Journal of Infection (2014) 68, 216e224
www.elsevierhealth.com/journals/jinf
Ommaya reservoir-related infections: Clinical manifestations and treatment outcomes Ariel D. Szvalb a,b,*, Issam I. Raad a,b, Jeffrey S. Weinberg c, Dima Suki c, Rory Mayer c, George M. Viola a,b a
Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA b Department of Infectious Diseases, Baylor College of Medicine, Houston, TX, USA c Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Accepted 11 December 2013 Available online 17 December 2013
KEYWORDS Central nervous system; Device; Infection; Ommaya reservoir; Meningitis
Summary Objectives: As infection is a severe complication of Ommaya reservoirs (OR), and existing data is limited, herein we describe the largest study of the clinical manifestations and treatment outcomes of Ommaya reservoir-related infections (ORRI). Methods: We retrospectively reviewed the records of all patients at our institution who had an OR placed, and developed a definite device-related infection between 2001 and 2011. Results: Among 501 OR placements, 40 patients (8%) developed an ORRI. These presented with meningitis and/or meningoencephalitis (60%), cellulitis (20%), or a combination thereof (20%). Approximately 40% occurred 30 days of OR placement, while 60% occurred 10 days after the device was last accessed. Only 20% presented with leukocytosis, while another 18% had a normal cerebrospinal fluid (CSF). Gram-positive skin flora accounted >80% of the pathogens. The median hospital stay and duration of antibiotics were 13 and 24 days, respectively. Although mortality rates (z10%) were similar among all treatment groups (p > 0.99), shorter hospitalization and antimicrobial treatment durations were obtained with early versus late device removal (p < 0.038). Conclusions: As clinical symptoms can be non-specific and CSF parameters may be within normal limits, a high suspicion for infection is required. The shortest hospitalization and treatment course was achieved with early device removal. ª 2013 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1460, Houston, TX 77030, USA. Tel.: þ1 713 792 5158; fax: þ1 713 794 4351. E-mail address: [email protected] (A.D. Szvalb). 0163-4453/$36 ª 2013 The British Infection Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jinf.2013.12.002
Ommaya reservoir-related infections
Introduction In 1963 Dr. Ayub Ommaya introduced a subcutaneous reservoir and pump for repeated access and drug delivery to the cerebrospinal fluid (CSF).1 This device was initially intended for the administration of antimicrobials for the treatment of fungal meningitis.2 Soon thereafter, the Ommaya reservoir became the preferred method for the infusion of intrathecal chemotherapy in patients with leptomeningeal malignancies.3,4 This device is a small dome-shaped reservoir placed subcutaneously in the scalp and connected through a burr hole to an intraventricular catheter. Complications associated with Ommaya reservoirs include device malfunction, seizures, and bleeding.5 Similarly to other foreign medical materials, the Ommaya reservoir is also prone to microbial adherence, colonization, infection, and subsequent extension of the infectious process into the surrounding skin, soft tissues, and central nervous system (CNS) compartments.6,7 The rate of Ommaya reservoir-related infections ranges from 2 to 15%.5,8e10 Clinical manifestations and current treatment strategies are based on limited numbers of case reports and small case series that at times are in diametrical opposition to one another.5,8e12 A better understanding of the infectious process that occurs using the Ommaya reservoir, its manifestations, and outcomes is clearly needed for earlier identification and better management of this complication. Herein, we examined the epidemiological, clinical, microbiological, and laboratory characteristics as well as treatment outcomes of patients with Ommaya reservoirrelated infections at a National Cancer Institute designated comprehensive cancer center.
Patients and methods Hospital setting and study population This retrospective study was conducted at The University of Texas MD Anderson Cancer Center, Houston, Texas. Medical records of all 501 patients, adults and children, who underwent an Ommaya reservoir placement between January 1, 2001, and December 31, 2011, were reviewed. All episodes that fulfilled our strict definition criteria (see below) for Ommaya reservoir-related infection were included in the final analysis. The study was approved by the institutional review board.
Definition An infection was considered to be associated with an Ommaya reservoir if both clinical and microbiological criteria were satisfied. We excluded from our analysis any patient who did not fulfill both of the above criteria. Local clinical manifestations of a skin and soft tissue infection (SSTI) overlying the reservoir included at least one of the following: erythema, tenderness, discharge, warmth and wound dehiscence with device exposure. Meningitis was defined by the presence of at least 2 of the following: persistent headaches, fever, neck rigidity, nausea or vomiting; while meningoencephalitis included those patients
217 with meningitis plus altered mental status. All of the above clinical manifestation could not be explained by an alternative diagnosis. The microbiological criteria were confirmed if growth from at least one of the following sources was observed: CSF drawn from the reservoir, removed device material, intraoperative surgical cultures, or purulent collection adjacent to the reservoir.
Data collection Information on patient demographics, comorbid conditions, and type of cancer, as well as Ommaya reservoir characteristics and clinical presentation at the time of admission, was collected. Additionally, laboratory, microbiological, and imaging data were analyzed. The duration of antimicrobial therapy, necessity for device removal, length of hospitalization, and overall outcomes were also reviewed.
Statistical analysis Descriptive statistics were performed on patients’ demographic, clinical and laboratory data. Continuous variables were summarized using median with 25th and 75th percentile (Q1eQ3). Categorical variables were summarized using frequencies and percentages. Continuous variables were compared using Wilcoxon rank sum tests and categorical variables were compared using Chi-square or Fisher’s exact tests, as appropriate. KruskaleWallis tests were used to compare continuous variables among three groups. If a significant result (p < 0.05) was detected from a KruskaleWallis test, then Wilcoxon rank sum tests were used for the pairwise comparisons. The a levels of the post-hoc pairwise comparisons were adjusted using a sequential Bonferroni adjustment. All tests except those for pairwise comparisons were two-sided tests with a significance level of 0.05. The statistical analyses were performed using SAS version 9.3 (SAS Institute Inc., Cary, NC).
Results Demographic and Ommaya reservoir characteristics Among the 501 patients that had an Ommaya reservoir placed, we identified a total of 65 patients who fulfilled the microbiological criteria. However, only 40 of these met our strict criteria for Ommaya reservoir-related infection (an overall rate for infection of 8%) and were the subject of further analysis. At the time of diagnosis, the median patient age was 43 (range 6e77) (Table 1). Most of the infections occurred in white (80%) men (63%). Over 60% of the patients had an underlying hematologic malignancy, while the rest had a solid cancer. Other comorbid conditions such as diabetes, congestive heart failure, chronic obstructive pulmonary disease, cirrhosis, and tobacco use were rare. All patients had the Ommaya reservoir implanted for the administration of intrathecal chemotherapy. None of the patients had an episode of bacteremia or an external ventricular device placed within the preceding 3 months of device implantation or fever at time of surgery. All patients had received perioperative
218 Table 1
A.D. Szvalb et al. Characteristics of patients with and without Ommaya reservoir-related infections.
Variable
Infected cases (n Z 40)
Non-infected cases (n Z 461)
Age in years, median (range) Male Ethnicity White Hispanic Black Asian Comorbidities Hematologic malignancy Non-primary CNS lymphoma Acute leukemia Chronic leukemia Waldenstrom’s and Multiple Myeloma Primary CNS lymphoma Solid malignancy Non-primary CNS tumor Primary CNS tumor Tobacco Diabetes HIV Othera Reason for Ommaya reservoir placement Intrathecal chemotherapy Pain management Other
43 (6e77) 25 (63)
52 (2e81) 205 (44)
32 (80) 6 (15) 2 (5) 0
366 (79) 65 (14) 25 (5) 5 (1)
25 (63) 12 (30) 6 (15) 4 (10) 2 (5) 1 (3) 15 (38) 10 (25) 5 (13) 4 (10) 2 (5) 1 (3) 0
192 (42) 132 (29) 28 (6) 0 13 (3) 19 (4) 269 (58) 220 (48) 49 (11) 92 (20) 31 (7) 3 (1) 38 (8)
40 (100) 0 0
456 (99) 1 (0.2) 4 (0.9)
p-Value 0.07 0.028 0.97
0.011
0.011
>0.99
Note. Data are no. (%), unless otherwise indicated. Percentages were rounded up and may not add to 100%. CNS, central nervous system; HIV, human immunodeficiency virus. a Congestive heart failure, chronic obstructive pulmonary disease, intravenous drug use, alcohol abuse, liver failure, and cirrhosis.
antibiotics, with cefazolin being the most common in 24 patients, followed by vancomycin in 7, and with 1 patient receiving both antibiotics. In the remaining 8 cases the antibiotic used was unknown. Ommaya related infections were more likely to occur among males (p Z 0.028), and individuals with hematological malignancies (p Z 0.011).
