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Aztreonam therapy for gram-negative pneumonia
Aztreonam Therapy for Gram-Negative Pneumonia
RICHARD N. GREENBERG, M.D. PATRICK M. REILLY, P.A. (C) KEVIN L. LUPPEN, P.A. (C) MARGARET BOLLINGER, M.T. (C) RAY McMILLIAN, Ph.D. St. Louis,
Missouri
From the Division of Infectious Diseases, bepartment of Internal Medicine, St. Louis University School of Medicine, and Microbiology Department, St. Louis City Hospital (RMcM), St. Louis, Missouri. Requests for reprints should be addressed to Dr. Richard N. Greenberg, Department of Internal Medicine, St. Louis University, 1402 South Grand Blvd., St. Louis, Missouri 63104.
Nineteen patients with community- or hospital-acquired gram-negative pneumonia were treated with aztreonam. Other gram-negative antibiotics were withheld. Thirteen patients (68 percent) had clinical cures and 15 (79 percent) had microbiologic cures with aztreonam. No adverse reactions or drug toxicity occurred in this population. Aztreonam was evaluated in the treatment of serious gram-negative infections at St. Louis City Hospital over a one-year period lasting from December 1982 until December 1983. The study is reported in detail elsewhere [I]. Of the adult patients who took part in that study, 19, who had either community- or hospital-acquired gram-negative pneumonia, are described herein. The cases of community-acquired gram-negative pneumonia included lung infection caused by Hemophilus influenzae; aerobic gram-negative bacilli in patients with such underlying illness as alcoholism, diabetes mellitus, or chronic pulmonary disease; or Klebsiella pneumoniae and gram-negative bacilli in the elderly [2,3]. Hospital-acquired gram-negative pneumonia most often occurred in patients who had aspirated while in the hospital or who were immunocompromised [4]. The primary exclusion criteria for the study were granulocytopenia, hyperbilirubinemia (greater than 1.5 mgidl), or meningitis; age under 13 years; pregnancy; or a history of anaphylaxis due to penicillin. Aerobic gram-negative organisms were isolated from culture material from each patient. Antibiotic susceptibilities of bacteria were determined by the Kirby-Bauer disc diffusion technique, using cation-supplemented Mueller-Hinton agar. Sensitivity was defined as a zone size of greater than 21 mm (aztreonam 30 pg disc). Microtiter minimal inhibitory concentration and minimal bactericidal concentration assays were also performed on many of the isolates. Patients who appeared septic were treated with intravenous aztreonam, 2 g every six hours; the remaining patients were treated with 1 to 2 g every eight to 12 hours, intramuscularly or intravenously. Patients were permitted other antibiotics with gram-positive or anaerobic coverage, but those with aerobic gram-negative coverage to the infecting organism were withheld. These 19 patients included seven residents of a nursing home, who were of an altered mental status and who had aspiration pneumonia; four young adults with sickle cell disease, hypogammaglobulinemia, or recent pneumococcocal pneumonia; three elderly patients with nosocomial pneumonia after cardiac arrest; three alcoholic patients or those with severe underlying pulmonary disease; one otherwise healthy young adult; and one otherwise healthy elderly male. Clinical cure was defined as complete resolution of sighs and symptoms of pneumonia five to nine days after therapy and microbiologic cure as the absence of pathogen in sputum culture collected during or after therapy. Four of the seven nursing home patients responded with complete clinical and microbiologic cures (Table I). One of the remaining three nursing home patients was showing evidence of improvement, with eradication of her Proteus mirabilis (minimal bactericidal concentration = 0.5 pgiml), but died on the sixth day of therapy from a
February
8, 1985
The
American
Journal
of Medicine
Volume
78 (suppl
2A)
31
AZTREONAM
TABLE
I
SYMPOSIUM-GREENBERG
Patient
ET AL
Results*
Organism (MBC or Kirby-Bauer)
Patient 1+
Proteus mirabilis (0.5 pg/ml) Providencia stuartii (0.125 pgiml) Escherichia coli (0.125 kg/ml) Citrobacter freundii (sensitive) Klebsiella pneumoniae (sensitive) Klebsiella pneumoniae
2
3
4
5
Klebsiella pneumoniae (0.125 pgiml) Pseudomonas aeruginosa (8 Mml) Pseudomonas aeruginosa (0.25 pgiml, 16 wgiml) Enterobacter cloacae (16 dml) Pseudomonas ,aeruginosa (16 pgiml, 128 pg/ml) Escherichia coli (0.125 pg/ml)
6 7
*Elderly ‘Patient cloacae
patients from nursing died from myocardial (32 pggiml).
