Report on Electroencephalographic Findings in Critically Ill Patients with COVID-19.

In March 2020, we treated a cohort of 26 critically ill hospitalized SARS-CoV-2-infected patients who underwent electroencephalography to assess unexplained altered mental status, loss of consciousness, or poor arousal and responsiveness. Of the 26 patients studied, 5 patients had electroencephalograms that showed periodic discharges consisting of high-amplitude frontal monomorphic delta waves with absence of epileptic activity. These findings may suggest central nervous system injury potentially related to COVID-19 in these patients. ANN NEUROL 2020;88:626-630.

Bridging the healthcare gap: Building the case for epilepsy virtual clinics in the current healthcare environment.

Access to quality healthcare remains a challenge that is complicated by mounting pressures to control costs, and now, as we witness, the unprecedented strain placed on our healthcare delivery systems due to the COVID-19 pandemic. Challenges in healthcare access have driven a need for innovative approaches ensuring connectivity to health providers. Telehealth services and virtual clinics offer accessible disease management pathways for patients living in health resource limited areas or, as in the case of the COVID-19 pandemic, where there may be potential barriers to existing healthcare resources. Those suffering with serious chronic disorders often cannot be seen by a healthcare specialist due to their limited availability, or the lack of a specialist within a reasonable proximity. Epilepsy represents such a disorder where most of the world's population lacks the availability of necessary specialists. Virtual clinics allow for specialist care and an ability to perform necessary ambulatory electroencephalogram (EEG) monitoring by placing the technologies directly in patients' homes or at local clinics near the patients' homes. By moving the diagnostic process out of the hospital or epilepsy center, it becomes possible to overcome growing gaps in neurology services. Virtual clinics have the potential to expand access to high-quality, cost-effective care for the patient. The virtual clinic remotely connects those in need of medical support with specialists anywhere in the world, at any time of the day.

Telemedicine and Epilepsy Care.

Telemedicine is a method of health care delivery well suited for epilepsy care, where there is an insufficient supply of trained specialists. The telemedicine "Hub and Spoke" approach allows patients to visit their local health clinic ('Spokes') to establish appropriate care and monitoring for their seizure disorder or epilepsy, and remotely connect with epileptologists or neurologists at centralized centers of expertise ('Hubs'). The COVID-19 pandemic resulted in an expansion of telemedicine capabilities and use, with favorable patient and provider experience and outcomes, allowing for its wide scale adoption beyond COVID-19.

A disease model descriptive of progression between chronic obstructive pulmonary disease exacerbations and community-acquired pneumonia: roles for underlying lung disease and the pharmacokinetics/pharmacodynamics of the antibiotic.

Patients with chronic obstructive pulmonary disease (COPD) may progress to community-acquired pneumonia (CAP), but there has been no formal study of the factors responsible. We studied the influence of severity of underlying lung disease, pathogen characteristics and the ratio of the area under the concentration-time curve from 0-24h to minimum inhibitory concentration (AUC24/MIC), i.e. the area under the inhibitory curve (AUIC), during the progression from acute exacerbation of chronic bronchitis (AECB) in COPD to CAP. The model parameters were derived from a multinational database of 3885 patients with AECB or CAP (April 1996 to July 2006). Patients with underlying COPD were evaluated in two separate analyses: infection progression between COPD and CAP within Global Initiative for Chronic Obstructive Lung Disease (GOLD)-like grouping (GLG); and distribution of pathogen by GLG, CAP and AECB. Secondary analyses examined the impact of target AUIC attainment on progression to CAP for Streptococcus pneumoniae. The relative impact of GLG and AUIC were modelled in multivariate logistic regression for S. pneumoniae. Progression to CAP linked directly with GLG I/II, III and IV (18.3%, 31.7% and 48.9%, respectively; P < 0.001). Progression to CAP was strongly associated with S. pneumoniae (57.3%), whilst other pathogens were predominant in AECB that did not progress to CAP (61.7%) (P = 0.002). AUIC > or = 100 was associated with AECB (65.1%) and AUIC < 100 with CAP (91.7%) (P < 0.001). In conclusion, the frequency of progression to CAP increases directly with GLG. For S. pneumoniae, achieving an AUIC > or =100 can attenuate progression, regardless of GLG. Thus, AUIC > or = 100 appears to be a viable antibiotic selection strategy to protect patients with S. pneumoniae from developing CAP.