Clinical manifestations and imaging characteristics The most frequent clinical syndrome at the time of admission was meningitis and/or meningoencephalitis in 24 (60%) patients, followed by a SSTI in 8 (20%), and a combination of both in 8 (20%). The most common systemic manifestation were headaches (83%), followed by fever (68%), neck rigidity (40%), nausea and vomiting (33%), and altered mental status (25%) (Table 2). The most frequent local manifestation was wound drainage (23%), erythema (20%), and wound dehiscence associated with device exposure (20%). Concomitant infectious processes included bacteremia and pneumonia (4 episodes each). The same pathogen was cultured in the CSF, in 3 of the 4 patients with a bloodstream infection. Approximately 45% of the patients had an imaging study of the head performed. Twelve (30%) patients had been examined by computed axial tomography, and only 2 of them had abnormal findings (one with meningeal enhancement and one with epidural abscess). Six (15%) other patients had been examined by magnetic resonance imaging, and 2 of them had meningeal enhancement, while the rest had a normal study.
Time to infection and number of times the reservoir was accessed prior to infection The median time between Ommaya reservoir placement and the appearance for infection was 41 days (Q1eQ3 Z 15.5e142.5 days; Table 3). Approximately 40% of the infections occurred within the first 30 days of placement, while almost 70% occurred within the first 90 days. Additionally, only 29 patients (73%) had their reservoir accessed, in which the median time between the device was last accessed to infection was 7 days (Q1eQ3 Z 4e30 days). Approximately 59% of these patients developed an infection within 10 days the device was last accessed, while the remaining occurred after this time frame. Furthermore, in those that had the reservoir accessed (29 patients), the reservoir was punctured with a median of 5 (Q1eQ3 Z 2e17) times, with 20 (69%) patients having the reservoir accessed fewer than 10 times. Eleven (28%) of the patients did not have the device accessed, 7 had developed a postoperative infection within 30 days, while 3 occurred within 31e90 days and 1 after 90 days postoperatively.
Laboratory analyses The median white blood cell count (WBC) was 6100 cells/mL (Q1eQ3 Z 3800e8950; Table 4). Only 8 (20%) patients had a WBC >10,000 cells/mL, while 5 (13%) patients had a WBC
Ommaya reservoir-related infections
219
Table 2 Clinical manifestations of Ommaya reservoirrelated infections. Variable
Headaches Fever Neck rigidity Nausea and vomiting Altered mental status Discharge Purulent Serohemorrhagic Cerebrospinal fluid Erythema Dehiscence/ exposure Warmth Tenderness Concomitant infection Bacteremiaa Pneumonia Urinary tract infection Subgaleal collection
M/ME
SSTI
Both
Total
24 (60)
8 (20)
8 (20)
40 (100)
23 (57.5) 17 (42.5) 11 (27.5) 9 (22.5)
3 (7.5) 2 (5) 0 1 (2.5)
7 8 5 3
33 27 16 13
5 (12.5)
0
5 (12.5) 10 (25)
0 0 0 0
5 3 1 1
0 0
5 (12.5) 3 (7.5) 4 (10) 4 (10)
8 (20) 8 (20)
0 0
3 (7.5) 2 (5)
2 (5) 0
5 (12.5) 2 (5)
3 (7.5) 3 (7.5) 1 (7.5)
0 0 0
1 (2.5) 1 (2.5) 1 (2.5)
4 (10) 4 (10) 2 (5)
1 (2.5)
0
0
1 (2.5)
(12.5) (7.5) (2.5) (2.5)
4 1 2 1
(17.5) (20) (12.5) (7.5)
(10) (2.5) (5) (2.5)
9 4 3 2
(82.5) (67.5) (40) (32.5)
(22.5) (10) (7.5) (5)
Note. Data are no. (%), unless otherwise indicated. M/ME, meningitis/meningoencephalitis; SSTI, skin and soft tissue infection. a In 3 of the 4 patients, the same pathogen was found concomitantly in the central nervous system and blood.
5 cells/mL), of which neutrophils were the predominant cell type in 61%, followed by lymphocytes in 39% of the patients. Only 8 patients (20%) were found to have malignant cells in the CSF. Interestingly, 6 (18%) of the patients had all of their CSF parameters within normal limits (leukocytes, glucose, and protein levels). Of these 6 patients, 1 presented with Propionibacterium acnes with local clinical manifestations and without affecting the CNS compartments. The remaining 5 patients presented with meningitis. Three of these were neutropenic at the time the CSF was obtained, with 2 of them revealing coagulase-negative staphylococci (CoNS), and the other with Enterococcus faecalis. A fourth patient, who had developed CoNS meningitis, was a non-neutropenic patient who was on high-dose prednisone (1 mg/kg/day). The above 5 patients, had an excellent clinical response after antibiotics were started and the reservoir was removed. The remaining patient with P. acnes meningitis and Waldenstrom’s macroglobulinemia on rituximab, cytarabine and methotrexate, resolved with antibiotic therapy only, without reservoir removal. None of those six patients had any malignant cells recovered in the CSF histopathological analysis.
Microbiology Gram staining of patients’ CSF obtained via the Ommaya reservoir revealed a microorganism in two thirds of cases (Table 4). A total of 52 positive cultures were analyzed. All 37 CSF cultures obtained through the reservoir and all 5 intraoperative wound cultures had grown a microorganism, while 10 of the 17 Ommaya tip cultures had grown a pathogen. A polymicrobial infection was encountered in 6 (15%) patients with a total of 12 organisms isolated (2 in each patient). These polymicrobial cultures were collected from the following sites: CSF recovered via the Ommaya reservoir (4 specimens), wound cultures (3 specimens), and from an Ommaya tip (1 specimen). Five of six patients had developed a dual Gram-positive and negative infection. All 6 patients had grown a Gram-positive organism, with CoNS occurring in 5, while Gram-negative organisms (all different), grew in 5 patients. Only 28 (70%) of the 40 patients had a blood culture obtained at the time of admission, in which 4 were positive, with 3 of them growing concomitantly in the CSF: Klebsiella pneumoniae, E. faecalis and CoNS. Gram-positive bacteria accounted for more than 80% of the infections (Table 5). Within this group, the most commonly isolated organisms were CoNS (54%), methicillin-susceptible Staphylococcus aureus (MSSA) (8%), P. acnes (8%), and a-hemolytic streptococci (6%). The most commonly encountered Gram-negative bacteria
Table 3 Device placement and access in relation to infection. Variable
Median (Q1eQ3)
Days to infection after device placement 90 Days to infection after device was last accesseda 30 Number of Ommaya taps prior to infection onseta 20
41 (15.5e142.5)
No. of patients (%)
15 (38) 12 (30) 13 (32) 7 (4e30)
17 (59) 5 (17) 7 (24) 5 (2e17)
20 (69) 5 (17) 4 (14)
Note. Percentages were rounded up and may not add to 100%. Q1eQ3, 25the75th percentile. a Eleven (28%) of the patients did not have the device accessed. Of these, 7 patients developed a postoperative infection within 30 days, while 3 occurred within 31e90 days and 1 after 90 days postoperatively. b Of these 17 patients, 8 developed a postoperative infection within 30 days, while 4 occurred within 31e90 days and 5 after 90 days postoperatively.
220
A.D. Szvalb et al.
