{'fraction_non_alphanumeric': 0.026148014129404668, 'fraction_numerical': 0.011889377100025847, 'mean_word_length': 5.4665738161559885, 'pattern_counts': {'":': 0, '<': 1, '<?xml version=': 0, '>': 4, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Treatment of Gram-negative bacillary meningitis with intrathecal gentamicin.

In order to evaluate the effect of intrathecal gentamicin on gram-negative bacillary meningitis, twenty-eight patients were treated with intralumbar or intraventricular gentamicin in combination with systemic gentamicin and with other antibiotics. Sterile cerebrospinal fluid was achieved in 21/22 (95%) episodes of documented gram-negative bacillary meningitis in patients who received more than one day of therapy. Seventy-seven percent of these patients survived their infection. The mean cerebrospinal fluid gentamicin level measured 24 hours after intrathecal administration was 5.9 ug/ml following intralumbar administration and 11.1 ug/ml following intraventricular administration. Toxic side effects due to intrathecal administration of gentamicin were not noted. These findings suggest that both intralumbar and intraventricular administration of gentamicin are safe and efficacious in the treatment of gram-negative bacillary meningitis.

Infection of the central nervous system with gram-negative enteric bacteria is a significant problem among neonatal and neurosurgical patients. We have previously reviewed the clinical characteristics of these patients [1]. Depressed host defenses, multiple surgical procedures, foreign bodies and pathogenicity of infecting bacteria all contribute to the low survival rate associated with these infections. Early therapy with antibiotics that achieve adequate cerebrospinal fluid levels would appear to be necessary to minimize neurologic damage and improve survival.
Penetration of aminoglycoside antibiotics across the blood-brain barrier is variable and little correlation between serum and cerebrospinal fluid concentrations has been observed [2][3][4][5]. Animal studies indicate that low levels of gentamicin in cerebrospinal fluid are associated with considerable neurologic toxicity [6] whereas human case reports have suggested that intrathecal injection of gentamicin is relatively safe [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]. However, these studies report a wide range of cerebrospinal fluid concentrations among patients who receive equivalent doses of intrathecal gentamicin (4 mg in adults and 1 mg in infants). Since clinical experience with intrathecal gentamicin is still quite limited, the efficacy, toxicity and appropriate dosage schedules remains unclear. Our experience with intrathecal gentamicin was begun in 1970 as a prospective, non-randomized investigation in an attempt to determine the efficacy and toxicity of this drug in patients with gram-negative bacillary meningitis. The present report describes our observations in twenty-eight patients treated with intrathecal gentamicin in combination with systemic gentamicin and with other antibiotics, and represents the largest single series of patients observed in one medical center.

METHODS Patient Selection
Patients were included in the study if their clinical course and cerebrospinal fluid analysis were consistent with acute bacterial meningitis which was either proved or suspected to be caused by gram-negative bacilli; if they were seen in consultation by one of us (RJM or VTA) at the onset of their illness; and if they or their families gave informed consent to receive the investigational drug. Twenty-eight patients (sixteen adults, one child, and eleven infants) with suspected gram-negative bacillary meningitis were treated with intrathecal and systemic gentamicin in combination with other systemic antibiotics (Table 1). One patient (Case 4) was treated for two separate infections. A bacteriologic diagnosis was confirmed by the isolation of gram-negative bacilli from the cerebrospinal fluid during twenty-three separate episodes of meningitis which occurred in twenty-two patients. Gram-negative bacilli were seen on the stained cerebrospinal fluid smear of the remaining six patients, although cultures were sterile in four, and yielded Staphylococcus epidermidis in one and an enterococcus in the other patient.