Changing the neurology policy landscape in the United States: Misconceptions and facts about epilepsy.

Epilepsy has a relatively high prevalence, and diagnosis and treatment are often challenging. Seizure freedom without significant side effects is the ultimate goal for both physicians and patients, but not always achievable. In those cases, the treatment goals of patients and providers may differ. In the United States, many clinicians continue to prescribe older AEDs, even though newer AEDs have a more desirable safety and tolerability profile, fewer drug-drug interactions, and are associated with lower epilepsy-related hospital visits. Newer AEDs are more commonly prescribed by neurologists and epilepsy center physicians, highlighting the importance of access to specialty care. We report that antiepileptic drugs are not the dominant cost driver for patients with epilepsy and costs are considerably higher in patients with uncontrolled epilepsy. Poor drug adherence is considered a main cause of unsuccessful epilepsy treatment and is associated with increases in inpatient and emergency department admissions and related costs. Interventions and educational programs are needed to address the reasons for nonadherence. Coverage policies placing a higher cost burden on patients with epilepsy lead to lower treatment adherence, which can result in higher future health care spending. Epilepsy is lagging behind other neurological conditions in terms of funding and treatment innovation. Increased investment in epilepsy research may be particularly beneficial given current funding levels and the high prevalence of epilepsy.

Streptococcus pneumoniae bacteraemia: pharmacodynamic correlations with outcome and macrolide resistance--a controlled study.

There are few data on macrolide pharmacodynamics in pneumococcal infections. We evaluated pneumococcal area under the inhibitory concentration-time curve (AUIC) values at the point of hospital admission in 59 bacteraemic patients failing in the community and in 98 bacteraemic controls without macrolide exposure. The area under the 24-h concentration-time curve (AUC24) was calculated for each patient using age, weight and daily dose; using minimum inhibitory concentrations (MICs), the values of AUIC (i.e. AUC24/MIC) were then computed. Clinical and outcome information was also collected in hospital. Five of six patients who died of pneumococcal bacteraemia in hospital received azithromycin, with a mean AUIC of 8.1 prior to hospital admission. Resistant isolates were recovered in 35 (59%) macrolide failures and in only 28 (29%) controls (P=0.001). Azithromycin AUICs averaged 10 in failure patients and 17 in controls. For clarithromycin and erythromycin, the mean AUIC values in failures were 31 and 53, respectively, and the AUIC in controls was >100. Low AUIC values against Streptococcus pneumoniae precede macrolide failures in the community. Patient factors do not predict these outcomes and thus the most likely explanation for macrolide failure in the community is inadequate macrolide activity in patients who receive these antibiotics for treatment of organisms that are not sufficiently susceptible.

The bioequivalence of telithromycin administered orally as crushed tablets versus tablets swallowed whole.

This open-label, randomized, crossover study was conducted to demonstrate bioequivalence for telithromycin administered as crushed or whole tablets. Single 800-mg telithromycin doses (2x400-mg tablets) were administered as crushed tablets mixed in 240 mL nutritional supplement drink followed by 120 mL water or as whole tablets swallowed with 240 mL water. Plasma telithromycin concentrations were measured by liquid chromatography/mass spectrometry; pharmacokinetic parameters were determined using noncompartmental methods. Average bioequivalence criteria were applied. Thirty-two subjects received telithromycin by both methods. The 90% confidence intervals for the geometric mean ratios of maximum plasma concentration and area under the plasma concentration-time curve to 24 hours were within the 0.80 to 1.25 range. Median tmax was 3.00 hours for both treatments. Both methods of administration were well tolerated. Crushing telithromycin tablets and administering them with a nutritional supplement drink is bioequivalent to ingesting whole tablets and could be a viable method of administration for patients unable to swallow tablets whole.