Table 4 Laboratory analysis of patients with Ommaya reservoir infection. Variable
Median (Q1eQ3)
Peripheral WBC/mL
6100 (3800e8950)
Leukocytes >10,000 cells/mL CSF valuesa Glucose, mg/dL Protein, mg/dL Leukocytes, cells/mL Neutrophils, % Lymphocytes, % Red blood cells/mL Normal CSF valuesa Leukocytes Protein Glucose Leukocytes, protein, and glucose Cytologyb Benign Malignant Gram stainc Gram-positive cocci Gram-negative rods Gram-positive rods Negative smear Positive culturesd CSF from Ommaya reservoir Ommaya tip Intraoperative wound culture
No. of patients (%)
8 (20)
59 (47e74) 41 (24e114) 45 (3.5e241) 65 (12.5e92) 21 (4e67.5) 9 (0.5e66) 10/36 (28) 8/35 (51) 28/35 (80) 6/34 (18)
34 (85) 26 (65) 8 (20) 37 (93) 18 (45) 5 (13) 1 (2) 13 (33) 37/37 (100) 10/17 (59) 5/5 (100)
Note. Percentages were rounded up and may not add up to 100%. CSF, cerebrospinal fluid; Q1eQ3, 25the75th percentile; WBC; white blood cells. a Although 36 patients had their CSF analyzed, not all laboratory parameters were performed in every episode. b Not done for 6 of the 40 patients. c Not done for 3 of the 40 patients. d Number of positive cultures/total number of cultures (%).
were Pseudomonas spp. (8%), followed by Enterobacter aerogenes, Escherichia coli, K. pneumoniae, and nontypable Haemophilus influenzae (2% each). Candida albicans had grown in only one culture. Within the first 30 days from the time of device placement or within the first 10 days the reservoir was accessed, the majority of the infections were caused by Gram-positive bacteria. However, the prevalence of Gram-negative isolates increase beyond the first 30 days of having the Ommaya reservoir placed (Tables 5 and 6). Not only is this an important clinical observation, but one that may have significant therapeutic implications, such as the need of also providing Gram-negative coverage for those patients who
develop an infection during this late postoperative period.
Treatment modality and outcome Overall, the median time of hospitalization was 13 days (Q1eQ3 Z 10e22 days), with a median antimicrobial therapy duration of 24 days (Q1eQ3 Z 15e34 days; Table 7). During the index hospitalization, 4 (10%) patients died, most likely as a result of the infection. At the 12month follow-up period, none of the remaining patients had a recurrent infection. The treatment strategy for 22 of the 40 patients was early removal of the device (median Z 3 days, Q1eQ3 Z 1e5 days from time of admission to device removal). This group had the shortest hospital stay (median Z 10 days, Q1eQ3 Z 7e15 days) and duration of antimicrobial therapy (median Z 16 days, Q1eQ3 Z 14e28 days). For the other 18 patients, the strategy was to attempt to retain the device by treating the infection solely with antimicrobials. This conservative, non-surgical strategy resulted in a clinical and microbiological cure in only 9 of the 18 patients. The median hospital stay for these 9 patients was 15 days (Q1eQ3 Z 10e24 days), with a median duration of antimicrobial therapy of 24 days (Q1eQ3 Z 23e35 days). In the remaining 9 patients, due to their lack of a clinical and/or microbiological response, the reservoir was removed within a median of 14 days (Q1eQ3 Z 10e20 days). This treatment strategy resulted in both the longest median hospitalization (18 days; Q1eQ3 Z 15e31 days) and median duration of antimicrobial therapy (26 days; Q1eQ3 Z 24e38 days). The differences between the groups who underwent early and late removal were significant, both for hospitalization (p Z 0.035) and antibiotic duration (p Z 0.038). Nonetheless, mortality rates were similar for all treatment groups (early device removal, no removal, and late removal; p > 0.99). Of interest, CoNS was the predominant bacteria in all the treatment groups, while the more virulent organisms, including MSSA, MRSA, a-hemolytic Streptococcus as well as Pseudomonas, were only present in the groups that required having the Ommaya reservoir removed (Table 7). Also, only 2 of 4 patients, in our study had a successful outcome with the use of intrathecal antimicrobials. The first 2 successfully treated patients had a CoNS Ommaya reservoir infection, and were treated with systemic and intrathecal vancomycin combined with oral rifampin. The remaining 2 had the implant removed after failing to respond to the initial salvage antimicrobial regimen. One patient was found to have an infection with a multidrugresistant E. aerogenes and was treated with systemic and intrathecal gentamicin in combination with systemic meropenem, while the other with a CoNS infection was treated with systemic and intrathecal vancomycin combined with oral rifampin.
Discussion To the best of our knowledge, this study represents the largest evaluation of patients with Ommaya reservoirrelated infections. The overall infection rate and
Ommaya reservoir-related infections Table 5
221
Pathogens isolated in Ommaya reservoir-related infections, stratified by time of placement.
Pathogen
Overalla (n Z 52)
90 days (n Z 15)
Gram-positive bacteria CoNS Propionibacterium acnes MSSA a-Hemolytic streptococci Corynebacterium spp. Enterococcus faecalis MRSA Gram-negative bacteria Pseudomonas spp. Enterobacter aerogenes Escherichia coli Bacteroides fragilis Non-typable haemophili Klebsiella pneumoniae Fungi Candida albicans
42 (81) 28 4 4 3 1 1 1 9 (17) 4 1 1 1 1 1
17 11 3 1 1 1 e e 1 e 1 e e e e
13 7 1 3 1 e 1 e 5 3 e 1 1 e e
12 10 e e 1 e e 1 3 1 e e e 1 1
1 (2)
1
e
e
Note. Data are no. (%), unless otherwise indicated. Percentages were rounded up to the whole number and may not add up to 100%. CoNS, coagulase-negative staphylococci; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus. a Of the 40 cases of infection, 6 were polymicrobial.
predominant microorganisms were similar to those reported in previous studies.5,10e13 However, we identified several other key points. First, although 80% of our patients presented with clinical manifestations of meningitis or meningoencephalitis, and different from acute bacterial meningitis, the vast majority presented in a mild-tomoderate manner, with no evidence of obtundation,
Table 6
coma, seizures, disseminated intravascular coagulation, cerebral herniation, severe sepsis, or septic shock. Furthermore, one third did not even mount a febrile response, less than half of them had neck rigidity, and less than a quarter presented with altered mental status. This lack of severe clinical manifestations is probably the reflection of low-virulent, slow-growing, biofilm-forming pathogens, as
Pathogens isolated in Ommaya reservoir-related infections, stratified by time of last reservoir access.
Pathogen
Overalla (n Z 39)
30 days (n Z 9)
Gram-positive bacteria CoNS Propionibacterium acnes MSSA a-Hemolytic streptococci Corynebacterium spp. Enterococcus faecalis MRSA Gram-negative bacteria Pseudomonas spp. Escherichia coli Bacteroides fragilis Non-typable haemophili Klebsiella pneumoniae Fungi Candida albicans
32 (82) 20 3
20 12 2
5 3 1
7 5 e
3 3
2 2
1 e
e 1
1 1 1 6 (16) 2 1 1 1
1 1 e 4 1 1 1 1
e e e e e e e e
e e 1 2 1 e e e
1
e
e
1
1 (2)
1
e
e
Note. Data are no. (%), unless otherwise indicated. Percentages were rounded up to the whole number and may not add up to 100%. CoNS, coagulase-negative staphylococci; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus. a Of the 29 patients whose Ommaya reservoir had been accessed, 5 had infections that were polymicrobial.
222 Table 7
A.D. Szvalb et al. Treatment and outcomes of Ommaya reservoir-related infections.
