RADAR study

Accepted Manuscript Invasive meningococcal disease: Impact of short course therapy. A DOOR/RADAR study. Carmen Cabellos, Ivan Pelegrín, Eva Benavent, Francesc Gudiol, Fe Tubau, Dolores Garcia-Somoza, Ricard Verdaguer, Javier Ariza, Pedro Fernandez-Viladrich PII:

S0163-4453(17)30266-9

DOI:

10.1016/j.jinf.2017.08.009

Reference:

YJINF 3970

To appear in:

Journal of Infection

Received Date: 10 January 2017 Revised Date:

8 August 2017

Accepted Date: 18 August 2017

Please cite this article as: RRH: Four days therapy in meningococcal disease This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Invasive meningococcal disease: Impact of short course therapy. A DOOR/RADAR study. Carmen Cabellos1, Ivan Pelegrín1, Eva Benavent1, Francesc Gudiol1, Fe Tubau2, Dolores Garcia-Somoza2, Ricard Verdaguer2, Javier Ariza1, Pedro Fernandez-

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Viladrich1. Infectious Diseases Department 1 and Microbiology Department2. IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, Barcelona, Spain.

bacterial meningitis, antibiotic therapy,

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Key words: Neisseria meningitidis, DOOR/RADAR

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Running title: Four days therapy in meningococcal disease Corresponding author: Carmen Cabellos Infectious Diseases Department Hospital Universitari de Bellvitge

Barcelona, Spain

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08907 L’Hospitalet de Llobregat

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Telf +34932607625 [email protected]

Alternate corresponding author: Ivan Pelegrín

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Infectious Disease Department Hospital Universitari de Bellvitge 08907 L’Hospitalet de Llobregat Barcelona, Spain Telf +34932607625 [email protected]

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Abstract Background: Invasive meningococcal disease is a severe infection. The appropriate duration of antibiotic therapy is not well established. Methods: Two hundred and sixty-three consecutive patients with invasive

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meningococcal disease treated with 4 days’ antibiotic therapy were compared with 264 consecutive patients treated previously at the same center with 7 days’ antibiotic therapy. A Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of

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Antibiotic Risk (RADAR) study was also performed.

Results: No relapses were recorded in any patient. Patients on the 4-day course were 63% female, with a median age of 23 years old (IQR 16-54) and patients on the 7-day

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course were 61% female, with a median age of 17 years old (IQR 12-43). Case fatality rate was 7% in the 4-d patients and 6% in the 7-d patients (p=0.582). Neurological sequelae were recorded in 6% of the 4-d group and in 7% of the 7-d group ((p=0.509) and cutaneous sequelae in 3% in both groups. There were no statistical significant differences between the groups in terms of clinical characteristics, laboratory findings

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or complications. The probability that a patient had a randomly chosen DOOR better with the 4-day regimen than with the 7-day regimen was 80.4% [95% CI 80.1% -80.7%]. Conclusion: Invasive meningococcal disease may be successfully treated with a four-

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day course of antibiotic therapy without relapses.

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Introduction Invasive meningococcal disease (IMD, sepsis and/or meningitis), is an infection with an overall case fatality rate ranging from 5 to 16%. This rate is significantly increased with

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meningococcal septicemia, particularly when there has been a delay in the diagnosis. [1-6])

Despite the introduction of effective vaccines, IMD remains prevalent throughout the world and represents a serious health problem. Beside prevention, early recognition

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and aggressive treatment are the only effective measures against this invasive disease. Once the antibiotic has been started the response is in general very good, with very

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fast improvement. Therefore, a recurrent issue is the duration of therapy. As in other forms of meningitis, forty years ago, antibiotic therapy lasted 10 to 14 days [7]. Duration was more recently shortened to 7 days [3-4]. Several studies have shown equal outcomes with 7 days and shorter schedules [8-10] but, for no clear reason, long therapy remains the current practice in most hospitals and in some popular guidelines

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despite the good results with short therapy regimens [11-12]. In 1984, in view of the fact that patients who died did so in the first 24 to 48 h of therapy and the remainder showed rapid clinical improvement usually within the first 24 h, we started routine use of 4-day antibiotic therapy, and reported our experience with the first 50 consecutive

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patients [13]. Since then, the 4-day regimen has been our standard practice in IMD and no relapses have been recorded.

