S586
Aztreonam in the Treatment of Gram-Negative Bacterial Meningitis Arnold L. Lentnek and R. Rex Williams
From the Department of Medicine, Helene Fuld Medical Center, Trenton, New Jersey; and Clinical Research, Bristol-Myers Squibb Institute for Medical Research, Princeton, New Jersey
Individuals who develop bacterial meningitis due to either
Haemophilus irfiuenzae or gram-negative bacilli generally have well-characterized risk factors that distinguish them from the general population. For H. injluenzae meningitis, the principal risk factor is the presence of bacteremic infection caused by the same organism in children between the ages of 1 month and 6 years [1]. From gram-negative bacillary meningitis, patients at risk include neonates and patients with recent head trauma, gram-negative sepsis, underlying malignancy, or underlying immunodeficiency [2]. The selection of an antibiotic for the treatment of H. injluenzae and gram-negative bacillary meningitis remains an area of controversy, fueled by considerations such as the rate of development of antibiotic resistance, the need for penetration ofthe CSF by the antibiotic, and the advantages ofbactericidal as opposed to bacteriostatic concentrations of antibiotic
Informed consent was obtained from the patients or their guardians, and studies were conducted in accordance with the guidelines for human experimentation of the institutions involved. Dr. Williams is an employee of Bristol-Myers Squibb, the commercial vendor of aztreonam. The investigatorswho participated in this study were Drs. George K. Daikos, Athens, Greece; Carlo DeMartinis, Torrette, Italy; Joan S. DeMendonca, Sao Paulo, Brazil; Richard 1. Duma, Richmond, VA, USA; Paulo Ayroza Galvao, Sao Paulo; Nabil I. Girgis, Cairo, Egypt; Richard Greenman, Miami, FL, USA; Rudolf Uri Hutzler, Sao Paulo; Zenat Isani, Karachi, Pakistan; Eckhard Klein, Berlin, Germany; Thomas 1. Louie, Winnipeg, Manitoba, Canada; Melvin I. Marks, Oklahoma City, OK, USA; Peter P. McKellar, Phoenix, AZ, USA; Virgilio Goncalues Periera, Sao Paulo; Stanley A. Plotkin, Philadelphia, PA, USA; Claudio Ramirez, Guatemala City, Guatemala; William 1. Rodriguez, Washington, D.C., USA; Walter F. Schlech, Nova Scotia, Canada; Abdourahmane Sow,Dakar, Senegal; and Hugo Trujillo, Medellin, Colombia. Reprints and correspondence: Dr. Arnold L. Lentnek, Department of Medicine, Helene Fuld Medical Center, 750 Brunswick Avenue, Trenton, New Jersey 08638. Reviews of Infectious Diseases 1991;13(Suppl 7):S586-9O © 1991 by The University of Chicago. All rights reserved. 0162-0886/91/1303-0042$02.00
in the CSF [3]. Formerly, chloramphenicol was commonly used for treatment of these infections. However, lack of bactericidal activity against many species of Enterobacteriaceae and poor activity against Pseudomonas aeruginosa have resulted in the infrequent use of this agent as empiric, firstline therapy for gram-negative bacillary meningitis. Aminoglycosides also have fallen into disfavor because of issues regarding CSF penetration and because aminoglycosides administered intrathecally do not reach the cerebral ventricles [4]. More recently, a variety of third-generation cephalosporins have become the antibiotics of choice for treatment of H. influenzae and gram-negative bacillary meningitis [5]. However, even these agents are not entirely satisfactory. Their wide spectrum of activity, which includes obligate anaerobic bacteria, has been associated with alteration of "colonization resistance" [6]. Moreover, these antibiotics have been associated with bacterial resistance, unexpected failures of efficacy, and development of a bleeding diathesis due to platelet dysfunction and hypoprothrombinemia [7]. Aztreonam is the first commercially available monobactam antibiotic. Its spectrum of activity includes a broad range of aerobic gram-negative bacteria, including P. aeruginosa and H. inftuenzae [8]. Previously published studies have demonstrated that aztreonam administered iv reaches therapeutic levels in CSF of individuals with either inflamed or uninflamed meninges [9, 10]. In view of its spectrum of activity and pharmacokinetic characteristics, the efficacy of aztreonam in the treatment of meningitis due to H. injluenzae or gram-negative bacilli was evaluated in two open, multicenter, international trials. The results of those trials form the basis of this report.