Therapy
Gentamicin sulfate in saline (2 mg per cc) (investigational drug, Schering Corporation, Newark, New Jersey), was administered either intrathecally by barbotage or intraventricularly by a Richham or Ommaya reservoir. The decision to administer gentamicin intraventricularly was determined by the presence of a Richham or Ommaya reservoir which had been inserted previously because of the patients underlying disease, e.g., hydrocephalus. In the absence of a reservoir, intrathecal gentamicin was given by barbotage into the intralumbar subarachnoid space. Intrathecal gentamicin in a dose of 4 mg was administered to thirteen adults at intervals of 24 hours for two to fifteen successive days. Two adults received 2 mg/day for seven and ten successive days respectively and one adult received 3 mg/day for nine successive days. The eleven infants and one child received 1 or 2 mg at 24 hour intervals for one to twenty-three successive days. Gentamicin sulfate was also administered intravenously or intramuscularly in a dose of 3-5 mg/kg per day. Other antibiotics administered concurrently are listed in Table 1. In an attempt to evaluate the effectiveness of intrathecal and intraventricular gentamicin in the treatment of documented gram-negative bacillary meningitis in a non-randomized way, we compared the survival rates of patients treated in the present series, with survival rates of other patients with documented gram-negative bacillary meningitis who were seen in this medical center during the same time period, but who did not receive intrathecal or intraventricular gentamicin, although most were treated with either systemic gentamicin alone or in combination with other antibiotics [1].

Aminoglycoside Analysis
Gentamicin serum and cerebrospinal fluid levels were measured by a bioassay method previously reported [11]. The test organism, Bacillus globigii, was grown in 30 ml of brain-heart-infusion broth for 6 hours at 370 C. Then 3 ml of this culture was added to 36 ml of modified Triptocase soy agar. Thirty-six milliliters was then poured into petri dishes and allowed to solidify. One milliliter of penicillinase was added to this mixture prior to cooling in all patients who were also receiving a penicillin antibiotic. Samples obtained from patients who were receiving either oxacillin or a cephalosporin were tested against Enterobacter aerogenes rather than Bacillus globigii in the bioassay. This strain of Enterobacter aerogenes is sensitive only to aminoglycoside antibiotics. After the medium was solidified, it was cooled at 50 C for fifteen minutes. Wells were produced with a 4 mm diameter bore and filled in duplicate with gentamicin standard samples and with the patient's serum or cerebrospinal fluid. The plates were then incubated overnight at 370C. The diameter of the zone of inhibition for the gentamicin standards and the unknown body fluid sample was measured with a millimeter ruler. Gentamicin concentrations were calculated by regression analysis.

RESULTS
Twenty-eight patients (eleven infants, one child and sixteen adults) received intrathecal or intraventricular gentamicin (Table 1). There were twenty-three episodes of gram-negative bacillary meningitis, which occurred in twenty-two patients, one of whom was treated for two separate infections. Two additional patients had grampositive coccal meningitis, and no etiologic agent could be recovered from the cerebrospinal fluid cultures of four others. Gentamicin was administered intraventricularly to nine infants with documented meningitis who had Rickham or Ommaya reservoirs in place at the onset of their infection ( Table 1). Six of these nine infants survived and were cured of their meningitis; two infants died, one of whom (patient #5) also received intralumbar gentamicin in a dose of 2 mg/day concomitantly with intraventricular gentamicin; and one infant experienced a relapse of his E. coli meningitis three days after completing a fourteen day course of intraventricular gentamicin ( Table 2). Cerebrospinal fluid concentrations of gentamicin were obtained in seven of these nine infants 24 hours (± 2 hours) after daily intraventricular installation of I to 2 mg, and ranged from 3 to 30.5 ug/ml with a mean of 11.1 ug/ml ( Fig. 1). Intralumbar gentamicin was administered to twenty patients, sixteen adults, one child, and three infants ( Table 1). Sixteen of these twenty patients had documented infections, fifteen of which were caused by gram-negative bacilli, and one was caused by an enterococcus. Twelve of the sixteen patients with documented meningitis who received intralumbar gentamicin, were cured of their infection and four patients died. Four additional patients received intralumbar gentamicin for suspected gram-negative meningitis but their cerebrospinal fluid cultures were sterile. Two of these patients survived and two died (Tables 1 and 2). Cerebrospinal fluid concentrations of gentamicin obtained 24 hours (± 2 hours) after daily intralumbar administration ranged from 1 ug/ml to 20 ug/ml (mean 5.9 ug/ml) in these patients (Fig. 1). Concentrations of cerebrospinal fluid gentamicin were significantly higher during the first six days of therapy when compared to the 7th through the 13th days of therapy (p < .001) (mean for days 1-6 = 9.168 ug/ml, S.E.