Non-surgical treatment of residual periodontal pockets using sodium hypochlorite/amino acid gel and cross-linked hyaluronic acid-a 9-month pilot randomized controlled clinical trial.

OBJECTIVES: This pilot randomized controlled clinical trial compares the clinical outcome obtained in persistent periodontal pockets during 9-month follow-up of supportive periodontal step 4 treatment performed by either combining subgingival instrumentation with adjunctively used sodium hypochlorite/amino acid gel and crosslinked hyaluronic acid (xHyA) or subgingival instrumentation alone. MATERIALS AND METHODS: Study protocol is registered under NCT06438354 at Clinicaltrials.gov. Patients seeking further therapy after completed step 2 non-surgical periodontal treatment underwent either repeated subgingival instrumentation with adjunctive application of sodium hypochlorite/amino acid gel and crosslinked hyaluronic acid (group A) or repeated subgingival instrumentation alone (group B). One calibrated investigator performed the treatment sequence in both groups accordingly. Subgingival instrumentation of the residual pockets was carried out under local anaesthesia using hand- and ultrasonic instruments, as well as air polishing in both groups. Patients were instructed to continue oral hygiene without any restriction. At 3-month re-evaluation treatment was repeated accordingly at sites with persistent 5 mm probing depth and BoP + . Clinical attachment level (CAL), pocket probing depth (PPD), gingival recession (GR), and bleeding on probing (BoP) were recorded at baseline (T1), 3- (T2) and 9-month (T3) post-op, with CAL as a primary outcome measure. RESULTS: In total 52 patients (20 females and 32 males, mean age 58.4 ± 2.4 years) presenting with 1448 sites which required further periodontal treatment were enrolled. Both groups exhibited homogeneity in terms of age, gender, smoking habit, initial number of sites, and BOP. At 9-month evaluation, PD reduction and CAL gain showed significant differences between the test and control group, favouring the adjunctive treatment. GR tended to exhibit more recovery in the test group compared to the control group. Although BOP frequency effectively reduced in both groups, there was no statistically significant difference between the two groups. CONCLUSION: Within the limits of the study, the present data indicates that, during subgingival instrumentation of persistent pockets, the adjunctive usage of sodium hypochlorite/amino acid gel and xHyA sufficiently improves the clinical outcomes. The continuous improvement of CAL in association with the GR scores observed in group A, indicates that sites subjected to adjunctive treatment may indicate a tendency for a regenerative response to treatment within the 9-month follow-up period.

The Purinergic P2X7 Receptor as a Target for Adjunctive Treatment for Drug-Refractory Epilepsy.

Epilepsy is one of the most common neurological diseases worldwide. Anti-seizure medications (ASMs) with anticonvulsants remain the mainstay of epilepsy treatment. Currently used ASMs are, however, ineffective to suppress seizures in about one third of all patients. Moreover, ASMs show no significant impact on the pathogenic mechanisms involved in epilepsy development or disease progression and may cause serious side-effects, highlighting the need for the identification of new drug targets for a more causal therapy. Compelling evidence has demonstrated a role for purinergic signalling, including the nucleotide adenosine 5'-triphosphate (ATP) during the generation of seizures and epilepsy. Consequently, drugs targeting specific ATP-gated purinergic receptors have been suggested as promising treatment options for epilepsy including the cationic P2X7 receptor (P27XR). P2X7R protein levels have been shown to be increased in the brain of experimental models of epilepsy and in the resected brain tissue of patients with epilepsy. Animal studies have provided evidence that P2X7R blocking can reduce the severity of acute seizures and the epileptic phenotype. The current review will provide a brief summary of recent key findings on P2X7R signalling during seizures and epilepsy focusing on the potential clinical use of treatments based on the P2X7R as an adjunctive therapeutic strategy for drug-refractory seizures and epilepsy.

Minocycline as Treatment for Psychiatric and Neurological Conditions: A Systematic Review and Meta-Analysis.