Patients and Methods Two open studies evaluating the efficacy and safety of aztreonam in the treatment of gram-negative bacterial meningitis were performed. Protocols differed only insofar as
Downloaded from http://cid.oxfordjournals.org/ at University of New South Wales on July 28, 2015
Aztreonam was administered to 122 patients with presumptive or confirmed gram-negative bacillary meningitis in an open, multinational study. The antibiotic was administered at a dosage of 1-2 g to adults, 50 mg/kg to children >2 years old, and 30 mg/kg to infants three or four times daily. Seventy-seven patients had microbiologically confirmed gram-negative meningitis due to an aztreonam-susceptible organism and received aztreonam for at least 48 hours. Haemophilus inftuenzae was the most frequently recovered pathogen (40 patients), followed by Enterobacteriaceae (16patients), Neisseria meningitidis (15patients), and Pseudomonas species(six patients). All but four patients weremicrobiologically cured. Microbiologic failure was associated with either a persistent intracerebral abscess (one patient) or a foreshortened course of therapy beforemicrobiologicreevaluation and death (at 48 hours, 48 hours, and 72 hours after initiation of treatment, respectively). These data suggest that aztreonam is effective in the treatment of gram-negative bacillary meningitis caused by susceptible organisms.
RID 1991;13 (Suppl 7)
Aztreonam for Gram-Negative Meningitis
determining the clinical response, and data in the patient's case report provided the basis for determining the microbiologic response. The categories of clinical response were as follows: cureresolution of clinical signs and symptoms as specified under entry criteria; partial response-substantial or temporary improvement in signs and symptoms present at study entry; failure - absence of any substantial improvement in signs and symptoms from baseline values after 48 hours of aztreonam treatment. Microbiologic outcome was based on the results of culture of the last CSF specimen obtained before completion of therapy and on the results of culture of CSF specimens obtained at the posttherapy evaluation as follows: cure-minimum of 5 days of aztreonam treatment completed, last CSF specimen obtained during therapy sterile, and no positive CSF specimen obtained during the follow-upperiod; cure with relapsecure, except for a follow-up CSF specimen positive for the original pathogen; cure with reinfection - cure, except for a follow-up CSF specimen positive for a pathogen other than the original causative organism; failure-saminimum of 48 hours of aztreonam treatment completed, with the last CSF specimen obtained during therapy positive for the original pathogen; superinfection - development during aztreonam treatment of meningeal infection with a pathogen other than the original causative organism. Prior to study initiation, each investigator obtained approval from the appropriate institutional review board for participation in these clinical trials. Each patient (or responsible guardian) provided informed consent before enrollment in this study.
Results A total of 20 investigators worldwide participated in these studies, enrolling 122 patients with confirmed or presumptive meningitis due to gram-negative organisms. Of those enrolled, 45 patients were not assessable for efficacy of therapy for the reasons presented in table 1.
Table 1. Primary reasons for exclusion of patients from evaluation of efficacy in study of aztreonam for the treatment of gramnegative bacterial meningitis. Reason for exclusion No aerobic, gram-negative organism susceptible. to aztreonam isolated before therapy or no valid pretreatment culture Susceptibility to aztreonam not specified Fewer than required days of treatment Treated concomitantly with antibiotics effective against causative organisms No follow-up cultures or culture not done at proper time Causative organism resistant to aztreonam Total
No. of patients
27
6 5 4 2
1 45
Downloaded from http://cid.oxfordjournals.org/ at University of New South Wales on July 28, 2015
enrollment in one study was limited to individuals ~18 years old and enrollment in the other was restricted to patients >18 years old. Patients eligible for enrollment were those for whom a gram-negative pathogen was recovered from spinal fluid and who had one more of the following clinical findings: (1) fever (>37°C orally); (2) recent onset of neurologic abnormalities (including impaired higher integrative function or focal cerebral signs); (3) CSF pleocytosis with a predominance of neutrophils (>50%), level of glucose in spinal fluid ~30 mg/dL or two-thirds or less of the concomitant level in serum, or CSF protein concentration ~150 mg/dL; or (4) meningeal signs, including neck stiffness or positive Kernig's or Brudzinski's sign. Pending results of culture, additional antibiotics with only gram-positive activity were permitted. Patients with any of the following conditions were excluded from the study: type I hypersensitivity reactions to penicillin; granulocytopenia; severe hepatic dysfunction; serum creatinine level above the upper limit of normal for age and weight; lactation or pregnancy; concurrent severe disease (e.g., neoplastic disease) that might limit patient survival during the study period; coma; papilledema or other evidence of markedly elevated intracranial pressure; meningitis occurring after neurosurgery in which the pathogen was not known. The recommended dosage of aztreonam for adults was 2 g iv every 6 hours. For children 2-12 years old, the recommended dosage was 50 mg/kg iv every 6 hours. Infants