Comparison of hospitalization rates in patients with community-acquired pneumonia treated with telithromycin for 5 or 7 days or clarithromycin for 10 days.

AIMS: To compare the impact on hospitalization rates and the clinical efficacy of oral telithromycin and clarithromycin treatment in patients with community-acquired pneumonia (CAP). METHODS: A total of 581 patients with CAP were enrolled in this randomized, double-blind, parallel group, multinational study, of whom 575 were evaluated for healthcare resource utilization from a payer perspective (intent to treat [ITT] population). Patients received telithromycin 800 mg once daily for 5 (n = 193) or 7 (n = 195)days, or clarithromycin 500 mg once daily for 10 days (n = 187). The primary efficacy endpoint was clinical outcome at test of cure (Days 17-24) in the per-protocol population. Frequency of CAP-related hospitalizations, physician visits/tests/procedures, and additional respiratory tract infection-related antibacterial use were compared by treatment group (ITT) up to late post- for clarithromycin vs dollars 37930 (difference: -26446; therapy (Days 31-36). Study investigators blinded to treatment assessed whether hospital admissions were CAP-related or not. CAP-related hospitalization costs (USdollars) for telithromycin and clarithromycin were compared. RESULTS: Clinical cure rates were similar in patients who received clarithromycin for 10 days and telithromycin for 5 or 7 days: 91.8% (134/146), 89.3% (142/159), and 88.8% (143/161), respectively, and both 5- and 7-day telithromycin were statistically equivalent to clarithromycin (difference: -2.5 and -3.0%, respectively; 95% CI: -9.7, 4.7 and -10.2, 4.3, respectively). There were 7 CAP-related hospital admissions among clarithromycin patients vs 3 (p = 0.283) and 1 (p = 0.021) admissions among 5- and 7-day telithromycin patients, respectively. The number of hospital days/100 patients was 40.1 for clarithromycin vs 17.1 and 7.2 for 5- and 7-day telithromycin, respectively. Projected hospitalization costs/100 patients were dollars 86205 95% CI: -66 654; 13 762) and dollars 16 091 (difference: -37 847; 95% CI: -77953; 2259) for 5- and 7-day telithromycin, respectively. CONCLUSIONS: Data from this study demonstrate that telithromycin 800 mg once daily for 5 or 7 days with fewer hospital days and potentially lower is an effective treatment for CAP,and that telithromycin treatment of CAP may be associated hospitalization costs than clarithromycin treatment.

Hospitalization rates among patients with community-acquired pneumonia treated with telithromycin vs clarithromycin: results from two randomized, double-blind, clinical trials.

AIMS: To compare hospitalization rates among patients with community-acquired pneumonia (CAP) treated with oral telithromycin and clarithromycin, based on pooled data from two randomized, double-blind, multinational clinical trials. PATIENTS AND METHODS: Adult patients with CAP eligible for oral therapy (Study 1, n = 448; Study 2, n = 575) received telithromycin 800 mg once daily for 10 (Study 1, 2-arms), 5 or 7 (Study 2, 3-arms) days, or clarithromycin 500 mg twice daily for 10 days. Frequency of CAP-related hospitalizations, physician visits/tests/procedures, and additional respiratory tract infection-related antibacterial use, as well as CAP-related length of hospital stay and hospitalization costs, were compared by treatment group (intent to treat populations) up until the late post-therapy visit (Days 31-36). Study investigators blinded to treatment regimen assessed whether hospital admissions were CAP related. RESULTS: Despite equivalent clinical efficacy for telithromycin vs clarithromycin in the clinically evaluable per-protocol populations (n = 784) (88.8% [428/482] vs 90.1% [272/302]--difference: -1.3%; 95% CI: -6.0, 3.4), telithromycin treatment for 5, 7, or 10 days was associated with significantly fewer CAP-related hospitalizations (p = 0.023) and CAP-related hospital days (p = 0.025) vs clarithromycin (reduction of 2.3 hospitalizations and 23.4 hospital days per 100 patients). Accordingly, estimated CAP-related hospitalization costs were significantly lower (p = 0.025) for telithromycin recipients (30,231 US dollars less per 100 patients). CAP-related hospitalizations, duration of hospital stay, and hospitalization costs for 7- to 10-day telithromycin--the approved dosing regimen for CAP--were significantly lower (p = 0.023, 0.025, and 0.025, respectively) than for clarithromycin. CONCLUSIONS: Data from this study indicate that telithromycin 800 mg once daily for 5, 7, or 10 days provides an effective therapy for patients with CAP, and may be associated with fewer CAP-related hospitalizations and hospital days than clarithromycin 500 mg twice daily for 10 days. Treatment with telithromycin could, therefore, potentially translate into cost savings in the management of CAP.