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The objective of this study is to present our experience in 4-day antibiotic therapy compared with 7-day regimen over a long period of time in a cohort with a high percentage of adult patients. We used the new Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR) techniques designed to

evaluate appropriate use of antibiotics [14].

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Patients and methods This is an observational cohort study of patients with IMD admitted to our hospital from 1977 to 2013. The Hospital Universitari de Bellvitge is a large university hospital in

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Barcelona (Spain). Since 1977, all cases of bacterial meningitis or IMD have been routinely recorded in a 120-variable computer-assisted protocol. For the purpose of this study, we selected all episodes of IMD, with or without meningitis. An episode was considered to

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have occurred when there were clinical findings of sepsis and/or meningitis, and N. meningitidis was isolated in blood, cerebrospinal fluid (CSF), pharyngeal swab or joint fluid, or, in the absence of positive cultures, when Gram-negative diplococci were

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detected in the CSF Gram stain, or in the hyperendemic period when patients presented findings of acute bacterial meningitis or sepsis with characteristic skin lesions. Patients with IMD were classified as sepsis (meningococcal disease without meningitis) or meningitis. Meningitis was diagnosed by inflammatory parameters in CSF, at least 5 white blood cells (WBC)/mm3, or positive CSF culture. These meningitis

none to septic shock.

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patients manifested varying symptoms and signs of the sepsis criteria, ranging from

Duration of therapy was 7 days from 1977 until 1983 (long therapy) and 4 days from

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1984 to 2013 (short therapy). Patients attended in these two periods (and thus treated with either 7 or 4 days) were the compared populations. Patients who died in the first

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few days are included in all the analyses in their respective treatment group (7 vs 4 days).

From 1977 to 1994 our hospital admitted patients as young as seven years old. Since 1994, however, only patients aged 14 years or older have been admitted; very young pediatric patients are now seen at other hospitals in our area. All patients were evaluated daily and received complete hematological counts and biochemical tests within 48 hours of admission, during hospitalization, and once more in the outpatient clinic. All patients surviving IMD were controlled at the outpatient

ACCEPTED MANUSCRIPT clinic and were followed up later until resolution of all the symptoms or consideration of the symptoms as permanent sequelae, one year after the initial infection. Case fatality rate during hospitalization was recorded. The mechanism of death was classified as early sepsis (first 48 h), early neurological, late neurological and late non-

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neurological (due to complications other than neurological problems). Lesions requiring plastic surgery repair or amputation were considered as cutaneous sequelae. Neurological sequelae were considered at 1 year.

The isolates were identified and characterized using conventional microbiologic

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methods [15-16].

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Statistical analysis: Continuous variables were expressed as the mean (SD) or the median with interquartile range (Q1-Q3). For descriptive analysis of episodes of IMD, categorical data were compared using the Chi-square test or Fisher exact test, and continuous data with the t-test or Mann-Whitney test. We analyzed the impact of short or long therapy (4 vs 7 days) on outcome using a logistic regression model. Associations are given as odds ratios (ORs) with 95% confidence intervals (95% CIs).

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Although no differences were found in outcome, a propensity score was also calculated to study differences in the probability of receiving either therapy. The short or long therapy strategy were also studied using a novel methodology, the desirability

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of outcome ranking/response adjusted for duration of antibiotics (DOOR/RADAR) technique [14]. Using this methodology, outcomes are used to analyze patients rather

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than using patients to analyze outcomes. Five general, mutually exclusive hierarchical clinical outcomes – cured without sequelae, cured with cutaneous sequelae, cured with neurological sequelae, early mortality (< 48 h) and late mortality (> 48 h) – were defined and patients were classified in one of these groups. Duration of therapy in days make a second classification, and then short and long therapy results were compared.