Aztreonam in the Treatment of Gram-Negative Bacterial Meningitis Arnold L. Lentnek and R. Rex Williams
From the Department of Medicine, Helene Fuld Medical Center, Trenton, New Jersey; and Clinical Research, Bristol-Myers Squibb Institute for Medical Research, Princeton, New Jersey
Individuals who develop bacterial meningitis due to either
Haemophilus irfiuenzae or gram-negative bacilli generally have well-characterized risk factors that distinguish them from the general population. For H. injluenzae meningitis, the principal risk factor is the presence of bacteremic infection caused by the same organism in children between the ages of 1 month and 6 years [1]. From gram-negative bacillary meningitis, patients at risk include neonates and patients with recent head trauma, gram-negative sepsis, underlying malignancy, or underlying immunodeficiency [2]. The selection of an antibiotic for the treatment of H. injluenzae and gram-negative bacillary meningitis remains an area of controversy, fueled by considerations such as the rate of development of antibiotic resistance, the need for penetration ofthe CSF by the antibiotic, and the advantages ofbactericidal as opposed to bacteriostatic concentrations of antibiotic
Informed consent was obtained from the patients or their guardians, and studies were conducted in accordance with the guidelines for human experimentation of the institutions involved. Dr. Williams is an employee of Bristol-Myers Squibb, the commercial vendor of aztreonam. The investigatorswho participated in this study were Drs. George K. Daikos, Athens, Greece; Carlo DeMartinis, Torrette, Italy; Joan S. DeMendonca, Sao Paulo, Brazil; Richard 1. Duma, Richmond, VA, USA; Paulo Ayroza Galvao, Sao Paulo; Nabil I. Girgis, Cairo, Egypt; Richard Greenman, Miami, FL, USA; Rudolf Uri Hutzler, Sao Paulo; Zenat Isani, Karachi, Pakistan; Eckhard Klein, Berlin, Germany; Thomas 1. Louie, Winnipeg, Manitoba, Canada; Melvin I. Marks, Oklahoma City, OK, USA; Peter P. McKellar, Phoenix, AZ, USA; Virgilio Goncalues Periera, Sao Paulo; Stanley A. Plotkin, Philadelphia, PA, USA; Claudio Ramirez, Guatemala City, Guatemala; William 1. Rodriguez, Washington, D.C., USA; Walter F. Schlech, Nova Scotia, Canada; Abdourahmane Sow,Dakar, Senegal; and Hugo Trujillo, Medellin, Colombia. Reprints and correspondence: Dr. Arnold L. Lentnek, Department of Medicine, Helene Fuld Medical Center, 750 Brunswick Avenue, Trenton, New Jersey 08638. Reviews of Infectious Diseases 1991;13(Suppl 7):S586-9O © 1991 by The University of Chicago. All rights reserved. 0162-0886/91/1303-0042$02.00
in the CSF [3]. Formerly, chloramphenicol was commonly used for treatment of these infections. However, lack of bactericidal activity against many species of Enterobacteriaceae and poor activity against Pseudomonas aeruginosa have resulted in the infrequent use of this agent as empiric, firstline therapy for gram-negative bacillary meningitis. Aminoglycosides also have fallen into disfavor because of issues regarding CSF penetration and because aminoglycosides administered intrathecally do not reach the cerebral ventricles [4]. More recently, a variety of third-generation cephalosporins have become the antibiotics of choice for treatment of H. influenzae and gram-negative bacillary meningitis [5]. However, even these agents are not entirely satisfactory. Their wide spectrum of activity, which includes obligate anaerobic bacteria, has been associated with alteration of "colonization resistance" [6]. Moreover, these antibiotics have been associated with bacterial resistance, unexpected failures of efficacy, and development of a bleeding diathesis due to platelet dysfunction and hypoprothrombinemia [7]. Aztreonam is the first commercially available monobactam antibiotic. Its spectrum of activity includes a broad range of aerobic gram-negative bacteria, including P. aeruginosa and H. inftuenzae [8]. Previously published studies have demonstrated that aztreonam administered iv reaches therapeutic levels in CSF of individuals with either inflamed or uninflamed meninges [9, 10]. In view of its spectrum of activity and pharmacokinetic characteristics, the efficacy of aztreonam in the treatment of meningitis due to H. injluenzae or gram-negative bacilli was evaluated in two open, multicenter, international trials. The results of those trials form the basis of this report.