Trends in anti-bacterial resistance among Streptococcus pneumoniae isolated in the USA, 2000-2003: PROTEKT US years 1-3.

OBJECTIVES: To determine geographic and temporal trends in anti-bacterial resistance among Streptococcus pneumoniae isolated from patients with respiratory tract infections as part of the PROTEKT US surveillance study (2000-2003). METHODS: From 2000 to 2003, 31 001 isolates of S. pneumoniae were collected. Anti-bacterial minimum inhibitory concentrations were determined at a central laboratory using the CLSI broth microdilution method. Macrolide resistance genotypes were determined by PCR. RESULTS: Overall, 29.4, 22.5, 0.9, and 0.02% of S. pneumoniae isolates were resistant to erythromycin, penicillin, levofloxacin, and telithromycin, respectively, with considerable regional variability. Multidrug resistance was stable at approx. 31%. Among macrolide-resistant isolates, mef(A) was the most prevalent resistance gene identified; however, the percentage of isolates with this gene decreased from 68.8% (2000) to 63.9% (2003), while the prevalence of isolates containing both the erm(B) and mef(A) genes increased (2000, 9.7%; 2003, 16.4%). Over 90% of these erm(B)+mef(A)-positive isolates were also resistant to penicillin, tetracycline, or trimethoprim-sulfamethoxazole, while 98.6% were susceptible to levofloxacin and 99.1% were susceptible to telithromycin. CONCLUSIONS: Penicillin and erythromycin resistance among isolates of S. pneumoniae from the U.S.A. remained high over the 3 years of the study. Telithromycin demonstrated potent in vitro activity against pneumococcal strains.

Emergence and spread of Streptococcus pneumoniae with erm(B) and mef(A) resistance.

Streptococcus pneumoniae isolates (N = 31,001) were collected from patients with community-acquired respiratory tract infections during the PROTEKT US surveillance study (2000-2003). While the macrolide (erythromycin) resistance rate remained stable at approximately 29%, the prevalence of resistant isolates containing both erm(B) and mef(A) increased from 9.7% in year 1 to 16.4% in year 3, with substantial regional variability. Almost all (99.2%) dual erm(B) + mef(A) macrolide-resistant isolates exhibited multidrug resistance, whereas 98.6% and 99.0% were levofloxacin- and telithromycin-susceptible, respectively. These strains were most commonly isolated from the ear or middle-ear fluid of children. Of 152 representative erm(B)+mef(A) isolates, >90% were clonally related to the multidrug-resistant international Taiwan19F-14 clonal complex 271 (CC271). Of 366 erm(B)+mef(A) isolates from the PROTEKT global study (1999-2003), 83.3% were CC271, with the highest prevalence seen in South Africa, South Korea, and the United States. This study confirms the increasing global emergence and rapidly increasing US prevalence of this multidrug-resistant pneumococcal clone.

Meta-analysis of bacterial resistance to macrolides.