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Results Between 1977 and 2013, 527 episodes of invasive meningococcal disease were recorded at our hospital: 57 cases of sepsis (11%) and 470 of meningitis with/without sepsis (89%). Three hundred and twenty-five patients (61%) were women, and the

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median age was 19 yrs (7-87). Four hundred and sixty-six episodes (88%) occurred in the first half of the period; after this, the incidence decreased sharply. Clinical and laboratory characteristics are shown in Tables 1 and 2. There were no relevant differences between groups, though patients in the 4-day therapy group were older

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than those in the 7-day group (see methods). Other differences were also due to the therapy in use at the given time: for instance, heparin was used as therapy for

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disseminated intravascular coagulation in the first period, but it was not recommended in the second period.

Penicillin was used in 337 patients (64%), ampicillin in seven (1%) cefotaxime in 12 (2%), ceftriaxone in 155 (29%), chloramphenicol in 10 (2%) and another agent in four (0.8%). Two patients did not receive therapy because of overwhelming sepsis with very

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early mortality. The 4-day course was used in 263 patients (50%), in cases of either sepsis or meningitis, and the 7-day course in 264. Specific antibiotics are shown in Table 3. Due to the different time periods, patients with 7-day therapy were treated mainly with penicillin while patients in the 4-day group were treated with penicillin or

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ceftriaxone. No differences were found between patients treated with either 4 or 7 days in terms of case fatality rate (7% vs 6% p=0.582) cutaneous sequelae (3% in both

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cases) or neurological sequelae (5% vs 7% p=0.509) and there were no relapses. A multivariate analysis did not associate the 4-day therapy with mortality (p=0.108, OR 2.187, 95% CI 0.843 5.669). We also analyzed the influence of 4-day or 7-day therapy on mortality using the propensity score as a covariate in a multivariate analysis, which confirmed the lack of influence of short or long therapy on outcome p=0.115, OR 4.194 (95% CI 0.706 - 24.913). The propensity score has an area of 0.906 (95% CI 0.878 0.935). Nor were statistically significant differences found in complications presented, except for more urinary tract infections in patients in the 7-day group (Table 3). Overall outcome with the two therapies was similar with all comparative methods used.

ACCEPTED MANUSCRIPT The new DOOR/RADAR technique, tailored for trials that compare strategies to optimize antibiotic use, showed no statistically significant differences (p-value = 0.912) between the distribution of the DOOR score in patients treated with 7 or 4 days according to the Wilcoxon test. The DOOR/RADAR results are shown in Table 4 and Fig 1. The probability that a patient had a better randomly chosen DOOR using 4-day

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treatment than using 7-day treatment was 80.4% [95% CI 80.1% -80.7%].

Discussion

Duration of antibiotic therapy in bacterial meningitis has been a controversial topic for

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several years, and the recommendations in the guidelines continue to vary [12]. Our experience with a short 4-day therapy for IMD is consistent with other reports like the

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New Zealand study in which 58 consecutive patients were treated for 3 days without relapses [8] and with others from the African meningitis belt [17]. Previous experiences have included a Swiss clinical trial which found similar results when comparing 4-day and 8-day regimens [10] and a Greek clinical trial [9] which presented good results without relapses. Our groups were very similar in all characteristics, and presented the

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same mortality and sequelae with the short and long therapy; the propensity score test showed that groups receiving either therapy were similar and the DOOR/RADAR technique also showed an advantage for short therapy, since the results were the same with fewer days of therapy. Since publishing our experience in 1986 [13], we

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have used short course therapy as standard practice for 30 years, without relapses. Health care has improved constantly over the time span of the study (36 years) but

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these two groups of patients of very similar characteristics presented similar outcomes. Shortening therapy by three days may not be a great deal in sporadic cases in big cities, but it may be of great interest in certain circumstances such as epidemics or in areas with poor resources. Of course, in an era of growing antibiotic resistance in which improving antibiotic use means shortening antibiotic regimens of all kinds, this practice could be a contribution. Moreover, if we use the same new techniques as we use in nosocomial infections such as DOOR/RADAR the 4-day regimen also emerges as the chosen schedule. Our study has some limitations. For example, it is not a clinical trial, but since our aim was to demonstrate the lack of differences between the two populations and their

ACCEPTED MANUSCRIPT outcomes, our two groups of 264 and 263 consecutive patients offer a good reflection of the situation. Also, since patients have been treated in 2 different periods of time, some measures such as resuscitation and intensive care support would benefit patients treated in the last period, which are the 4-day regimen patients. In any case the lack of differences in outcome might show that in the present time, 4-day therapy

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is enough or a therapy as good as 7-day therapy. Late non neurological mortality was higher in the 4-day therapy, which may be attributed to the higher age of this group, five out of seven patients were older than 75 yrs and died due to renal or heart failure, gastrointestinal bleeding or post intubation pulmonary complications.