Patients and Methods Two open studies evaluating the efficacy and safety of aztreonam in the treatment of gram-negative bacterial meningitis were performed. Protocols differed only insofar as
Downloaded from http://cid.oxfordjournals.org/ at University of New South Wales on July 28, 2015
Aztreonam was administered to 122 patients with presumptive or confirmed gram-negative bacillary meningitis in an open, multinational study. The antibiotic was administered at a dosage of 1-2 g to adults, 50 mg/kg to children >2 years old, and 30 mg/kg to infants three or four times daily. Seventy-seven patients had microbiologically confirmed gram-negative meningitis due to an aztreonam-susceptible organism and received aztreonam for at least 48 hours. Haemophilus inftuenzae was the most frequently recovered pathogen (40 patients), followed by Enterobacteriaceae (16patients), Neisseria meningitidis (15patients), and Pseudomonas species(six patients). All but four patients weremicrobiologically cured. Microbiologic failure was associated with either a persistent intracerebral abscess (one patient) or a foreshortened course of therapy beforemicrobiologicreevaluation and death (at 48 hours, 48 hours, and 72 hours after initiation of treatment, respectively). These data suggest that aztreonam is effective in the treatment of gram-negative bacillary meningitis caused by susceptible organisms.
RID 1991;13 (Suppl 7)
Aztreonam for Gram-Negative Meningitis
determining the clinical response, and data in the patient's case report provided the basis for determining the microbiologic response. The categories of clinical response were as follows: cureresolution of clinical signs and symptoms as specified under entry criteria; partial response-substantial or temporary improvement in signs and symptoms present at study entry; failure - absence of any substantial improvement in signs and symptoms from baseline values after 48 hours of aztreonam treatment. Microbiologic outcome was based on the results of culture of the last CSF specimen obtained before completion of therapy and on the results of culture of CSF specimens obtained at the posttherapy evaluation as follows: cure-minimum of 5 days of aztreonam treatment completed, last CSF specimen obtained during therapy sterile, and no positive CSF specimen obtained during the follow-upperiod; cure with relapsecure, except for a follow-up CSF specimen positive for the original pathogen; cure with reinfection - cure, except for a follow-up CSF specimen positive for a pathogen other than the original causative organism; failure-saminimum of 48 hours of aztreonam treatment completed, with the last CSF specimen obtained during therapy positive for the original pathogen; superinfection - development during aztreonam treatment of meningeal infection with a pathogen other than the original causative organism. Prior to study initiation, each investigator obtained approval from the appropriate institutional review board for participation in these clinical trials. Each patient (or responsible guardian) provided informed consent before enrollment in this study.
Results A total of 20 investigators worldwide participated in these studies, enrolling 122 patients with confirmed or presumptive meningitis due to gram-negative organisms. Of those enrolled, 45 patients were not assessable for efficacy of therapy for the reasons presented in table 1.
Table 1. Primary reasons for exclusion of patients from evaluation of efficacy in study of aztreonam for the treatment of gramnegative bacterial meningitis. Reason for exclusion No aerobic, gram-negative organism susceptible. to aztreonam isolated before therapy or no valid pretreatment culture Susceptibility to aztreonam not specified Fewer than required days of treatment Treated concomitantly with antibiotics effective against causative organisms No follow-up cultures or culture not done at proper time Causative organism resistant to aztreonam Total
No. of patients
27
6 5 4 2
1 45
Downloaded from http://cid.oxfordjournals.org/ at University of New South Wales on July 28, 2015
enrollment in one study was limited to individuals ~18 years old and enrollment in the other was restricted to patients >18 years old. Patients eligible for enrollment were those for whom a gram-negative pathogen was recovered from spinal fluid and who had one more of the following clinical findings: (1) fever (>37°C orally); (2) recent onset of neurologic abnormalities (including impaired higher integrative function or focal cerebral signs); (3) CSF pleocytosis with a predominance of neutrophils (>50%), level of glucose in spinal fluid ~30 mg/dL or two-thirds or less of the concomitant level in serum, or CSF protein concentration ~150 mg/dL; or (4) meningeal signs, including neck stiffness or positive Kernig's or Brudzinski's sign. Pending results of culture, additional antibiotics with only gram-positive activity were permitted. Patients with any of the following conditions were excluded from the study: type I hypersensitivity reactions to penicillin; granulocytopenia; severe hepatic dysfunction; serum creatinine level above the upper limit of normal for age and weight; lactation or pregnancy; concurrent severe disease (e.g., neoplastic disease) that might limit patient survival during the study period; coma; papilledema or other evidence of markedly elevated intracranial pressure; meningitis occurring after neurosurgery in which the pathogen was not known. The recommended dosage of aztreonam for adults was 2 g iv every 6 hours. For children 2-12 years old, the recommended dosage was 50 mg/kg iv every 6 hours. Infants