Minocycline has anti-inflammatory, antioxidant, and anti-apoptotic properties that explain the renewed interest in its use as an adjunctive treatment for psychiatric and neurological conditions. Following the completion of several new clinical trials using minocycline, we proposed an up-to-date systematic review and meta-analysis of the data available. The PICO (patient/population, intervention, comparison and outcomes) framework was used to search 5 databases aiming to identify randomized controlled trials that used minocycline as an adjunctive treatment for psychiatric and neurological conditions. Search results, data extraction, and risk of bias were performed by two independent authors for each publication. Quantitative meta-analysis was performed using RevMan software. Literature search and review resulted in 32 studies being included in this review: 10 in schizophrenia, 3 studies in depression, and 7 in stroke, with the benefit of minocycline being used in some of the core symptoms evaluated; 2 in bipolar disorder and 2 in substance use, without demonstrating a benefit for using minocycline; 1 in obsessive-compulsive disorder, 2 in brain and spinal injuries, 2 in amyotrophic lateral sclerosis, 1 in Alzheimer's disease, 1 in multiple systems atrophy, and 1 in pain, with mixes results. For most of the conditions included in this review the data is still limited and difficult to interpret, warranting more well-designed and powered studies. On the other hand, the studies available for schizophrenia seem to suggest an overall benefit favoring the use of minocycline as an adjunctive treatment.

A Systematic Review and Meta-Analysis of the Clinical Outcomes for Adjunctive Physical, Chemical, and Biological Treatment of Dental Implants With Peri-Implantitis.

The present systematic review evaluated the efficacy of adjunctive therapies in the treatment of peri-implantitis. Studies comparing the outcome of conventional surgical- or nonsurgical mechanical debridement with the addition of an adjunctive therapeutic modality were identified through an electronic and hand search of available literature. Following data extraction, meta-analyses were performed on the primary outcome measures. The effects of the adjunctive therapies on bleeding on probing (13 studies), probing pocket depth (9 studies), and radiographic bone level changes (7 studies) were analyzed to evaluate potential clinical benefit. Heterogeneity was expressed as the I2 index. Fixed and random effect models were demonstrated. The potential benefit of adjunctive therapies over control procedures was evaluated in 18 studies, representing a total of 773 implants. Quality assessment of the studies found only 3 studies to be at a low risk of bias. Meta-analysis among the different additional modalities revealed chemical therapy demonstrating significant effects in probing pocket depth reduction (0.58 mm; 0.44-0.72) and radiographic bone level gain (0.54 mm; 0.16-0.92). No significant improvements in bleeding on probing reduction were found using any adjunctive therapy. Available evidence on the benefits of adjunctive therapy to nonsurgical or surgical mechanical debridement in the treatment of peri-implantitis is limited by low numbers of standardized, controlled studies for individual therapies, heterogeneity between studies, and a variety of outcome measures. The lack of effect of any adjunctive therapy in reducing bleeding on probing questions the overall effectiveness over conventional treatment. The long-term clinical benefit potential of these therapies is not demonstrated.

Metformin for the prevention of clozapine-induced weight gain: A retrospective naturalistic cohort study.