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Our experience with all these cases may encourage others to apply the 4-day therapy. In fact, the recent UK guidelines [18] now include a recommendation to stop therapy

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at five days in meningococcal meningitis.

In conclusion, a 4-day antibiotic regimen in invasive meningococcal disease provides safe and sufficient treatment.

Acknowledgments

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C. Cabellos, F. Gudiol and J. Ariza are members of REIPI RD12/0015. I. Pelegrin had a personal grant from IDIBELL. I. Pelegrin and C. Cabellos are members of ESGIB. We thank C. Tebé for statistical assistance.

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Funding section

This research did not receive any specific grant from funding agencies in the public, commercial, or

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not-for-profit sectors.

Transparency declaration None to declare

References:

1. Barquet N, Domingo P, Cayla JA et al. Meningococcal disease in a large urban population (Barcelona, 1987-1992). Predictors of dismal prognosis. Arch Intern Med, 1999; 159: 2329-2340.

ACCEPTED MANUSCRIPT 2. Domínguez A, Cardeñosa N, Pañella H, et al. Working Group on the Study of Meningococcal Disease in Catalonia, 1990-1997. The case-fatality rate of meningococcal disease in Catalonia, 1990-1997. Scand J Infect Dis. 2004; 36 :274-27. DS,

Greenwood

B,

Brandtzaeg

P.

Epidemic

meningitis,

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3. Stephens

meningococcaemia, and Neisseria meningitidis. Lancet. 2007; 369: 2196–2210. 4. Brigham KS, Sandorab TJ. Neisseria meningitidis: epidemiology, treatment and

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prevention in adolescents. Current Opinion in Pediatrics 2009; 21: 437–443.

5. Domingo P, Pomar V, Benito N, Coll P. The changing pattern of bacterial meningitis in adult patients at a large tertiary university hospital in Barcelona,

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Spain (1982-2010). J Infect. 2013; 66(2):147-154.

6. Dwilow R, Fanella S. Invasive Meningococcal Disease in the 21st Century—An Updatefor the Clinician. Curr Neurol Neurosci Rep. 2015; 15: 2-9.

7. Salmi I, Pettay 0, Simula I, et al: An epidemic due to sulphonamideresistant

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group A meningococci in the Helsinki area (Finland): Epidemiological and clinical observations. Scand J Infect Dis 1976;8:249-254 8. Ellis-Pegler R, Galler L, Roberts S, Thomas M, Woodhouse A. Three days of

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intravenous benzyl penicillin treatment of meningococcal disease in adults. Clin

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Infect Dis. 2003; 37: 658–662. 9. Kavaliotis J, Manios SG, Kansouzidou A, Danielidis V. Treatment of childhood bacterial meningitis with ceftriaxone once daily: open, prospective, randomised, comparative study of short-course versus standard-length

therapy. Chemotherapy 1989; 35:296–303.

10. Martin E, Holhl P, Guggi T, Kayser FH, Fernex M. Short course single daily ceftriaxone monotherapy for acute bacterial meningitis in children: results of a Swiss Multicenter Study. Part I: clinical results. Members of the Swiss Multicenter Meningitis Study Group. Infection 1990; 18:70–7.

ACCEPTED MANUSCRIPT 11. Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM, Whitley

RJ. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39(9):1267-84.

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12. van de Beek D, Cabellos C, Dzupova O, Esposito S, Klein M, Kloek AT, et al . ESCMID guideline: diagnosis and treatment of acute bacterial meningitis. Clin Microbiol Infect. 2016; 22(3):S37-62.