Outcomes
Overall (n Z 40)
Median days from diagnosis of infection and device removal (Q1eQ3) Median days of hospitalization (Q1eQ3) Median days of antibiotic use (Q1eQ3)e Death due to infection, n (%)
N/A
Early removala (n Z 22) 3 (1e5)
Device retainedb (n Z 9)
Late removalc (n Z 9)
p-Value
N/A
14 (10e20)
0.99
e
Note. Abbreviation: (Q1eQ3): 25the75th percentile; CoNS, coagulase-negative Staphylococcus; MSSA, methicillin-susceptible Staphylococcus aureus; MRSA, methicillin-resistant Staphylococcus aureus. a Early removal group isolates (n): CoNS (15); MSSA (3); a-hemolytic Streptococcus (2); P. acnes (2); P. aeruginosa(2); P. vesicularis (1); MRSA (1); E. coli (1); B. fragilis (1). b Device retained group isolates (n): CoNS (6); P. acnes (2); K. pneumoniae (1); Non-type b haemophilus influenzae. c Late removal group isolates (n): CoNS (7); MSSA (1); a-hemolytic Streptococcus (1); E. aerogenes (1); P. aeruginosa (1); E. faecalis (1); Corynebacterium sp.(1); C. albicans (1). d Pairwise comparison was only significant between the early and late removal groups. e Four patients received also intrathecal antibiotics. Two belonged to the retained-reservoir group and the other two to the late removal group. f Two patients received suppressive antibiotic therapy: one received trimethoprim-sulfamethoxazole and the other received doxycycline for 3 months each. g One of the two patients died as a result of purulent meningoencephalitis and ventriculitis. The other patient had a severe case of multidrug-resistant Pseudomonas aeruginosa ventriculitis after an external ventricular drain placement. h The patient had meningoencephalitis, a myocardial infarct, and acute pneumonia. i The patient had methicillin-sensitive Staphylococcus aureus meningitis.
seen with other CNS device-related infections, such as with ventriculoperitoneal shunt (VPS) infections.10,14,15 Second, even though all patients had a definite Ommaya reservoir-related infection, several had normal laboratory findings. Additionally, 80% of the patients had a WBCs of 30 days). Approximately 40% of the patients presented with an early infection, occurring within 30 days after the reservoir was placed, while 70% occurred within 90 days of placement. The presence of Gram-positive organisms during the late postoperative period most probably was secondary to the slow proliferation of a critical mass of low-virulent organisms, as seen with VPS and prosthetic joint infections.14,18,19 Also, approximately 60% of our patients developed an infectious process within 10 days after the reservoir was last accessed. Most probably the high predominance of skin microbial flora during this early time period may be secondary to: (a) contamination of the reservoir during the perioperative period, or (b) frequent non-sterile manipulation of the Ommaya reservoir within the first months following placement of the Ommaya reservoir. Lastly, in the 11 patients (28%) whose device was never accessed, other factors not related to the frequent access of the reservoirdsuch as local trauma, wound dehiscence, or hematogenous spread from a distant focus in patients undergoing systemic chemotherapydmight account for the infection. Therefore, in order to decrease the high rate of infections occurring soon after Ommaya reservoir placement or access, further understanding of the risk factors for infection, and infectious preventive measures are warranted.
Ommaya reservoir-related infections Fourth, as no specific guidelines for managing these complex infections are available, patient-specific recommendations were made based on the overall clinical presentation, estimated life expectancy, and the necessity for future intrathecal chemotherapy. Several studies have recommended initiating intravenous antimicrobials with or without the addition of intrathecal antibiotics (such as vancomycin or aminoglycosides).8e10,20e24 If the above conservative measures fail to eradicate the infection, or if there were any signs suggestive of a persistent CNS infection, removal of the reservoir is warranted. This stepwise treatment strategy could decrease the complications associated with the removal and reimplantation of the Ommaya reservoir and thus would especially benefit patients with a reduced life expectancy. However, we found that in situations, in which an early decision to remove the device was made over intending to retain the reservoir (conservative approach), patients were hospitalized for a shorter time period, and received a shorter duration of antimicrobials. Approximately 50% of our patients in the conservative group had a successful outcome, while the remaining patients, due to clinical or microbiological failure, required removal of the reservoir at a later stage. Although the latter group had the longest hospitalization and duration of antimicrobial therapy, none had a recurrence of the infectious process, and the mortality rates for all treatment strategies were relatively similar. Also, despite the bacterial spectrum differences among the 3 treatment groups not being statistically significant, it was noteworthy the presence of MSSA, MRSA, a-hemolytic Streptococcus, and Pseudomonas in the removal groups, and their absence among the retained-reservoir cases. It is likely that these “more virulent organisms,” have prompted the treating clinician to remove the infected device at an early stage due to an acute clinical presentation, or because of the known ability of these organisms to cause a complex biofilm phenomenon difficult to eradicate with antimicrobials alone, as seen with other device-related infections. Low platelets, poor performance status, and delay in microbiological growth, may preclude the treating physician from removing the device early on. However, the presence of these organisms should be another important factor when deciding whether or not the device should be removed, regardless of the patients overall condition. Fifth, the addition of intrathecal antibiotics has been utilized with the objective of enhancing CNS and antimicrobial biofilm penetration and thus eradicating the infection without removal of the device. However, as seen with our 4 patients and in the literature, this treatment strategy has reported variable success.20e24 Therefore, based on limited data, if the device cannot be removed, the addition of biofilm-active intrathecal antimicrobials to systemic antibiotics may be an alterative to having the device removed at an early stage. The main limitation of our study is the retrospective single center design and potential for referral bias. Additionally, by only including patients who met our specific clinical and microbiological criteria for infection, we have likely underestimated the true rate of Ommaya reservoirrelated infections. Nevertheless, by only including patients with a definite device-related infection, and having reviewed the records of an institution with a high volume of
223 device placements, we believe our study reveals several noteworthy clinical and therapeutic implications. In conclusion, as patients with Ommaya reservoirrelated infections are not always severely ill-appearing, and the results of ancillary studies, including CSF parameters, at times may be within normal limits, these should not be used solely to exclude an infection. Also, even though mortality rates among all treatment groups were similar, it is apparent that the most convenient strategy in terms of hospital stay and duration of antibiotic therapy is early removal of the device. Further animal and clinical studies of the risk factors and treatment strategies of these neglected device-related infections are warranted.
Conflicts of interests All authors: none declared.
Funding This study was supported in part by funds from The University of Texas MD Anderson Cancer Center, Houston, Texas.
References 1. Ommaya AK. Subcutaneous reservoir and pump for sterile access to ventricular cerebrospinal fluid. Lancet 1963;2(7315): 983e4. 2. Witorsch P, Williams TW, Ommaya AK, Utz JP. Intraventricular administration of amphotericin B. Use of subcutaneous reservoir in four patients with mycotic meningitis. J Am Med Assoc 1965;194(7):699e702. 3. Ommaya AK, Rubin RC, Henderson ES, Rall DP, Gieseke FG, Bering EA, et al. A new approach to the treatment of inoperable brain tumors. Med Ann Dist Columbia 1965;34(10):455e8. 4. Ratcheson RA, Ommaya AK. Experience with the subcutaneous cerebrospinal-fluid reservoir. Preliminary report of 60 cases. N Engl J Med 1968;279(19):1025e31. 5. Obbens EA, Leavens ME, Beal JW, Lee YY. Ommaya reservoirs in 387 cancer patients: a 15-year experience. Neurology 1985; 35(9):1274e8. 6. Galicich JH, Guido LJ. Ommaya device in carcinomatous and leukemic meningitis: surgical experience in 45 cases. Surg Clin North Am 1974;54(4):915e22. 7. Darouiche RO. Treatment of infections associated with surgical implants. N Engl J Med 2004;350(14):1422e9. 8. Dinndorf PA, Bleyer WA. Management of infectious complications of intraventricular reservoirs in cancer patients: low incidence and successful treatment without reservoir removal. Cancer Drug Deliv 1987;4(2):105e17. 9. Gower DJ, Gower VC. Infected Ommaya reservoirs. Neurosurgery 1988;22(6 Pt 1):1116. 10. Mechleb B, Khater F, Eid A, David G, Moorman JP. Late onset Ommaya reservoir infection due to Staphylococcus aureus: case report and review of Ommaya infections. J Infect 2003; 46(3):196e8. 11. Lishner M, Perrin RG, Feld R, Messner HA, Tuffnell PG, Elhakim T, et al. Complications associated with Ommaya reservoirs in patients with cancer. The Princess Margaret Hospital experience and a review of the literature. Arch Intern Med 1990;150(1):173e6. 12. Perrin RG, Lishner M, Guha A, Curtis J, Feld R, Messner H. Experience with Ommaya reservoir in 120 consecutive
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14.