OBJECTIVES: Understanding changing resistance patterns is important in determining appropriate antibiotic treatments. This meta-analysis systematically evaluated resistance of Streptococcus pneumoniae and Streptococcus pyogenes to macrolide antibiotics among patients with community-acquired respiratory tract infections. METHODS: MEDLINE and EMBASE databases were searched and experts were consulted to identify published and unpublished literature reporting macrolide resistance rates. Identified studies were evaluated by two independent reviewers; those meeting a priori specified criteria (resistance by patient condition and strain, resistance thresholds, 1997-2003 isolates) were included. Data from included studies were abstracted by two independent reviewers using a standard review form. Discrepancies in abstracted data were resolved by the study investigator. RESULTS: Random-effects meta-analysis was performed for outcomes present in at least four studies overall and for specified subgroups. We identified 3849 studies and performed detailed review on 407; of these 29, published between 1998-2003, met the inclusion criteria. Mean resistance of S. pneumoniae isolates to azithromycin was 27.2% [95% confidence interval (CI) 24.6-29.7]; mean resistance to erythromycin was statistically equivalent (30.4%; 95% CI 28.1-32.7). Resistance of S. pyogenes to erythromycin (30.0%; CI 18.6-41.5) was similar to that of S. pneumoniae. Too few studies of clarithromycin were included to allow evaluation of resistance. In subgroup analyses, substantial variation in resistance to erythromycin was seen by geographic area. CONCLUSIONS: Reported macrolide resistance of S. pneumoniae varies substantially and may be a significant issue in certain regions. Use of meta-analysis to aggregate individual studies enabled determination of robust values for macrolide resistance. This information is useful for clinical and policy decision makers in developing appropriate antibiotic strategies.

Endocarditis due to vancomycin-resistant Enterococcus faecium in an immunocompromised patient: cure by administering combination therapy with quinupristin/dalfopristin and high-dose ampicillin.

A 56-year-old man with diabetes mellitus and cadaveric renal transplantation had vancomycin-resistant Enterococcus faecium tricuspid valve endocarditis. Relapse followed 6 weeks of treatment with intravenous gentamicin and high-dose ampicillin. On the basis of previous data suggesting the potential for synergistic activity of quinupristin/dalfopristin plus high-dose ampicillin, therapy with this combination was administered for 63 days. Cure was achieved and later confirmed at 2-year follow-up.

Clinical and bacteriological efficacy and safety of 5 and 7 day regimens of telithromycin once daily compared with a 10 day regimen of clarithromycin twice daily in patients with mild to moderate community-acquired pneumonia.

OBJECTIVES: This study was conducted to investigate the potential equivalence in clinical efficacy and assess safety of a 5 or 7 day regimen of oral telithromycin (800 mg once daily) and a 10 day regimen of oral clarithromycin (500 mg twice daily) in treating community-acquired pneumonia (CAP). Bacteriological efficacy was also compared. METHODS: This was a multicentre, randomized, double-blind, active-controlled study. Patients with mild to moderate CAP received telithromycin 800 mg once a day for 5 (n=193) or 7 (n=195) days or clarithromycin 500 mg twice a day for 10 days (n=187). In these groups, 159, 161 and 146 patients, respectively, completed the study. RESULTS: At the post-therapy/test-of-cure evaluation, clinical cure rates (per-protocol clinical population) were 89.3% (5 days) and 88.8% (7 days) for telithromycin, and 91.8% for clarithromycin 10 days. Satisfactory bacteriological outcome rates (per-protocol bacteriological population) were 87.7% and 80.0% for 5 and 7 days of telithromycin, respectively, and 83.3% for 10 days of clarithromycin. Bacteriological eradication rates in the respective treatment groups were, for Streptococcus pneumoniae, 95.8% (23/24), 96.7% (29/30) and 88.5% (23/26); for Haemophilus influenzae, 88.0% (22/25), 84.0% (21/25) and 88.2% (15/17) and for Moraxella catarrhalis, 1/1, 4/5 and 3/4. Both telithromycin regimens demonstrated clinical efficacy against pneumococcal bacteraemia (19/19), atypical pathogens (9/9) and erythromycin-resistant S. pneumoniae isolates (5/5). Most treatment-emergent adverse events were mild to moderate in intensity with most commonly reported adverse events involving the gastrointestinal system. CONCLUSIONS: Telithromycin 800 mg administered once a day for 5 or 7 days was as effective and safe as clarithromycin 500 mg administered twice a day for 10 days in treating patients with CAP caused by common respiratory pathogens, including macrolide-resistant isolates, and pneumococcal bacteraemia.