±1.36, mean for days 7-13 = 3.149 ug/ml,S.E. ± 0.65). In no patient was there an indication of gentamicin accumulation in the cerebrospinal fluid after successive doses. In order to determine whether there were changes in opening pressure of the lumbar punctures over the course of therapy which were related to the decreasing cerebrospinal fluid gentamicin levels, opening pressures were plotted against time in six patients and no trend in these pressures over the course of therapy was observed. Of thirty-eight lumbar cerebrospinal fluid samples obtained in nine patients during the first seven days of therapy (24 hours after the intralumbar administered dose) the gentamicin level was greater than 2 ug/ml in thirty-one samples, and greater than 3 ug/ml in twenty-five samples from all patients studied. Specifically, most of the cerebrospinal fluid samples from every patient contained concentrations of gentamicin in excess of 3 ug/ml 24 hours after intralumbar instillation. In several instances, cerebrospinal fluid and serum samples were obtained from the same patient at the same time. Cerebrospinal fluid and serum were obtained 24 hours after the last intrathecal or intraventricular dose and 4-6 hours after the previous systemic dose. Regression analysis of simultaneous cerebrospinal fluid and serum gentamicin levels revealed no significant correlation (correlation coefficient r = 0.44).
Cerebrospinal fluid was cultured daily during intrathecal therapy. The median time that sterile cerebrospinal fluid was achieved was 72-96 hours after institution of therapy (Fig. 2). However, several patients that survived required more than one week of therapy before eradication of their meningitis.
Blood urea nitrogen and serum creatinine remained normal in twenty-eight pa-    Therefore, gentamicin was discontinued after 48 hours. tients treated with intrathecal or intraventricular gentamicin. No acute toxicity was noted following the instillation of gentamicin. No transient hypotension or respiratory distress was observed. Pre-treatment auditory and vestibular function was not evaluated because of the critically ill status of the patients prior to therapy. Eight patients, followed four months to three years after intrathecal therapy had no evidence of vestibular or auditory dysfunction. One child was noted to have a broad gait two years after therapy. However, since the meningitis had occurred following surgical exploration of the posterior fossa and partial resection of the cerebellum, vestibular damage due to gentamicin was difficult to assess. Another infant was severely retarded with cortical blindness and absence of control of lower extremities, bladder, and bowel three years after hospitalization. However, since she had had multiple surgical procedures for meningomyelocele repair as well as ventricular shunts, the possibility of gentamicin toxicity could not be evaluated. Meningitis was documented in twenty-four of twenty-eight patients treated in this study. One of these twenty-four patients had two separate documented episodes of infection thereby permitting an evaluation of the efficacy of gentamicin, when administered directly into the cerebrospinal fluid, in twenty-five separate episodes of meningitis in twenty-four patients. Eighteen of these twenty-four patients with documented meningitis, including the patient with two episodes of meningitis, survived their infection, although one patient relapsed and was subsequently cured with chloramphenicol. Furthermore, infection was eradicated prior to death in four of the six patients who died from severe neurological damage. Therefore, sterile cerebrospinal fluid was observed in twenty-one of twenty-four patients with documented meningitis. Survival rate in patients with documented infections, was not influenced in this series by the method of gentamicin administration; i.e., intralumbar by barbotage (twelve cures, four deaths) as compared to intraventricular (six cures, one relapse, two deaths) p=>0.50), or by age, i.e., infants (seven cures, one relapse, three deaths) as compared to adults (eleven cures, three deaths) (p = >0.20). Furthermore, there was no significant difference in survival rates between infants (six cures, one relapse, three deaths) and adults (ten cures, three deaths) (p =>0.10), or method of gentamicin administration, intralumbar (eleven cures, four deaths) as compared to intraventricular (five cures, one relapse, two deaths) (p =>0.30) for those patients with documented gram-negative bacillary meningitis.