15. 16.
17.
18.
A.D. Szvalb et al. patients with meningeal malignancy. Can J Neurol Sci 1990; 17(2):190e2. Sundaresan N, Suite ND. Optimal use of the Ommaya reservoir in clinical oncology. Oncology (Williston Park) 1989;3(12): 15e22 [discussion 3]. Conen A, Walti LN, Merlo A, Fluckiger U, Battegay M, Trampuz A. Characteristics and treatment outcome of cerebrospinal fluid shunt-associated infections in adults: a retrospective analysis over an 11-year period. Clin Infect Dis 2008; 47(1):73e82. Park DM, DeAngelis LM. Delayed infection of the Ommaya reservoir. Neurology 2002;59(6):956e7. Viola GM, Awan LL, Darouiche RO. Nonstaphylococcal infections of cardiac implantable electronic devices. Circulation 2010;121(19):2085e91. Raad I, Hanna H, Maki D. Intravascular catheter-related infections: advances in diagnosis, prevention, and management. Lancet Infect Dis 2007;7(10):645e57. Melamed E, Cohen I, Robinson D. Prosthetic-joint infections. N Engl J Med 2005;352(1):95e7 [author reply -7].
19. Del Pozo JL, Patel R. Clinical practice. Infection associated with prosthetic joints. N Engl J Med 2009;361(8):787e94. 20. Lishner M, Scheinbaum R, Messner HA. Intrathecal vancomycin in the treatment of Ommaya reservoir infection by Staphylococcus epidermidis. Scand J Infect Dis 1991;23(1):101e4. 21. Siegal T, Pfeffer MR, Steiner I. Antibiotic therapy for infected Ommaya reservoir systems. Neurosurgery 1988;22(1 Pt 1): 97e100. 22. Sutherland GE, Palitang EG, Marr JJ, Luedke SL. Sterilization of Ommaya reservoir by instillation of vancomycin. Am J Med 1981;71(6):1068e70. 23. Hirsch BE, Amodio M, Einzig AI, Halevy R, Soeiro R. Instillation of vancomycin into a cerebrospinal fluid reservoir to clear infection: pharmacokinetic considerations. J Infect Dis 1991; 163(1):197e200. 24. Eiland LS, Luedtke SA, Chuachingco JC. Intraventricular tobramycin in a premature infant with pseudomonas meningitis. J Pediatr Pharmacol Ther 2004;9(1):55e62.
www.elsevierhealth.com/journals/jinf
Ommaya reservoir-related infections: Clinical manifestations and treatment outcomes Ariel D. Szvalb a,b,*, Issam I. Raad a,b, Jeffrey S. Weinberg c, Dima Suki c, Rory Mayer c, George M. Viola a,b a
Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA b Department of Infectious Diseases, Baylor College of Medicine, Houston, TX, USA c Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Accepted 11 December 2013 Available online 17 December 2013
KEYWORDS Central nervous system; Device; Infection; Ommaya reservoir; Meningitis
Summary Objectives: As infection is a severe complication of Ommaya reservoirs (OR), and existing data is limited, herein we describe the largest study of the clinical manifestations and treatment outcomes of Ommaya reservoir-related infections (ORRI). Methods: We retrospectively reviewed the records of all patients at our institution who had an OR placed, and developed a definite device-related infection between 2001 and 2011. Results: Among 501 OR placements, 40 patients (8%) developed an ORRI. These presented with meningitis and/or meningoencephalitis (60%), cellulitis (20%), or a combination thereof (20%). Approximately 40% occurred 30 days of OR placement, while 60% occurred 10 days after the device was last accessed. Only 20% presented with leukocytosis, while another 18% had a normal cerebrospinal fluid (CSF). Gram-positive skin flora accounted >80% of the pathogens. The median hospital stay and duration of antibiotics were 13 and 24 days, respectively. Although mortality rates (z10%) were similar among all treatment groups (p > 0.99), shorter hospitalization and antimicrobial treatment durations were obtained with early versus late device removal (p < 0.038). Conclusions: As clinical symptoms can be non-specific and CSF parameters may be within normal limits, a high suspicion for infection is required. The shortest hospitalization and treatment course was achieved with early device removal. ª 2013 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1460, Houston, TX 77030, USA. Tel.: þ1 713 792 5158; fax: þ1 713 794 4351. E-mail address: [email protected] (A.D. Szvalb). 0163-4453/$36 ª 2013 The British Infection Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jinf.2013.12.002
Ommaya reservoir-related infections
Introduction In 1963 Dr. Ayub Ommaya introduced a subcutaneous reservoir and pump for repeated access and drug delivery to the cerebrospinal fluid (CSF).1 This device was initially intended for the administration of antimicrobials for the treatment of fungal meningitis.2 Soon thereafter, the Ommaya reservoir became the preferred method for the infusion of intrathecal chemotherapy in patients with leptomeningeal malignancies.3,4 This device is a small dome-shaped reservoir placed subcutaneously in the scalp and connected through a burr hole to an intraventricular catheter. Complications associated with Ommaya reservoirs include device malfunction, seizures, and bleeding.5 Similarly to other foreign medical materials, the Ommaya reservoir is also prone to microbial adherence, colonization, infection, and subsequent extension of the infectious process into the surrounding skin, soft tissues, and central nervous system (CNS) compartments.6,7 The rate of Ommaya reservoir-related infections ranges from 2 to 15%.5,8e10 Clinical manifestations and current treatment strategies are based on limited numbers of case reports and small case series that at times are in diametrical opposition to one another.5,8e12 A better understanding of the infectious process that occurs using the Ommaya reservoir, its manifestations, and outcomes is clearly needed for earlier identification and better management of this complication. Herein, we examined the epidemiological, clinical, microbiological, and laboratory characteristics as well as treatment outcomes of patients with Ommaya reservoirrelated infections at a National Cancer Institute designated comprehensive cancer center.
Patients and methods Hospital setting and study population This retrospective study was conducted at The University of Texas MD Anderson Cancer Center, Houston, Texas. Medical records of all 501 patients, adults and children, who underwent an Ommaya reservoir placement between January 1, 2001, and December 31, 2011, were reviewed. All episodes that fulfilled our strict definition criteria (see below) for Ommaya reservoir-related infection were included in the final analysis. The study was approved by the institutional review board.
Definition An infection was considered to be associated with an Ommaya reservoir if both clinical and microbiological criteria were satisfied. We excluded from our analysis any patient who did not fulfill both of the above criteria. Local clinical manifestations of a skin and soft tissue infection (SSTI) overlying the reservoir included at least one of the following: erythema, tenderness, discharge, warmth and wound dehiscence with device exposure. Meningitis was defined by the presence of at least 2 of the following: persistent headaches, fever, neck rigidity, nausea or vomiting; while meningoencephalitis included those patients
217 with meningitis plus altered mental status. All of the above clinical manifestation could not be explained by an alternative diagnosis. The microbiological criteria were confirmed if growth from at least one of the following sources was observed: CSF drawn from the reservoir, removed device material, intraoperative surgical cultures, or purulent collection adjacent to the reservoir.
Data collection Information on patient demographics, comorbid conditions, and type of cancer, as well as Ommaya reservoir characteristics and clinical presentation at the time of admission, was collected. Additionally, laboratory, microbiological, and imaging data were analyzed. The duration of antimicrobial therapy, necessity for device removal, length of hospitalization, and overall outcomes were also reviewed.
Statistical analysis Descriptive statistics were performed on patients’ demographic, clinical and laboratory data. Continuous variables were summarized using median with 25th and 75th percentile (Q1eQ3). Categorical variables were summarized using frequencies and percentages. Continuous variables were compared using Wilcoxon rank sum tests and categorical variables were compared using Chi-square or Fisher’s exact tests, as appropriate. KruskaleWallis tests were used to compare continuous variables among three groups. If a significant result (p < 0.05) was detected from a KruskaleWallis test, then Wilcoxon rank sum tests were used for the pairwise comparisons. The a levels of the post-hoc pairwise comparisons were adjusted using a sequential Bonferroni adjustment. All tests except those for pairwise comparisons were two-sided tests with a significance level of 0.05. The statistical analyses were performed using SAS version 9.3 (SAS Institute Inc., Cary, NC).