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13. Viladrich PF, Pallares R, Ariza J, Rufi G, Gudiol F. Four days of penicillin therapy for meningococcal meningitis. Arch Intern Med. 1986; 146(12):2380-2382.

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14. Evans Scott R, Rubin Daniel, Follmann Dean, Pennello Gene, Huskins W Charles, Powers John H, Schoenfeld David, Chuang-Stein Christy, Cosgrove Sara E, Fowler Vance G, Lautenbach Ebbing, Chambers Henry F. Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR). Clin Infect Dis. 2015; 61:800-6

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15. Janda WM and Gaydos CH, Neisseria p 601-620 In PR Murray, EJ Baron, JH Jorgensen, ML Landry and MA Pfaller (ed) Manual of Clinical Microbiology , 9th ed; Vol 1. ASM Press Washington, DC. 2007.

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16. Clinical and Laboratory Standards Institute (Formerly NCCLS). Performance Standards for Antimicrobial Susceptibility Testing: Twenty-Fourth Informational

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Supplement. CLSI document M100-S24 Vol 34 No.1 Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 US, 2014 January.

17. Nathan N, Borel T, Djibo A, Evans D et al. Ceftriaxone as effective as long-acting chloramphenicol in short course therapy in meningococcal meningitis during epidemics: a randomised non inferiority study. The Lancet. 2005; 366: 3018313

ACCEPTED MANUSCRIPT 18. McGill F, Heyderman RS, Michael BD, Defres S, Beeching NJ, Borrow R, Glennie L, Gaillemin O, Wyncoll D, Kaczmarski E, Nadel S, Thwaites G, Cohen J, Davies NWS, Miller A, Rhodes A. The UK joint specialist societies guideline on the diagnosis and management of acute meningitis and meningococcal sepsis

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in immunocompetent adults. Journal of Infection 2016; 72: 405-438

Table 1. Clinical characteristics of patients with invasive meningococcal disease treated for either 7 or 4 days.

N= 264 (50%) 240 (91%)

Age yrs (Median, range and IQR)

N= 263 (50%) 230 (88%)

0.201

17 7-80 (12 43)

23 7-87 (16 54)

<0.001

Gender (Female)

165 (63%)

160 (61%)

0.695

Underlying disease

44 (17%)

45 (17%)

0.468

87 (73%)

124 (79%)

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Meningitis

4 days

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7 days

Serogroup

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12 (10%)

26 (17%)

20 (17%)

7 (4%)

66 (25%)

59 (23%)

0.504

165 (63%)

165 (63%)

0.955

Very fast disease < 12 h

51 (19%)

51 (19%)

0.983

Late consultation > 48 h

37 (14%)

40 (15%)

0.725

Odynophagia

98 (38%)

112 (44%)

0.208

Fever

244 (96%)

247 (96%)

0.809

Fever in emergency room

161 (68%)

169 (66%)

0.700

Shock

41 (16%)

27 (10%)

0.071

Other

Autumn-winter occurrence

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Length of pre-hospital disease

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Previous antibiotic

Clinical characteristics

ACCEPTED MANUSCRIPT 239 (93%)

229 (88%)

0.056

Nuchal stiffness

226 (88%)

213 (82%)

0.069

Nausea/vomiting

230 (90%)

200 (78%)

<0.001

Skin lesions

221 (84%)

222 (84%)

0.905

Coma on admission

37 (14%)

41 (16%)

0.650

Cranial nerve palsy

18 (7%)

Hemiparesis

9 (3%)

Seizures

15 (6%)

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Headache

0.884

4 (2%)

0.162

14 (5%)

0.832

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19 (7%)

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IQR: Interquartile range

ACCEPTED MANUSCRIPT Table 2. Laboratory findings in patients with invasive meningococcal disease treated for 7 or 4 days.