In the present series, all patients received systemic gentamicin in addition to gentamicin administered directly into the cerebrospinal fluid either by intralumbar barbotage or by intraventricular injection. Other systemic antibiotics were administered concurrently to the twenty-two patients during twenty-three separate episodes of documented gram-negative bacillary meningitis as follows: three patients received no other therapy; seven received an antibiotic to which the infecting organism was resistant; five received chloramphenicol; five received ampicillin; two received both chloramphenicol and ampicillin; and one received carbenicillin ( Table 1). The infecting organism was eliminated from the cerebrospinal fluid in twenty-one of these twenty-three episodes of documented gram-negative bacillary meningitis. One patient (Case 3) died within 12 hours of admission and received only one dose of antibiotic therapy. Therefore, intrathecal gentamicin was associated with elimination of the infecting bacteria from the cerebrospinal fluid in 21/22 episodes (95%) of meningitis in patients who received more than one day of therapy. In the present series, seventyseven percent, 17/22 episodes, of patients survived their infection. The mortality rate in the present study of 23%, in patients who have received intrathecal gentamicin for documented gram-negative bacillary meningitis is the lowest that we have observed in patients with this infection who were seen during the same time period at this medical center [1]. Specifically, we have observed a mortality rate of 100% in five patients with documented gram-negative bacillary meningitis who received no antibiotic therapy for their infection, and a mortality rate of 50% in forty-six patients with documented gram-negative bacillary meningitis who were treated with systemic antibiotics, including amihoglycosides, but who did not receive intrathecal gentamicin [1]. These patients were comparable in age and underlying disease to the present group of patients who received intrathecal therapy [1]. Although the differences in mortality rates between those patients with documented gram-negative bacillary meningitis who received systemic antibiotics without intrathecal gentamicin (23/46) and those who received systemic antibiotics with intrathecal gentamicin (5/22) are not statistically significant (X2 = 3.51, p = 0.05 -0.10), the numbers of patients are small and the results indicate a trend toward statistical significance. DISCUSSION Therapy of patients with central nervous system infection due to gram-negative enteric bacteria remains an unsolved problem in the modern medical era. These infections are of major concern among patients with depressed host defenses, following neurosurgery and in the neonatal period [1,22]. Chloramphenicol is the only antimicrobial agent currently available that offers both a wide spectrum of activity against gram-negative organisms and excellent penetrance across the blood-brain barrier. However, this agent is frequently not suitable for neonatal patients. Pene-trance of cephalosporin and aminoglycoside antibiotics into the cerebrospinal fluid is not adequate to treat meningitis [1,24]. The spectrum of antibacterial activity of ampicillin is too narrow to treat many of these infections and there is little experience with carbenicillin or trimethoprim-sulfamethoxazole. Since preliminary studies had demonstrated that intrathecal gentamicin might be a safe and efficacious drug for the treatment of meningitis, the present clinical study was begun six years ago. Our results indicate that the administration of 4 mg of gentamicin intrathecally usually provides therapeutic levels of antibiotic for at least 24 hours. This treatment schedule is well tolerated with no obvious major toxicity. The survival rate in the present series of patients compares favorably to previous reports of patients with gram-negative bacillary meningitis.