Results Demographic and Ommaya reservoir characteristics Among the 501 patients that had an Ommaya reservoir placed, we identified a total of 65 patients who fulfilled the microbiological criteria. However, only 40 of these met our strict criteria for Ommaya reservoir-related infection (an overall rate for infection of 8%) and were the subject of further analysis. At the time of diagnosis, the median patient age was 43 (range 6e77) (Table 1). Most of the infections occurred in white (80%) men (63%). Over 60% of the patients had an underlying hematologic malignancy, while the rest had a solid cancer. Other comorbid conditions such as diabetes, congestive heart failure, chronic obstructive pulmonary disease, cirrhosis, and tobacco use were rare. All patients had the Ommaya reservoir implanted for the administration of intrathecal chemotherapy. None of the patients had an episode of bacteremia or an external ventricular device placed within the preceding 3 months of device implantation or fever at time of surgery. All patients had received perioperative
218 Table 1
A.D. Szvalb et al. Characteristics of patients with and without Ommaya reservoir-related infections.
Variable
Infected cases (n Z 40)
Non-infected cases (n Z 461)
Age in years, median (range) Male Ethnicity White Hispanic Black Asian Comorbidities Hematologic malignancy Non-primary CNS lymphoma Acute leukemia Chronic leukemia Waldenstrom’s and Multiple Myeloma Primary CNS lymphoma Solid malignancy Non-primary CNS tumor Primary CNS tumor Tobacco Diabetes HIV Othera Reason for Ommaya reservoir placement Intrathecal chemotherapy Pain management Other
43 (6e77) 25 (63)
52 (2e81) 205 (44)
32 (80) 6 (15) 2 (5) 0
366 (79) 65 (14) 25 (5) 5 (1)
25 (63) 12 (30) 6 (15) 4 (10) 2 (5) 1 (3) 15 (38) 10 (25) 5 (13) 4 (10) 2 (5) 1 (3) 0
192 (42) 132 (29) 28 (6) 0 13 (3) 19 (4) 269 (58) 220 (48) 49 (11) 92 (20) 31 (7) 3 (1) 38 (8)
40 (100) 0 0
456 (99) 1 (0.2) 4 (0.9)
p-Value 0.07 0.028 0.97
0.011
0.011
>0.99
Note. Data are no. (%), unless otherwise indicated. Percentages were rounded up and may not add to 100%. CNS, central nervous system; HIV, human immunodeficiency virus. a Congestive heart failure, chronic obstructive pulmonary disease, intravenous drug use, alcohol abuse, liver failure, and cirrhosis.
antibiotics, with cefazolin being the most common in 24 patients, followed by vancomycin in 7, and with 1 patient receiving both antibiotics. In the remaining 8 cases the antibiotic used was unknown. Ommaya related infections were more likely to occur among males (p Z 0.028), and individuals with hematological malignancies (p Z 0.011).
Clinical manifestations and imaging characteristics The most frequent clinical syndrome at the time of admission was meningitis and/or meningoencephalitis in 24 (60%) patients, followed by a SSTI in 8 (20%), and a combination of both in 8 (20%). The most common systemic manifestation were headaches (83%), followed by fever (68%), neck rigidity (40%), nausea and vomiting (33%), and altered mental status (25%) (Table 2). The most frequent local manifestation was wound drainage (23%), erythema (20%), and wound dehiscence associated with device exposure (20%). Concomitant infectious processes included bacteremia and pneumonia (4 episodes each). The same pathogen was cultured in the CSF, in 3 of the 4 patients with a bloodstream infection. Approximately 45% of the patients had an imaging study of the head performed. Twelve (30%) patients had been examined by computed axial tomography, and only 2 of them had abnormal findings (one with meningeal enhancement and one with epidural abscess). Six (15%) other patients had been examined by magnetic resonance imaging, and 2 of them had meningeal enhancement, while the rest had a normal study.
Time to infection and number of times the reservoir was accessed prior to infection The median time between Ommaya reservoir placement and the appearance for infection was 41 days (Q1eQ3 Z 15.5e142.5 days; Table 3). Approximately 40% of the infections occurred within the first 30 days of placement, while almost 70% occurred within the first 90 days. Additionally, only 29 patients (73%) had their reservoir accessed, in which the median time between the device was last accessed to infection was 7 days (Q1eQ3 Z 4e30 days). Approximately 59% of these patients developed an infection within 10 days the device was last accessed, while the remaining occurred after this time frame. Furthermore, in those that had the reservoir accessed (29 patients), the reservoir was punctured with a median of 5 (Q1eQ3 Z 2e17) times, with 20 (69%) patients having the reservoir accessed fewer than 10 times. Eleven (28%) of the patients did not have the device accessed, 7 had developed a postoperative infection within 30 days, while 3 occurred within 31e90 days and 1 after 90 days postoperatively.
Laboratory analyses The median white blood cell count (WBC) was 6100 cells/mL (Q1eQ3 Z 3800e8950; Table 4). Only 8 (20%) patients had a WBC >10,000 cells/mL, while 5 (13%) patients had a WBC
Ommaya reservoir-related infections
219
Table 2 Clinical manifestations of Ommaya reservoirrelated infections. Variable
Headaches Fever Neck rigidity Nausea and vomiting Altered mental status Discharge Purulent Serohemorrhagic Cerebrospinal fluid Erythema Dehiscence/ exposure Warmth Tenderness Concomitant infection Bacteremiaa Pneumonia Urinary tract infection Subgaleal collection
M/ME
SSTI
Both
Total
24 (60)
8 (20)
8 (20)
40 (100)
23 (57.5) 17 (42.5) 11 (27.5) 9 (22.5)
3 (7.5) 2 (5) 0 1 (2.5)
7 8 5 3
33 27 16 13
5 (12.5)
0
5 (12.5) 10 (25)
0 0 0 0
5 3 1 1
0 0
5 (12.5) 3 (7.5) 4 (10) 4 (10)
8 (20) 8 (20)
0 0
3 (7.5) 2 (5)
2 (5) 0
5 (12.5) 2 (5)
3 (7.5) 3 (7.5) 1 (7.5)
0 0 0
1 (2.5) 1 (2.5) 1 (2.5)
4 (10) 4 (10) 2 (5)
1 (2.5)
0
0
1 (2.5)
(12.5) (7.5) (2.5) (2.5)
4 1 2 1
(17.5) (20) (12.5) (7.5)
(10) (2.5) (5) (2.5)
9 4 3 2
(82.5) (67.5) (40) (32.5)
(22.5) (10) (7.5) (5)
Note. Data are no. (%), unless otherwise indicated. M/ME, meningitis/meningoencephalitis; SSTI, skin and soft tissue infection. a In 3 of the 4 patients, the same pathogen was found concomitantly in the central nervous system and blood.
5 cells/mL), of which neutrophils were the predominant cell type in 61%, followed by lymphocytes in 39% of the patients. Only 8 patients (20%) were found to have malignant cells in the CSF. Interestingly, 6 (18%) of the patients had all of their CSF parameters within normal limits (leukocytes, glucose, and protein levels). Of these 6 patients, 1 presented with Propionibacterium acnes with local clinical manifestations and without affecting the CNS compartments. The remaining 5 patients presented with meningitis. Three of these were neutropenic at the time the CSF was obtained, with 2 of them revealing coagulase-negative staphylococci (CoNS), and the other with Enterococcus faecalis. A fourth patient, who had developed CoNS meningitis, was a non-neutropenic patient who was on high-dose prednisone (1 mg/kg/day). The above 5 patients, had an excellent clinical response after antibiotics were started and the reservoir was removed. The remaining patient with P. acnes meningitis and Waldenstrom’s macroglobulinemia on rituximab, cytarabine and methotrexate, resolved with antibiotic therapy only, without reservoir removal. None of those six patients had any malignant cells recovered in the CSF histopathological analysis.