OBJECTIVE: Clozapine is presently the sole antipsychotic with an indication for treatment-resistant Schizophrenia, but is associated with significant weight gain and other metabolic aberrations. This retrospective chart review aimed to evaluate the effectiveness of adjunctive metformin in preventing clozapine-induced weight gain. METHODS: We conducted a retrospective chart review of patients newly initiated on clozapine at the Centre for Addiction and Mental Health in Canada, from November 2014 to April 2021. Our primary outcome was body weight at 6 and 12 months after clozapine initiation. Other metabolic parameters served as secondary outcomes. RESULTS: Among 396 patients (males: 71.5%, mean age: 42.8 years) initiated on clozapine, 69 were on metformin or prescribed it ≤3 months after clozapine initiation. The clozapine+metformin group demonstrated less weight gain compared with the clozapine-only group at 6 months (clozapine+metformin: -0.15 kg [SE = 1.08] vs. clozapine-only: 2.99 kg, SE = 0.54) and 12 months after clozapine initiation (clozapine+metformin: -0.67 kg, SE = 1.22 vs. clozapine-only: 4.72 kg, SE = 0.67). Adaptive changes were also observed for fasting glucose (F = 3.10, p = 0.046) and triglycerides (F = 8.56, p < 0.001) in the clozapine+metformin group compared with clozapine only. CONCLUSION: In this large retrospective naturalistic cohort study, co-prescription of clozapine and metformin was associated with less weight gain and related metabolic dysfunction at 6 and 12 months after initiation versus clozapine alone. These findings provide evidence for the effectiveness of metformin in preventing clozapine-induced weight gain; larger randomized controlled trials are needed to confirm these results.

Stress urinary incontinence and the forgotten female hormones.

The use of hormones to treat stress urinary incontinence (SUI) has fallen out of favor because of concerns over safety following publication of the Women's Health Initiative study. In addition, there are data that suggest that estrogen treatment does not help SUI. As women age, the decline in androgen output mirrors the increasing prevalence of SUI implying a potential causal association. Therefore, we suggest that androgens are the 'forgotten female hormone.' Vaginal estrogens can treat pelvic floor structures without significant systemic effects; we suggest that vaginal androgens can act similarly and thereby avoid the unwanted systemic effects of androgenization in women. Based on available preclinical and clinical data, we suggest that research should investigate vaginal treatment with androgen hormones as adjunctive therapy to pelvic floor exercises for SUI. In a postmenopausal woman, this could be supplemented with estrogens if trial data warrant it.

Beneficial Effects of Melatonin on Periodontitis Management: Far More Than Oral Cavity.

Periodontitis as a highly prevalent chronic infection/inflammatory disease can eventually lead to tooth loss and masticatory dysfunction. It also has a negative impact on general health and largely impairs quality of life. The tissue destruction during periodontitis is mainly caused by the excessive immune-inflammatory response; hence, how to modulate the host's reaction is of profound importance for effective periodontal treatment and tissue protection. Melatonin, as an endogenous hormone exhibiting multiple biological functions such as circadian rhythm regulation, antioxidant, and anti-inflammation, has been widely used in general healthcare. Notably, the past few years have witnessed increasing evidence for the application of melatonin as an adjunctive approach in the treatment of periodontitis and periodontitis-related systemic comorbidities. The detailed underlying mechanisms and more verification from clinical practice are still lacking, however, and further investigations are highly required. Importantly, it is essential to establish standard guidelines in the near future for the clinical administration of melatonin for periodontal health and general wellbeing.

The effects of anti-inflammatory agents as host-directed adjunct treatment of tuberculosis in humans: a systematic review and meta-analysis.