Following intralumbar administration of gentamicin, a peak level in excess of 50 ug/ml is achieved with a subsequent T 1/2 of about 51/2 to 6 hours [19,20]. In the present study, the levels of gentamicin obtained in the cerebrospinal fluid 24 hours after intrathecal antibiotic administration, in all patients studied, were greater than 2 ug/ml in 31/38 determinations and greater than 3 ug/ml in 25/38 determinations tested during the first week of therapy. Our results are in contrast to those of Rahal who noted levels of less than 3 ug/ml in two-thirds of the patients' samples studied twenty hours after intrathecal gentamicin administration [19]. This difference may be explained, in part, by differences in the method of administering intralumbar gentamicin, which in the present study, was given by barbotage. The great majority of gramnegative bacillary central nervous system infections are due to either E. coli or Klebsiella [1]. These bacteria are usually sensitive to concentrations of gentamicin below 2 ug/ml [23]. Therefore, we disagree with the 18 hour dosage schedule previously recommended by others [19], and we continue to administer intrathecal therapy every 24 hours. Our observations suggest that the trough gentamicin level is in excess of the minimum bactericidal concentration in the majority of cases. Furthermore, this regimen appears to provide acceptable clinical results and may also decrease the risk of drug toxicity. Highly resistant organisms may, of course, require higher doses of gentamicin or more frequent intrathecal therapy.
We did observe higher mean cerebrospinal fluid gentamicin concentrations following intraventricular as compared to intralumbar therapy. In addition, as noted by Kaiser and McGee [20], intraventricular cerebrospinal fluid aminoglycoside levels may be unsatisfactory despite therapeutic levels of drug in the lumbar cerebrospinal fluid. Although this consideration is certainly valid, the importance and toxicity of high intraventricular levels is unknown. In addition, it is very often not feasible to initiate intraventricular therapy in acutely ill patients who do not have an indwelling ventricular reservoir. Therefore, until further data are available, we would agree that when available, intraventricular therapy is probably preferable to the intralumbar route. However, our observations do not support the conclusion of others that intralumbar therapy has no advantage over intravenous administration. In addition, since delay in therapy significantly reduced prognosis of meningitis, intralumbar administration should be initiated prior to surgery if a reservoir is to be placed.
Lower concentrations of cerebrospinal fluid gentamicin were noted during the second week of therapy. One possible explanation for this observation may be to decrease inflammation of the meninges associated with improved circulation and drainage of cerebrospinal fluid. Cerebrospinal fluid gentamicin levels in the suboptimal therapeutic range during the second week of treatment do not appear to be of major clinical significance since only one patient relapsed following intrathecal gentamicin therapy. Subtle neurologic toxicity due to intrathecal gentamicin could not be adequately assessed because many patients were critically ill, and because of the associated comorbid factors of neurosurgery and/or congenital central nervous system defects. However, no vestibular or audio toxicity could be directly attributed to gentamicin. Cerebrospinal fluid gentamicin levels were in excess of 10 ug per milliliter 24 hours after installation in at least eight patients. Presumably the level is even higher immediately following administration of the antibiotic. This apparent tolerance of humans to high levels of cerebrospinal fluid gentamicin is in contrast to vestibular dysfunction noted in cats with cerebrospinal fluid gentamicin concentrations that are only 1% of serum levels [6]. Previous reviews of gram-negative bacillary meningitis indicate a survival rate between 20-60% [1,22]. In the present study infection was eradicated in 95% of episodes of gram-negative meningitis in patients who received more than one day of therapy. Seventy-seven percent of these patients survived their infection. Although the patients in the present study were not randomized and comparison with other studies is difficult, the high survival rate of the present study suggests that intrathecal gentamicin is an effective form of therapy. It should be noted that some individual patients suffered irreparable neurologic damage despite the fact that central nervous system infection was cured. Therefore, early diagnosis and treatment appears to be an essential aspect of therapy. We currently recommend that intrathecal gentamicin in combination with other broad spectrum antibiotics be instituted in cases of suspected gram-negative bacillary meningitis in high risk patients such as neonatal, postsurgical or immunosuppressed individuals. Since E. coli and Streptococcus pyogenes, group B are the major cause of neonatal meningitis, we initiate therapy with ampicillin, and intrathecal and intravenous gentamicin in these patients. Older children and adults with gram-negative bacillary meningitis are initially treated with chloramphenicol, and intrathecal and intravenous gentamicin.