Microbiology Gram staining of patients’ CSF obtained via the Ommaya reservoir revealed a microorganism in two thirds of cases (Table 4). A total of 52 positive cultures were analyzed. All 37 CSF cultures obtained through the reservoir and all 5 intraoperative wound cultures had grown a microorganism, while 10 of the 17 Ommaya tip cultures had grown a pathogen. A polymicrobial infection was encountered in 6 (15%) patients with a total of 12 organisms isolated (2 in each patient). These polymicrobial cultures were collected from the following sites: CSF recovered via the Ommaya reservoir (4 specimens), wound cultures (3 specimens), and from an Ommaya tip (1 specimen). Five of six patients had developed a dual Gram-positive and negative infection. All 6 patients had grown a Gram-positive organism, with CoNS occurring in 5, while Gram-negative organisms (all different), grew in 5 patients. Only 28 (70%) of the 40 patients had a blood culture obtained at the time of admission, in which 4 were positive, with 3 of them growing concomitantly in the CSF: Klebsiella pneumoniae, E. faecalis and CoNS. Gram-positive bacteria accounted for more than 80% of the infections (Table 5). Within this group, the most commonly isolated organisms were CoNS (54%), methicillin-susceptible Staphylococcus aureus (MSSA) (8%), P. acnes (8%), and a-hemolytic streptococci (6%). The most commonly encountered Gram-negative bacteria
Table 3 Device placement and access in relation to infection. Variable
Median (Q1eQ3)
Days to infection after device placement 90 Days to infection after device was last accesseda 30 Number of Ommaya taps prior to infection onseta 20
41 (15.5e142.5)
No. of patients (%)
15 (38) 12 (30) 13 (32) 7 (4e30)
17 (59) 5 (17) 7 (24) 5 (2e17)
20 (69) 5 (17) 4 (14)
Note. Percentages were rounded up and may not add to 100%. Q1eQ3, 25the75th percentile. a Eleven (28%) of the patients did not have the device accessed. Of these, 7 patients developed a postoperative infection within 30 days, while 3 occurred within 31e90 days and 1 after 90 days postoperatively. b Of these 17 patients, 8 developed a postoperative infection within 30 days, while 4 occurred within 31e90 days and 5 after 90 days postoperatively.
220
A.D. Szvalb et al.
Table 4 Laboratory analysis of patients with Ommaya reservoir infection. Variable
Median (Q1eQ3)
Peripheral WBC/mL
6100 (3800e8950)
Leukocytes >10,000 cells/mL CSF valuesa Glucose, mg/dL Protein, mg/dL Leukocytes, cells/mL Neutrophils, % Lymphocytes, % Red blood cells/mL Normal CSF valuesa Leukocytes Protein Glucose Leukocytes, protein, and glucose Cytologyb Benign Malignant Gram stainc Gram-positive cocci Gram-negative rods Gram-positive rods Negative smear Positive culturesd CSF from Ommaya reservoir Ommaya tip Intraoperative wound culture
No. of patients (%)
8 (20)
59 (47e74) 41 (24e114) 45 (3.5e241) 65 (12.5e92) 21 (4e67.5) 9 (0.5e66) 10/36 (28) 8/35 (51) 28/35 (80) 6/34 (18)
34 (85) 26 (65) 8 (20) 37 (93) 18 (45) 5 (13) 1 (2) 13 (33) 37/37 (100) 10/17 (59) 5/5 (100)
Note. Percentages were rounded up and may not add up to 100%. CSF, cerebrospinal fluid; Q1eQ3, 25the75th percentile; WBC; white blood cells. a Although 36 patients had their CSF analyzed, not all laboratory parameters were performed in every episode. b Not done for 6 of the 40 patients. c Not done for 3 of the 40 patients. d Number of positive cultures/total number of cultures (%).
were Pseudomonas spp. (8%), followed by Enterobacter aerogenes, Escherichia coli, K. pneumoniae, and nontypable Haemophilus influenzae (2% each). Candida albicans had grown in only one culture. Within the first 30 days from the time of device placement or within the first 10 days the reservoir was accessed, the majority of the infections were caused by Gram-positive bacteria. However, the prevalence of Gram-negative isolates increase beyond the first 30 days of having the Ommaya reservoir placed (Tables 5 and 6). Not only is this an important clinical observation, but one that may have significant therapeutic implications, such as the need of also providing Gram-negative coverage for those patients who
develop an infection during this late postoperative period.
Treatment modality and outcome Overall, the median time of hospitalization was 13 days (Q1eQ3 Z 10e22 days), with a median antimicrobial therapy duration of 24 days (Q1eQ3 Z 15e34 days; Table 7). During the index hospitalization, 4 (10%) patients died, most likely as a result of the infection. At the 12month follow-up period, none of the remaining patients had a recurrent infection. The treatment strategy for 22 of the 40 patients was early removal of the device (median Z 3 days, Q1eQ3 Z 1e5 days from time of admission to device removal). This group had the shortest hospital stay (median Z 10 days, Q1eQ3 Z 7e15 days) and duration of antimicrobial therapy (median Z 16 days, Q1eQ3 Z 14e28 days). For the other 18 patients, the strategy was to attempt to retain the device by treating the infection solely with antimicrobials. This conservative, non-surgical strategy resulted in a clinical and microbiological cure in only 9 of the 18 patients. The median hospital stay for these 9 patients was 15 days (Q1eQ3 Z 10e24 days), with a median duration of antimicrobial therapy of 24 days (Q1eQ3 Z 23e35 days). In the remaining 9 patients, due to their lack of a clinical and/or microbiological response, the reservoir was removed within a median of 14 days (Q1eQ3 Z 10e20 days). This treatment strategy resulted in both the longest median hospitalization (18 days; Q1eQ3 Z 15e31 days) and median duration of antimicrobial therapy (26 days; Q1eQ3 Z 24e38 days). The differences between the groups who underwent early and late removal were significant, both for hospitalization (p Z 0.035) and antibiotic duration (p Z 0.038). Nonetheless, mortality rates were similar for all treatment groups (early device removal, no removal, and late removal; p > 0.99). Of interest, CoNS was the predominant bacteria in all the treatment groups, while the more virulent organisms, including MSSA, MRSA, a-hemolytic Streptococcus as well as Pseudomonas, were only present in the groups that required having the Ommaya reservoir removed (Table 7). Also, only 2 of 4 patients, in our study had a successful outcome with the use of intrathecal antimicrobials. The first 2 successfully treated patients had a CoNS Ommaya reservoir infection, and were treated with systemic and intrathecal vancomycin combined with oral rifampin. The remaining 2 had the implant removed after failing to respond to the initial salvage antimicrobial regimen. One patient was found to have an infection with a multidrugresistant E. aerogenes and was treated with systemic and intrathecal gentamicin in combination with systemic meropenem, while the other with a CoNS infection was treated with systemic and intrathecal vancomycin combined with oral rifampin.
Discussion To the best of our knowledge, this study represents the largest evaluation of patients with Ommaya reservoirrelated infections. The overall infection rate and
Ommaya reservoir-related infections Table 5
221
Pathogens isolated in Ommaya reservoir-related infections, stratified by time of placement.
Pathogen
Overalla (n Z 52)
90 days (n Z 15)
Gram-positive bacteria CoNS Propionibacterium acnes MSSA a-Hemolytic streptococci Corynebacterium spp. Enterococcus faecalis MRSA Gram-negative bacteria Pseudomonas spp. Enterobacter aerogenes Escherichia coli Bacteroides fragilis Non-typable haemophili Klebsiella pneumoniae Fungi Candida albicans
42 (81) 28 4 4 3 1 1 1 9 (17) 4 1 1 1 1 1
17 11 3 1 1 1 e e 1 e 1 e e e e
13 7 1 3 1 e 1 e 5 3 e 1 1 e e
12 10 e e 1 e e 1 3 1 e e e 1 1
1 (2)
1
e
e
Note. Data are no. (%), unless otherwise indicated. Percentages were rounded up to the whole number and may not add up to 100%. CoNS, coagulase-negative staphylococci; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus. a Of the 40 cases of infection, 6 were polymicrobial.
predominant microorganisms were similar to those reported in previous studies.5,10e13 However, we identified several other key points. First, although 80% of our patients presented with clinical manifestations of meningitis or meningoencephalitis, and different from acute bacterial meningitis, the vast majority presented in a mild-tomoderate manner, with no evidence of obtundation,
Table 6
coma, seizures, disseminated intravascular coagulation, cerebral herniation, severe sepsis, or septic shock. Furthermore, one third did not even mount a febrile response, less than half of them had neck rigidity, and less than a quarter presented with altered mental status. This lack of severe clinical manifestations is probably the reflection of low-virulent, slow-growing, biofilm-forming pathogens, as
Pathogens isolated in Ommaya reservoir-related infections, stratified by time of last reservoir access.