TABLE
II
Patient
Source
Otner Organisms
Endotracheal tube Transtracheal aspiration
-
Sputum
-
Endotracheal
Staphylococcus aureus
Sputum
Staphylococcus aureus
Other Drugs
-
Transtracheal aspiration Tracheostomy
-
Clinical
Microbiologic
Clindamycin
Improved
Cured
Penicillin
Cured
Cured
Penicillin
Cured
Cured
Clindamycin, vancomycin, oxacillin Oxacillin, penicillin
Cured
Cured
Cured
Cured
Oxacillin, penicillin -
Improved
Failure
Improved
Failure
homes, with altered mental status and aspiration pneumonia. Treatment infarction on the sixth day. Her pneumonia was resolving; her endotracheal
lasted 12 days, 2 g every eight hours. tube was colonized with Enterobacter
Results* Outcome
Patient
8 9 10 11
Organism (MBC or Kirby-Bauer) Escherichia coli (0.125 pgiml) Hemophilus aphrophilus (sensitive) Hemophilus influenzae (sensitive) Enterobacter aerogenes (32 b@fW
Source
Other Organisms
Sputum
-
Blood, sputum Blood, sputum Sputum
*Young adult patients with either sickle cell disease, mately 14 days, 2 g every eight hours.
February 8, 1985
Microbiologic
Cured
Cured
-
Cured
Cured
-
Clindtimycin
Cured
Cured
-
Penicillin
Improved
Failure
hypogammaglobulinemia,
The American Journal of Medicine
Clinical
Penicillin, erythromycin -
or recent
pneumonococcal
pneumonia.
Treatment
lasted
approxi-
therapy, but P. aeruginosa (minimal bactericidal concentration = 8 kg/ml) continued to be in evidence in her sputum; on the seventh day of therapy she died from a noninfectious cause. All three patients with alcoholism or pulmonary disease and the one otherwise healthy young adult were completely cured (Tables IV and V). The otherwise healthy elderly male was improving during therapy and his sputum had been cleared of the pathogen when he died from a cardiac arrest on the eighth day of treatment.
myocardial infarction. The other two improved clinically, but aztreonam-resistant strains of Pseudomonas aeruginosa in sputum developed in each during therapy. Three of the four young adults responded with complete clinical and mikrobiologic cures (Table II). The remaining young adult patient improved but her sputum was not cleared of Enterobacter aerogenes (minimal bactericidal concentration = 32 pg/ml). Two of the three patients with nosocomial pneumonia after cardiac arrest (Table Ill) were completely cured. The third patient improved with
32
Other Drugs
Volume
78 (suppl
2A)
AZTREONAM
TABLE
III
Patient
SYMPOSIUM-GREENBERG
ET AL
Results* Outcome
Organism WW
Source
12
Klebsiella oxytoca (0.5 pg/ml)
Transtracheal aspiration
-
13
Pseudomonas (8 ,4-N Pseudomonas (8 m/ml)
Endotracheal tube Blood, endotracheal tube
Patient
14+ *Elderly +Patient
TABLE
aeruginosa aeruginosa
patients with pneumonia after cardiac arrest. Treatment died on seventh day of treatment, sputum grew scant
IV
Patient
Other Organisms
Other Drugs
Clinical
Microbiologic
Cured
Cured
-
Penicillin, oxacillin erythromycin Penicillin
Cured
Cured
-
Vancomycin
improved
Failure
lasted approximately 14 days, 2 g every eight hours. Pseudomonas aeruginosa, death was not related to infection.
Results* Outcome
Organism (MBC or Kirby-Bauer)
Patient 15
Enterobacter cloacae (0.125 pg/ml) Klebsiella pneumoniae (0.125 pg/ml) Klebsietla pneumoniae (0.25 ygiml) Escherichia coli (0.25 pgiml) Hemophilus influenzae (sensitive)
16 17
*Alcoholic
TABLE
patients
V
or patients
Patient
with severe
Source
Other Organisms
Other Orugs
Clinical
Microbiologic
Transtracheal aspiration
-
Erythromycin
Cured
Cured
Transtracheal aspiration Transtracheal aspiration
-
Clindamycin
Cured
Cured
-
Clindamycin
Cured
Cured
underlying
lung disease.