BACKGROUND: The potential role of adjunctive anti-inflammatory therapy to enhance tuberculosis (TB) treatment has recently received increasing interest. There is, therefore, a need to broadly examine current host-directed therapies (HDTs) that could accelerate treatment response and improve TB outcomes. METHODS: This systematic review and meta-analysis included randomised controlled trials of vitamin D and other HDT agents in patients receiving antibiotic treatment for pulmonary TB. Sputum smear conversion rate at 4-8 weeks was the primary outcome. Secondary outcomes included blood indices associated with infectivity and inflammation, chest radiology and incidence of adverse events. RESULTS: Fifty-five studies were screened for eligibility after the initial search, which yielded more than 1000 records. Of the 2540 participants in the 15 trials included in the meta-analysis, 1898 (74.7%) were male, and the age at entry ranged from 18 to 70 years. There was a 38% significantly (RR 1.38, 95% CI = 1.03-1.84) increased sputum smear negativity in patients administered with vitamin D in addition to standard TB treatment than those receiving only the TB treatment. Patients treated with other HDT anti-inflammatory agents in addition to TB treatment also had a 29% significantly increased sputum smear conversion rate (RR 1.29, 95% CI = 1.09-1.563). Lymphocyte to monocyte ratio was significantly higher in the vitamin D treatment groups compared to the controls (3.52 vs 2.70, 95% CI for difference 0.16-1.11, p = 0.009) and (adjusted mean difference 0.4, 95% CI 0.2 -- 0.6; p = 0.001); whilst tumour necrosis factor-alpha (TNF-α) showed a trend towards a reduction in prednisolone (p < 0.001) and pentoxifylline (p = 0.27) treatment groups. Vitamin D and N-acetylcysteine also accelerated radiographic resolution in treatment compared to placebo at 8 weeks. No differences were observed in the occurrence of adverse events among all HDT treatments. CONCLUSIONS: Vitamin D and other anti-inflammatory HDT medications used as adjunct TB treatment may be well tolerated and effective. They significantly improved sputum smear conversion rate and chest radiological appearance, and also exhibited an inflammation resolution effect.

Experimental cerebral malaria is associated with profound loss of both glycan and protein components of the endothelial glycocalyx.

Vascular pathology is central to malaria pathogenesis and associated with severity of disease. We have previously documented shedding of the cerebral endothelial glycocalyx in experimental malaria and hypothesized that this action is implicated in the pathogenesis of cerebral malaria (CM). Quantification and characterization of the intraluminal vascular glycocalyx are technically challenging. Here, we used ferritin labeling, computerized image analysis, and biochemical characterization by using in vivo biotinylation and pull down. Image analysis divided mice with CM and uncomplicated malaria and uninfected control mice into 3 non-overlapping groups. Biochemical assessment of the luminal surface revealed malaria-induced alterations in all components of the glycocalyx in CM. This loss was mirrored in increases of the same components in peripheral blood samples. Corticosteroid treatment protected against CM, reduced inflammation, and prevented glycocalyx loss. Adjunctive antithrombin-3 also prevented glycocalyx loss and significantly reduced CM-associated mortality, as well as reduced local inflammation and prevented blood-brain barrier leakage. In contrast, inhibition of matrix metalloproteases with batimastat had limited effects on the glycocalyx and disease progression. Thus, glycocalyx loss may be associated with malaria pathogenesis and could be targeted by adjunctive treatment.-Hempel, C., Sporring, J., Kurtzhals, J. A. L. Experimental cerebral malaria is associated with profound loss of both glycan and protein components of the endothelial glycocalyx.

Coprescription of mood stabilizers in schizophrenia, dosing, and clinical correlates: An international study.

OBJECTIVE: Studies examining coprescription and dosages of mood stabilizers (MSs) with antipsychotics for psychotic disorders are infrequent. Based on sparse extant data and clinical experience, we hypothesized that adjunctive MS use would be associated with certain demographic (e.g., younger age), clinical factors (e.g., longer illness duration), and characteristics of antipsychotic treatment (e.g., multiple or high antipsychotic doses). METHODS: Within an Asian research consortium focusing on pharmaco-epidemiological factors in schizophrenia, we evaluated rates of MS coprescription, including high doses (>1000 mg/day lithium-equivalents) and clinical correlates. RESULTS: Among 3557 subjects diagnosed with schizophrenia in 14 Asian countries, MSs were coprescribed with antipsychotics in 13.6% (n = 485) of the sample, with 10.9% (n = 53) on a high dose. Adjunctive MS treatment was associated (all p < 0.005) with demographic (female sex and younger age), setting (country and hospitalization), illness (longer duration, more hospitalizations, non-remission of illness, behavioral disorganization, aggression, affective symptoms, and social-occupational dysfunction), and treatment-related factors (higher antipsychotic dose, multiple antipsychotics, higher body mass index, and greater sedation). Patients given high doses of MSs had a less favorable illness course, more behavioral disorganization, poorer functioning, and higher antipsychotic doses. CONCLUSIONS: Schizophrenia patients receiving adjunctive MS treatment in Asian psychiatric centers are more severely ill and less responsive to simpler treatment regimens.

