezolid the bactericidal activity of penicillin is therefore slowed at six hours, but the combinations seem to have adequate bactericidal activity over 24 h, similar to penicillin alone, at least in vitro [20]; this appears to correspond with the superiority of the combination antimicrobial therapy regarding clinical outcomes when treating serious GAS infections [20].

Although there is lack of evidence, considering the beneficial pharmacokinetics of the antibiotic together with its ability to inhibit toxin production, linezolid can theoretically be the adjunctive antibiotic with benzylpenicillin in treating patients with GAS meningitis. High-dose clindamycin is the other option; however, it can potentially increase the risk of adverse effects. Necessity, safety, and efficacy of adjunctive antibiotics, including linezolid compared to standard- or high-dose clindamycin in patients with GAS meningitis needs further investigation. However, given the low incidence of GAS meningitis even on a national scale, clinical trials on human subjects are difficult to establish and therefore experimental studies on animal models of GAS meningitis should be done. Adverse effects, difference in risk of neurologic sequels, and mortality following GAS meningitis are some of the outcomes that need to be investigated.

Author contributions

OR, CR, JGH, NFM, and ZBH designed, wrote and commented on the manuscript. All authors approved the final version.

Acknowledgment

The authors thank Mads Frederik Eiberg, MD for his comment about possible animal models.

Disclosure statement

CR, JGH, and NFM reported no conflict of interest to declare.

Additional information

Funding

OR reports grant from the Research Foundation of Rigshospitalet and the A.P. Moller Foundation not related to this work. ZBH reports grants from the Independent Research Fund Denmark [grant number 0134-00257B], the Lundbeck Foundation [grant number R349-2020-835], and the Danish Cancer Society [grant number KBVU-MS R327-A19137] not related to this paper.