Treatment
lasted
approximately
21 days,
2 g every
eight hours.
Results* Outcome
Patient 18 19+
Organism (MBC or Kirby-Bauer) Hemophilus influenzae (sensitive) Klebsiella pneumoniae (0.125 wgiml) Escherichia coli (0.125 yglml)
Source
Other Organisms
Sputum
Pneumococcus
Metronidazole, penicillin Clindamycin
-
Sputum
*Adults with no risk factors. Treatment lasted five days, 2 g every +Patient died on eighth day of treatment from cardiac arrest.
Clinical
Microbiologic
Cured
Cured
Improved
Cured
eight hours.
REFERENCES
In total, there were 13 of 19 (68 percent) clinical cures and 15 of 19 (79 percent) microbiologic cures. All microbiologic and clinical cures occurred in patients in whom the infecting organism had a minimal bactericidal concentration of less than 8 pg/ml. The eradicated organisms were: seven Klebsiella, four Hemophilus, four Escherichia coli, two P. aeruginosa, and one each Providencia stuartii, P. mirabilis, and Enterobacter cloacae. Neither adverse reaction nor drug toxicity was a problem with this study group.
February
Other Drugs
8, 1985
1.
2.
3. 4.
The
Greenberg RN, Reilly PM, Luppen KL, et al: Treatment of serious gram-negative infections with aztreonam. J Infect Dis 1984; 150: 623630. Berk SL, Wiener SL, Eisner LB, et al: Mixed Streptococcus pneumoniae and gram-negative bacillary pneumonia in the elderly. South Med J 1981; 74: 144-l 46. Pierce AK, Sanford JP: Aerobic gram-negative bacillaty pneumonias. Am Rev Respir Dis 1974; 110: 647-658. Williams DM, Krick JA, Remington JS: Pulmonary infection in the compromised host. Am Rev Respir Dis 1976; 114: 359-394, 593-627.
American
Journal
of Medicine
Volume
78 (suppl
2A)
33
RICHARD N. GREENBERG, M.D. PATRICK M. REILLY, P.A. (C) KEVIN L. LUPPEN, P.A. (C) MARGARET BOLLINGER, M.T. (C) RAY McMILLIAN, Ph.D. St. Louis,
Missouri
From the Division of Infectious Diseases, bepartment of Internal Medicine, St. Louis University School of Medicine, and Microbiology Department, St. Louis City Hospital (RMcM), St. Louis, Missouri. Requests for reprints should be addressed to Dr. Richard N. Greenberg, Department of Internal Medicine, St. Louis University, 1402 South Grand Blvd., St. Louis, Missouri 63104.
Nineteen patients with community- or hospital-acquired gram-negative pneumonia were treated with aztreonam. Other gram-negative antibiotics were withheld. Thirteen patients (68 percent) had clinical cures and 15 (79 percent) had microbiologic cures with aztreonam. No adverse reactions or drug toxicity occurred in this population. Aztreonam was evaluated in the treatment of serious gram-negative infections at St. Louis City Hospital over a one-year period lasting from December 1982 until December 1983. The study is reported in detail elsewhere [I]. Of the adult patients who took part in that study, 19, who had either community- or hospital-acquired gram-negative pneumonia, are described herein. The cases of community-acquired gram-negative pneumonia included lung infection caused by Hemophilus influenzae; aerobic gram-negative bacilli in patients with such underlying illness as alcoholism, diabetes mellitus, or chronic pulmonary disease; or Klebsiella pneumoniae and gram-negative bacilli in the elderly [2,3]. Hospital-acquired gram-negative pneumonia most often occurred in patients who had aspirated while in the hospital or who were immunocompromised [4]. The primary exclusion criteria for the study were granulocytopenia, hyperbilirubinemia (greater than 1.5 mgidl), or meningitis; age under 13 years; pregnancy; or a history of anaphylaxis due to penicillin. Aerobic gram-negative organisms were isolated from culture material from each patient. Antibiotic