An exploratory study of experiences with conventional eating disorder treatment and ceremonial ayahuasca for the healing of eating disorders.

PURPOSE: Ayahuasca is a traditional Amazonian medicine that is currently being researched for its potential in treating a variety of mental disorders. This article reports on exploratory qualitative research relating to participant experiences with ceremonial ayahuasca drinking and conventional treatment for eating disorders (EDs). It also explores the potential for ayahuasca as an adjunctive ED treatment. METHODS: Thirteen individuals previously diagnosed with an ED participated in a semi-structured interview contrasting their experiences with conventional ED treatment with experiences from ceremonial ayahuasca. The interviews were analyzed using thematic analysis. RESULTS: Participant reports were organized with key themes including that ayahuasca: led to rapid reductions in ED thoughts and symptoms; allowed for the healing of the perceived root of the ED; helped to process painful feelings and memories; supported the internalization of greater self-love and self-acceptance; and catalyzed spiritual elements of healing. CONCLUSIONS: The results suggest that ayahuasca may have potential as a valuable therapeutic tool, and further research-including carefully controlled clinical trials-is warranted. LEVEL OF EVIDENCE: Level V, qualitative descriptive study.

Red blood cell exchange in treatment of severe cerebral P. falciparum malaria: A case report.

INTRODUCTION: Red blood cells exchange transfusion has been demonstrated to be helpful in treatment of sever P. falciparum malaria. However, no large scale randomized controlled trials have been completed to date and the CDC does not recommend RBC exchange transfusions as standard of care. We present a case of severe cerebral malaria in a patient with extremely high parasitemia and severe altered mental status who improved rapidly with automated RBC exchange. REPORT: Seventy-two year old female presented with 1 day history of weakness, altered mental status, malaise, and cyclic sweats after returning from a trip to Sierra Leone. Thick and Thin Smears demonstrated P. falciparum rings present and Quantitative malaria screen demonstrated 53.33% parasitemia. Patient was started on quinidine and doxycycline but continued to deteriorate. Automated RBC exchange transfusion was performed within 24 hours of admission and resulted in rapid improvement in symptomology. Repeat thick and thin smears revealed undetectable parasite load. CONCLUSION: Automated RBC exchange may improve outcomes in severe P. falciparum malaria when presenting parasite loads are very high.

ShenQi FuZheng injection as an adjunctive treatment to chemotherapy in breast cancer patients: a meta-analysis.

Context: Shenqi FuZheng injection (SFI) has been suggested as a complementary treatment of chemotherapy in China. However, little is known about it in western countries. Objective: This study assesses the clinical effect of SFI combined with chemotherapy for breast cancer patients. Materials and methods: Both English and Chinese databases were searched covering the time period of 1999- 2018 for relevant studies comparing the effect of SFI plus chemotherapy treatment with chemotherapy alone in patients with breast cancer. Target outcomes concerning treatment effect, performance status, immune system and toxic effects were extracted and combined using Stata version 15.0 software. Quality assessment was performed using the Jadad scale. Results: Forty-nine trials were included based on certain selection criteria. Only seven studies were rated as high-quality publications. Results of meta-analysis showed that SFI intervention can significantly improve objective tumour response, performance status, NK, CD3+, CD4+ and CD4+/CD8+ ratio and reduce occurrence of leucopenia, thrombocytopenia, haemoglobin reduction, liver dysfunction, gastrointestinal reaction, nausea and vomiting, bone marrow suppression and ECG changes. However, no significant difference was found between SFI and the control group regarding CD8+ levels, and renal disorders. Discussion and conclusions: SFI intervention appeared to be effective in improving clinical efficacy, immune function and reducing toxicity when combined with chemotherapy for breast cancer. However, our findings still need verification by high-quality trials.