Pathogen
Overalla (n Z 39)
30 days (n Z 9)
Gram-positive bacteria CoNS Propionibacterium acnes MSSA a-Hemolytic streptococci Corynebacterium spp. Enterococcus faecalis MRSA Gram-negative bacteria Pseudomonas spp. Escherichia coli Bacteroides fragilis Non-typable haemophili Klebsiella pneumoniae Fungi Candida albicans
32 (82) 20 3
20 12 2
5 3 1
7 5 e
3 3
2 2
1 e
e 1
1 1 1 6 (16) 2 1 1 1
1 1 e 4 1 1 1 1
e e e e e e e e
e e 1 2 1 e e e
1
e
e
1
1 (2)
1
e
e
Note. Data are no. (%), unless otherwise indicated. Percentages were rounded up to the whole number and may not add up to 100%. CoNS, coagulase-negative staphylococci; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus. a Of the 29 patients whose Ommaya reservoir had been accessed, 5 had infections that were polymicrobial.
222 Table 7
A.D. Szvalb et al. Treatment and outcomes of Ommaya reservoir-related infections.
Outcomes
Overall (n Z 40)
Median days from diagnosis of infection and device removal (Q1eQ3) Median days of hospitalization (Q1eQ3) Median days of antibiotic use (Q1eQ3)e Death due to infection, n (%)
N/A
Early removala (n Z 22) 3 (1e5)
Device retainedb (n Z 9)
Late removalc (n Z 9)
p-Value
N/A
14 (10e20)
0.99
e
Note. Abbreviation: (Q1eQ3): 25the75th percentile; CoNS, coagulase-negative Staphylococcus; MSSA, methicillin-susceptible Staphylococcus aureus; MRSA, methicillin-resistant Staphylococcus aureus. a Early removal group isolates (n): CoNS (15); MSSA (3); a-hemolytic Streptococcus (2); P. acnes (2); P. aeruginosa(2); P. vesicularis (1); MRSA (1); E. coli (1); B. fragilis (1). b Device retained group isolates (n): CoNS (6); P. acnes (2); K. pneumoniae (1); Non-type b haemophilus influenzae. c Late removal group isolates (n): CoNS (7); MSSA (1); a-hemolytic Streptococcus (1); E. aerogenes (1); P. aeruginosa (1); E. faecalis (1); Corynebacterium sp.(1); C. albicans (1). d Pairwise comparison was only significant between the early and late removal groups. e Four patients received also intrathecal antibiotics. Two belonged to the retained-reservoir group and the other two to the late removal group. f Two patients received suppressive antibiotic therapy: one received trimethoprim-sulfamethoxazole and the other received doxycycline for 3 months each. g One of the two patients died as a result of purulent meningoencephalitis and ventriculitis. The other patient had a severe case of multidrug-resistant Pseudomonas aeruginosa ventriculitis after an external ventricular drain placement. h The patient had meningoencephalitis, a myocardial infarct, and acute pneumonia. i The patient had methicillin-sensitive Staphylococcus aureus meningitis.
seen with other CNS device-related infections, such as with ventriculoperitoneal shunt (VPS) infections.10,14,15 Second, even though all patients had a definite Ommaya reservoir-related infection, several had normal laboratory findings. Additionally, 80% of the patients had a WBCs of 30 days). Approximately 40% of the patients presented with an early infection, occurring within 30 days after the reservoir was placed, while 70% occurred within 90 days of placement. The presence of Gram-positive organisms during the late postoperative period most probably was secondary to the slow proliferation of a critical mass of low-virulent organisms, as seen with VPS and prosthetic joint infections.14,18,19 Also, approximately 60% of our patients developed an infectious process within 10 days after the reservoir was last accessed. Most probably the high predominance of skin microbial flora during this early time period may be secondary to: (a) contamination of the reservoir during the perioperative period, or (b) frequent non-sterile manipulation of the Ommaya reservoir within the first months following placement of the Ommaya reservoir. Lastly, in the 11 patients (28%) whose device was never accessed, other factors not related to the frequent access of the reservoirdsuch as local trauma, wound dehiscence, or hematogenous spread from a distant focus in patients undergoing systemic chemotherapydmight account for the infection. Therefore, in order to decrease the high rate of infections occurring soon after Ommaya reservoir placement or access, further understanding of the risk factors for infection, and infectious preventive measures are warranted.
Ommaya reservoir-related infections Fourth, as no specific guidelines for managing these complex infections are available, patient-specific recommendations were made based on the overall clinical presentation, estimated life expectancy, and the necessity for future intrathecal chemotherapy. Several studies have recommended initiating intravenous antimicrobials with or without the addition of intrathecal antibiotics (such as vancomycin or aminoglycosides).8e10,20e24 If the above conservative measures fail to eradicate the infection, or if there were any signs suggestive of a persistent CNS infection, removal of the reservoir is warranted. This stepwise treatment strategy could decrease the complications associated with the removal and reimplantation of the Ommaya reservoir and thus would especially benefit patients with a reduced life expectancy. However, we found that in situations, in which an early decision to remove the device was made over intending to retain the reservoir (conservative approach), patients were hospitalized for a shorter time period, and received a shorter duration of antimicrobials. Approximately 50% of our patients in the conservative group had a successful outcome, while the remaining patients, due to clinical or microbiological failure, required removal of the reservoir at a later stage. Although the latter group had the longest hospitalization and duration of antimicrobial therapy, none had a recurrence of the infectious process, and the mortality rates for all treatment strategies were relatively similar. Also, despite the bacterial spectrum differences among the 3 treatment groups not being statistically significant, it was noteworthy the presence of MSSA, MRSA, a-hemolytic Streptococcus, and Pseudomonas in the removal groups, and their absence among the retained-reservoir cases. It is likely that these “more virulent organisms,” have prompted the treating clinician to remove the infected device at an early stage due to an acute clinical presentation, or because of the known ability of these organisms to cause a complex biofilm phenomenon difficult to eradicate with antimicrobials alone, as seen with other device-related infections. Low platelets, poor performance status, and delay in microbiological growth, may preclude the treating physician from removing the device early on. However, the presence of these organisms should be another important factor when deciding whether or not the device should be removed, regardless of the patients overall condition. Fifth, the addition of intrathecal antibiotics has been utilized with the objective of enhancing CNS and antimicrobial biofilm penetration and thus eradicating the infection without removal of the device. However, as seen with our 4 patients and in the literature, this treatment strategy has reported variable success.20e24 Therefore, based on limited data, if the device cannot be removed, the addition of biofilm-active intrathecal antimicrobials to systemic antibiotics may be an alterative to having the device removed at an early stage. The main limitation of our study is the retrospective single center design and potential for referral bias. Additionally, by only including patients who met our specific clinical and microbiological criteria for infection, we have likely underestimated the true rate of Ommaya reservoirrelated infections. Nevertheless, by only including patients with a definite device-related infection, and having reviewed the records of an institution with a high volume of
223 device placements, we believe our study reveals several noteworthy clinical and therapeutic implications. In conclusion, as patients with Ommaya reservoirrelated infections are not always severely ill-appearing, and the results of ancillary studies, including CSF parameters, at times may be within normal limits, these should not be used solely to exclude an infection. Also, even though mortality rates among all treatment groups were similar, it is apparent that the most convenient strategy in terms of hospital stay and duration of antibiotic therapy is early removal of the device. Further animal and clinical studies of the risk factors and treatment strategies of these neglected device-related infections are warranted.
Conflicts of interests All authors: none declared.
Funding This study was supported in part by funds from The University of Texas MD Anderson Cancer Center, Houston, Texas.
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