susceptibilities of bacteria were determined by the Kirby-Bauer disc diffusion technique, using cation-supplemented Mueller-Hinton agar. Sensitivity was defined as a zone size of greater than 21 mm (aztreonam 30 pg disc). Microtiter minimal inhibitory concentration and minimal bactericidal concentration assays were also performed on many of the isolates. Patients who appeared septic were treated with intravenous aztreonam, 2 g every six hours; the remaining patients were treated with 1 to 2 g every eight to 12 hours, intramuscularly or intravenously. Patients were permitted other antibiotics with gram-positive or anaerobic coverage, but those with aerobic gram-negative coverage to the infecting organism were withheld. These 19 patients included seven residents of a nursing home, who were of an altered mental status and who had aspiration pneumonia; four young adults with sickle cell disease, hypogammaglobulinemia, or recent pneumococcocal pneumonia; three elderly patients with nosocomial pneumonia after cardiac arrest; three alcoholic patients or those with severe underlying pulmonary disease; one otherwise healthy young adult; and one otherwise healthy elderly male. Clinical cure was defined as complete resolution of sighs and symptoms of pneumonia five to nine days after therapy and microbiologic cure as the absence of pathogen in sputum culture collected during or after therapy. Four of the seven nursing home patients responded with complete clinical and microbiologic cures (Table I). One of the remaining three nursing home patients was showing evidence of improvement, with eradication of her Proteus mirabilis (minimal bactericidal concentration = 0.5 pgiml), but died on the sixth day of therapy from a
February
8, 1985
The
American
Journal
of Medicine
Volume
78 (suppl
2A)
31
AZTREONAM
TABLE
I
SYMPOSIUM-GREENBERG
Patient
ET AL
Results*
Organism (MBC or Kirby-Bauer)
Patient 1+
Proteus mirabilis (0.5 pg/ml) Providencia stuartii (0.125 pgiml) Escherichia coli (0.125 kg/ml) Citrobacter freundii (sensitive) Klebsiella pneumoniae (sensitive) Klebsiella pneumoniae
2
3
4
5
Klebsiella pneumoniae (0.125 pgiml) Pseudomonas aeruginosa (8 Mml) Pseudomonas aeruginosa (0.25 pgiml, 16 wgiml) Enterobacter cloacae (16 dml) Pseudomonas ,aeruginosa (16 pgiml, 128 pg/ml) Escherichia coli (0.125 pg/ml)
6 7
*Elderly ‘Patient cloacae
patients from nursing died from myocardial (32 pggiml).
TABLE
II
Patient
Source
Otner Organisms
Endotracheal tube Transtracheal aspiration
-
Sputum
-
Endotracheal
Staphylococcus aureus
Sputum
Staphylococcus aureus
Other Drugs
-
Transtracheal aspiration Tracheostomy
-
Clinical
Microbiologic
Clindamycin
Improved
Cured
Penicillin
Cured
Cured
Penicillin
Cured
Cured
Clindamycin, vancomycin, oxacillin Oxacillin, penicillin
Cured
Cured
Cured
Cured
Oxacillin, penicillin -
Improved
Failure
Improved
Failure
homes, with altered mental status and aspiration pneumonia. Treatment infarction on the sixth day. Her pneumonia was resolving; her endotracheal
lasted 12 days, 2 g every eight hours. tube was colonized with Enterobacter
Results* Outcome
Patient
8 9 10 11
Organism (MBC or Kirby-Bauer) Escherichia coli (0.125 pgiml) Hemophilus aphrophilus (sensitive) Hemophilus influenzae (sensitive) Enterobacter aerogenes (32 b@fW
Source
Other Organisms
Sputum
-
Blood, sputum Blood, sputum Sputum
*Young adult patients with either sickle cell disease, mately 14 days, 2 g every eight hours.
February 8, 1985
Microbiologic
Cured
Cured
-
Cured
Cured
-
Clindtimycin
Cured
Cured
-
Penicillin
Improved
Failure
hypogammaglobulinemia,
The American Journal of Medicine
Clinical
Penicillin, erythromycin -
or recent
pneumonococcal
pneumonia.