Concurrent antipsychotic use in older adults treated with antidepressants in Asia.

AIM: Depressive disorders are common in old age. Antipsychotics (APs) are often used as an adjunctive treatment with antidepressants (ADs) in this population but its patterns of use in Asia are not known. This study explored the rate of combination of APs and ADs in older adult psychiatric patients in Asia. METHODS: This is a secondary analysis of the database of a multicentre study which recorded participants' basic demographical and clinical data in standardised format in 10 Asian countries and territories. The data were analysed using univariate and multivariate logistic regression analyses. RESULTS: A total of 955 older adult psychiatric in- and outpatients were included in this study. The proportion of concurrent AP and AD use was 32.0%, ranging from 23.3% in Korea to 44.0% in Taiwan. Multivariate logistic regression analysis found that younger age, inpatient status and diagnosis of schizophrenia, anxiety and other mental disorders were significantly related to a higher proportion of concurrent use of APs and ADs. CONCLUSION: Around a third of older adult psychiatric patients had concurrent AP and AD use in the Asian countries/regions surveyed. Considering the uncertain effectiveness and questionable safety of the AP and AD combination in this patient population, such should be cautiously used.

Neuroprotective effects of adjunctive treatments for acute stroke thrombolysis: a review of clinical evidence.

The narrow therapeutic time window and risk of intracranial hemorrhage largely restrict the clinical application of thrombolysis in acute ischemic stroke. Adjunctive treatments added to rt-PA may be beneficial to improve the capacity of neural cell to withstand ischemia, and to reduce the hemorrhage risk as well. This review aims to evaluate the neuroprotective effects of adjunctive treatments in combination with thrombolytic therapy for acute ischemic stroke. Relevant studies were searched in the PubMed, Web of Science and EMBASE database. In this review, we first interpret the potential role of adjunctive treatments to thrombolytic therapy in acute ischemic stroke. Furthermore, we summarize the current clinical evidence for the combination of intravenous recombinant tissue plasminogen activator and various adjunctive therapies in acute ischemic stroke, either pharmacological or non-pharmacological therapy, and discuss the mechanisms of some promising treatments, including uric acid, fingolimod, minocycline, remote ischemic conditioning, hypothermia and transcranial laser therapy. Even though fingolimod, minocycline, hypothermia and remote ischemic conditioning have yielded promising results, they still need to be rigorously investigated in further clinical trials. Further trials should also focus on neuroprotective approach with pleiotropic effects or combined agents with multiple protective mechanisms.

Clinical applications of herbal medicines for anxiety and insomnia; targeting patients with bipolar disorder.

OBJECTIVES: Patients with bipolar disorder frequently continue to experience residual anxiety and insomnia between mood episodes. In real-world practice, patients increasingly self-prescribe alternative medicines. METHODS: We reviewed case reports, open-label, and placebo-controlled trials investigating the use of herbal medicines to treat anxiety and insomnia, and discussed their potential applications for bipolar disorder. RESULTS: Eleven herbal medicines that have been studied in human subjects are included in this review. Mechanisms of action, efficacy, side effects, and drug-drug interactions are discussed. Based on currently available evidence, valerian seems to be the most promising candidate for insomnia and anxiety in bipolar disorder. CONCLUSIONS: Adjunctive herbal medicines may have the potential to alleviate these symptoms and improve the outcomes of standard treatment, despite limited evidence. Physicians need to have a more in-depth understanding of the evidence of benefits, risks, and drug interactions of alternative treatments.

A Real-life Study of Brexpiprazole as an Adjunctive Treatment for Major Depressive Disorder in Asian Patients in Singapore (BADA).