4 days

p

Positive blood culture

109 (41%)

100 (38%)

0.444

Thrombocytopenia (<100 x109)

58 (23%)

35 (14%)

0.008

Prothrombin time >13.5 s

128 (51%)

137 (56%)

0.230

Hypernatremia (>145 mmol/L)

4 (2%)

2 (1%))

0.414

Median CSFWBC Range (IQR) cells/µL

1984,1-51300(196- 6000)

1300, 1-49000 (126-5550)

0.262

Median CSF PMN%

94 1-99 (85 98)

94 12-99 (90-98)

0.429

CSF glucose (< 2.2 mmol/L or 50 % of 159 (66%) blood)

128 (55%)

0.012

CSF protein >1 g/L

156 (66%)

163 (70%)

0.373

CSF protein >5 g/L

57 (24%)

59 (25%)

0.770

Positive CSF Gram stain

139/245 (57%)

137/246 (56%)

0.815

165 (66%)

147 (62%)

0.361

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Positive CSF culture

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7 days

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IQR: Interquartile range; PMN: Polymorphonuclears

ACCEPTED MANUSCRIPT Table 3. Therapy and complications of patients treated for 7 or 4 days.

7 days n= 264

4 days n=263

Penicillin (2-3x 10 5 U/Kg/d)

249 (94%)

88 (34%)

Ceftriaxone (50 mg/Kg, 4 g as max. dose)

0 (0%)

Other

13 (5%)

No antibiotic therapy

2 (0.7)

Heparin

36/258 (14%)

3/259 (1%)

<0.001

Mechanical ventilation

27 (10%)

28 (11%)

0.934

35 (14%)

45 (17%)

0.254

15 (6%)

25 (10%)

0.105

7 (3%)

3 (1%)

0.165

21 (8%)

26 (10%)

0.470

27 (10%)

20 (8%)

0.266

17 (7%)

20 (8%)

0.635

42 (16%)

31 (12%)

0.175

Presence of herpes labialis

58 (22%)

66 (26%)

0.342

Catheter phlebitis

76 (29%)

62 (24%)

0.149

Urinary tract infection

9 (4%)

1 (0.4%)

0.010

Median hospitalization days, range (IQR)

10 1-99 (8 11)

7 1-99 (6 9)

<0.001

0

0

27 (10%)

22 (9%)

Cutaneous necrosis

9 (3%)

8 (3%)

0.811

Neurological

18 (7%)

14 (6%)

0.509

15 (6%)

18 (7%)

0.582

Relapse of fever Arthritis Pericarditis

Renal failure * Liver function impairment **

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DIC

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Heart failure

Sequelae

Case fatality rate

<0.001

155 (59%)

<0.001

20 (8%)

0.204

0 (0%)

0.157

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Complications

Relapse

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Therapy

ACCEPTED MANUSCRIPT 3 (1%)

3 (1%)

Late neurological

1(0.4%)

1 (0.4%)

Early sepsis

11 (4%)

7 (3%)

Late non-neurological

0 (0%)

7 (3%)

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Early neurological

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IQR: Interquartile range; DIC Disseminated intravascular coagulation; * Serum creatinine > 150 µmol/L; ** 2x previous value of transaminases or alkaline phosphatase

ACCEPTED MANUSCRIPT Table 4. Description of outcome Variables

7 day therapy

4 day therapy

n= 264

n=263

222 (84 %)

Cured with cutaneous sequelae

9 (3 %)

Cured with neurological sequelae

18 (7 %)

Early mortality

14 (5 %) 1 (0.38 %)

8 (3 %)

14 (5 %)

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Late mortality

223 (85 %)

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Cured without sequelae

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DOOR*

Duration of therapy Mean (SD) Median (IQR)

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Missing

4.81 (3.2)

7.00 (7.00-8.00)

4.00 (4.00-4.00)

4 (1.52 %)

0 (0 %)

*Wilcoxon Rank sum test: W= 34593; p-value=0.912

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8 (3 %)

7.69 (4.37)

SD: Standard deviation; IQR Interquantile range

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10 (4 %)

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4-d therapy

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ACCEPTED MANUSCRIPT

7-d therapy

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Figure 1. Box plot DOOR/RADAR score by study group. Each circle/point represent a patient, no extreme or outlier values were found.

ACCEPTED MANUSCRIPT Highlights: Short course antibiotic therapy in invasive meningococcal disease is presented. 263 patients treated with 4 days’ antibiotic were compared with 264 treated 7 days.

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Invasive meningococcal disease may be successfully treated for 4 days without relapse.