Treatment
lasted
approxi-
therapy, but P. aeruginosa (minimal bactericidal concentration = 8 kg/ml) continued to be in evidence in her sputum; on the seventh day of therapy she died from a noninfectious cause. All three patients with alcoholism or pulmonary disease and the one otherwise healthy young adult were completely cured (Tables IV and V). The otherwise healthy elderly male was improving during therapy and his sputum had been cleared of the pathogen when he died from a cardiac arrest on the eighth day of treatment.
myocardial infarction. The other two improved clinically, but aztreonam-resistant strains of Pseudomonas aeruginosa in sputum developed in each during therapy. Three of the four young adults responded with complete clinical and mikrobiologic cures (Table II). The remaining young adult patient improved but her sputum was not cleared of Enterobacter aerogenes (minimal bactericidal concentration = 32 pg/ml). Two of the three patients with nosocomial pneumonia after cardiac arrest (Table Ill) were completely cured. The third patient improved with
32
Other Drugs
Volume
78 (suppl
2A)
AZTREONAM
TABLE
III
Patient
SYMPOSIUM-GREENBERG
ET AL
Results* Outcome
Organism WW
Source
12
Klebsiella oxytoca (0.5 pg/ml)
Transtracheal aspiration
-
13
Pseudomonas (8 ,4-N Pseudomonas (8 m/ml)
Endotracheal tube Blood, endotracheal tube
Patient
14+ *Elderly +Patient
TABLE
aeruginosa aeruginosa
patients with pneumonia after cardiac arrest. Treatment died on seventh day of treatment, sputum grew scant
IV
Patient
Other Organisms
Other Drugs
Clinical
Microbiologic
Cured
Cured
-
Penicillin, oxacillin erythromycin Penicillin
Cured
Cured
-
Vancomycin
improved
Failure
lasted approximately 14 days, 2 g every eight hours. Pseudomonas aeruginosa, death was not related to infection.
Results* Outcome
Organism (MBC or Kirby-Bauer)
Patient 15
Enterobacter cloacae (0.125 pg/ml) Klebsiella pneumoniae (0.125 pg/ml) Klebsietla pneumoniae (0.25 ygiml) Escherichia coli (0.25 pgiml) Hemophilus influenzae (sensitive)
16 17
*Alcoholic
TABLE
patients
V
or patients
Patient
with severe
Source
Other Organisms
Other Orugs
Clinical
Microbiologic
Transtracheal aspiration
-
Erythromycin
Cured
Cured
Transtracheal aspiration Transtracheal aspiration
-
Clindamycin
Cured
Cured
-
Clindamycin
Cured
Cured
underlying
lung disease.
Treatment
lasted
approximately
21 days,
2 g every
eight hours.
Results* Outcome
Patient 18 19+
Organism (MBC or Kirby-Bauer) Hemophilus influenzae (sensitive) Klebsiella pneumoniae (0.125 wgiml) Escherichia coli (0.125 yglml)
Source
Other Organisms
Sputum
Pneumococcus
Metronidazole, penicillin Clindamycin
-
Sputum
*Adults with no risk factors. Treatment lasted five days, 2 g every +Patient died on eighth day of treatment from cardiac arrest.
Clinical
Microbiologic
Cured
Cured
Improved
Cured
eight hours.
REFERENCES
In total, there were 13 of 19 (68 percent) clinical cures and 15 of 19 (79 percent) microbiologic cures. All microbiologic and clinical cures occurred in patients in whom the infecting organism had a minimal bactericidal concentration of less than 8 pg/ml. The eradicated organisms were: seven Klebsiella, four Hemophilus, four Escherichia coli, two P. aeruginosa, and one each Providencia stuartii, P. mirabilis, and Enterobacter cloacae. Neither adverse reaction nor drug toxicity was a problem with this study group.
February
Other Drugs
8, 1985
1.
2.
3. 4.
The
Greenberg RN, Reilly PM, Luppen KL, et al: Treatment of serious gram-negative infections with aztreonam. J Infect Dis 1984; 150: 623630. Berk SL, Wiener SL, Eisner LB, et al: Mixed Streptococcus pneumoniae and gram-negative bacillary pneumonia in the elderly. South Med J 1981; 74: 144-l 46. Pierce AK, Sanford JP: Aerobic gram-negative bacillaty pneumonias. Am Rev Respir Dis 1974; 110: 647-658. Williams DM, Krick JA, Remington JS: Pulmonary infection in the compromised host. Am Rev Respir Dis 1976; 114: 359-394, 593-627.
American
Journal
of Medicine
Volume
78 (suppl
2A)
33