Objective: : To investigate the effectiveness and safety of brexpiprazole as an adjunctive treatment to antidepressant therapy (ADT) in Asian adults with major depressive disorder (MDD) and inadequate response in a real-life clinical setting in Singapore. Methods: : This was a prospective, observational 3-month study of patients with MDD who had brexpiprazole added to their existing ADT. The study was conducted at two sites in Singapore between September 2020 and October 2021. The co-primary endpoints were Patient Health Questionnaire-9 (PHQ-9) and Clinical Global Impression-Severity (CGI-S). Other endpoints included Clinical Global Impression-Improvement (CGI-I), Sheehan Disability Scale (SDS), Generalized Anxiety Disorder 7-item scale (GAD-7), and safety. Results: : Twenty patients were enrolled and 16 completed the study. There were improvements in PHQ-9, CGI-S, SDS, and GAD-7 scores from baseline at Week 12, with a mean difference of -4.8, -1.3, -8.5, and -6.2, respectively. The CGI-I score improved from baseline with a mean score of 2.3 at Week 12. One third achieved response and 25% achieved remission based on PHQ-9 scores at Week 12. Similar results were obtained using CGI-S scores (38% for both). The incidences of adverse events (AEs) and treatment-related AEs were 55% (11/20) and 50% (10/20), respectively. There were no deaths or severe AEs. Two patients withdrew brexpiprazole during the study. Conclusion: : The observed effects and safety of adjunctive brexpiprazole in Asian adults with MDD in the real-world setting in Singapore were consistent with those from clinical trials.

Adjunctive treatments for pneumococcal meningitis: a systematic review of experimental animal models.

New treatments are needed to improve the prognosis of pneumococcal meningitis. We performed a systematic review on adjunctive treatments in animal models of pneumococcal meningitis in order to identify treatments with the most potential to progress to clinical trials. Studies testing therapy adjunctive to antibiotics in animal models of pneumococcal meningitis were included. A literature search was performed using Medline, Embase and Scopus for studies published from 1990 up to 17 February 2023. Two investigators screened studies for inclusion and independently extracted data. Treatment effect was assessed on the clinical parameters disease severity, hearing loss and cognitive impairment and the biological parameters inflammation, brain injury and bacterial load. Adjunctive treatments were evaluated by their effect on these outcomes and the quality, number and size of studies that investigated the treatments. Risk of bias was assessed with the SYRCLE risk of bias tool. A total of 58 of 2462 identified studies were included, which used 2703 experimental animals. Disease modelling was performed in rats (29 studies), rabbits (13 studies), mice (12 studies), gerbils (3 studies) or both rats and mice (1 study). Meningitis was induced by injection of Streptococcus pneumoniae into the subarachnoid space. Randomization of experimental groups was performed in 37 of 58 studies (64%) and 12 studies (12%) were investigator-blinded. Overall, 54 treatment regimens using 46 adjunctive drugs were evaluated: most commonly dexamethasone (16 studies), daptomycin (5 studies), complement component 5 (C5; 3 studies) antibody and Mn(III)tetrakis(4-benzoicacid)porphyrin chloride (MnTBAP; 3 studies). The most frequently evaluated outcome parameters were inflammation [32 studies (55%)] and brain injury [32 studies (55%)], followed by disease severity [30 studies (52%)], hearing loss [24 studies (41%)], bacterial load [18 studies (31%)] and cognitive impairment [9 studies (16%)]. Adjunctive therapy that improved clinical outcomes in multiple studies was dexamethasone (6 studies), C5 antibodies (3 studies) and daptomycin (3 studies). HMGB1 inhibitors, matrix metalloproteinase inhibitors, neurotrophins, antioxidants and paquinimod also improved clinical parameters but only in single or small studies. Evaluating the treatment effect of adjunctive therapy was complicated by study heterogeneity regarding the animal models used and outcomes reported. In conclusion, 24 of 54 treatment regimens (44%) tested improved clinically relevant outcomes in experimental pneumococcal meningitis but few were tested in multiple well-designed studies. The most promising new adjunctive treatments are with C5 antibodies or daptomycin, suggesting that these drugs could be tested in clinical trials.