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Use of ceftazidime in the treatment of nosocomial lower respiratory infections
Use of Ceftazidime in the Treatment of Nosocomial Lower Respiratory Infections
Patients with hospital-acquired lower respiratory infections pose both diagnostic and therapeutic challenges. Such Infections are commonly seen In critically Ill patients. When nosocomlal pneumonia Is suspected, treatment Is generally inltlated wlth broad-spectrum antibiotics before culture results become available. The usual therapeutic regimen includes an aminoglycoside with or without a beta-la&am agent. In a clinical efficacy study of a single agent, ceftazldlme, in the treatment of 20 adults wlth hospital-acquired lower respiratory infection, 18 patients showed clinical improvement with ceftazidime therapy and pathogens were eradicated In 11. Therapeutic failures occurred in two patients who received empiric therapy prior to the isolation of pathogens resistant to ceftazidlme. The median minimal inhlbitory concentration of ceftazidime for the Isolated pathogens was 0.78 pglml. Of the 15 patients infected with Pseudomonas aeruglnosa, 14 showed a favorable clinical response. Therapy-limiting side effects occurred In two patfents and bacfltary resistance developed in one patient. The efficacy and safety of ceftazidlme in the treatment of hospital-acquired pneumonias were comparable to results previously demonstrated for amikacin, cefotaxime, and imipenem in studies conducted at our institution. In studies reported In the literature, 44 of 51 patients (88 percent) with nosocomial pneumonia who were treated with ceftazidlme had a favorable clinical response to therapy. The patients Included in these studles were nelther neutropenic nor commonly bacteremlc, and none had cystic fibrosis. Ceftazidime appears to be a useful agent in the treatment of selected patlents with nosocomial pneumonias, including those due to P. aeruginoea.
GORDON M. TRENHOLME, M.D. JOHN C. POTTAGE, Jr., M.D. PETER H. KARAKUSIS, M.D. Chicago,
Illinois
From Rush-Presbyterian-St. Luke’s Medical Center, Department of Medicine, Section of Infectious Disease, Chicago, Illinois. Requests for reprints should be addressed to Dr. Gordon M. Trenholme, Rush-Presbyterian-St. Luke’s Medical Center, Department of Medicine, Section of Infectious Diseases, 1753 West Congress Parkway, Chicago, Illinois 60612.
32
August
9,1995
The Amerkan
Journal
Patients with hospital-acquired pneumonia present both a diagnostic and a therapeutic challenge. Pneumonia is the third most common hospitalacquired infection and the most common infectious cause of death in hospitalized patients [l]. This infection has been associated with a number of risk factors, including advanced age, male sex, obesity, respiratory intubation, surgery, hospitalization in an intensive care unit, and antibiotics [2]. Fifty percent of nosocomial pneumonias occur in surgical patients [3]. Upper abdominal and thoracic surgery, surgical procedures of more than four hours’ duration, preoperative stay of more than seven days prior to surgery, and the severity of underlying diseases have been found to be independent risk factors for development of pneumonia in surgical patients [2]. Nosocomial lower respiratory infections appear to be related to introduction of organisms into the lower respiratory tract following intubation
of Medicine
Volume
79 (suppl2A)
SYMPOSIUM
IN CEPHALOSPORIN
THERAPY-TRENHOLME
ET AL
purulent sputum with microorganisms present on a gramstained specimen obtained from the lower respiratory tract, and roentgenographic evidence of a new or progressive pulmonary infiltrate. Criteria for diagnosis of tracheobronchitis were similar except that infiltrates were not present on chest roentgenography. Twenty patients received ceftazidime for hospital-acquired lower respiratory infections. Eighteen patients had pneumonia; two had tracheobronchitis. All of the patients had severe underlying conditions. No patient was neutropenic or had acute leukemia. Seven had recently undergone cardiovascular or abdominal surgery. Thirteen of the 20 patients were receiving mechanical ventilation at the time of diagnosis. Eighteen patients had received broad-spectrum antibiotics prior to ceftazidime. The mean age of patients was 66 years (range 24 to 86). The mean and range of the total white blood cell count and temperature prior to therapy were 14,600/mm3 (4,806 to 23,500/mm3) and 102.2”F (100 to 104°F). Ceftazidime was administered by intravenous infusion. One patient with renal insufficiency received 1 g of ceftazidime twice daily. Another patient received 2 g twice a day. A third patient initially received 6 g daily, but the dose was reduced to 3 g when renal failure developed. Seventeen patients received 2 g three times daily. The duration of therapy ranged between four and 17 days (mean 12.0 days). Initial susceptibilii studies were based on a standardized disk-testing method using 30 w disks of ceftazidime [ll]. Figure 1 shows the minimal inhibitory concentration of ceftazidime for the organisms isolated in our 26 patients. The median minimal inhibitory concentration of ceftazidime for the isolates was 0.78 &ml. Minimal inhibitory concentrations were determined by the broth dilution technique. The inoculum was IO* colony-forming units/ml. The response of patients to treatment with ceftazidime was classified as good, fair, or poor. A good response was defined as clinical and bacteriologic improvement. Clinical improvement was based on roentgenographic resolution of pulmonary infiltrates, defervescence, and a decrease in the amount and purulence of sputum. The bacteriologic response was based on the disappearance of the pathogen on repeated culture. A fair response was defined as clinical improvement with persistence of the pathogen. A poor response was defined as absence of clinical improvement regardless of bacteriologic response. Parameters assessed before therapy included a complete history and physical examination, complete blood cell count, platelet count, urinalysis, determination of blood urea nitrogen, serum creatinine, total protein, albumin, total bilirubin, cholesterol, alkaline phosphatase, glutamic oxalacetic transaminase, glutamic pyruvic transaminase, and lactate dehydrogenase levels, and direct Coombs’ test. These studies were repeated weekly and at the conclusion of therapy.
or aspiration. An inability to clear these organisms from the lower respiratory tract may result in either tracheobronchitis or pneumonia. The most common etiologic organisms are coagulase-positive staphylococci and aerobic gram-negative bacilli such as Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, and Enterobatter species [4]. Less common causes include anaerobic bacteria, viruses, and Legionella. Various viruses consistently account for a substantial number of nosocomial pneumonias, particularly in pediatric units. However, among adults, Hemophilus influenzae [5], Herpes simplex [S] and respiratory syncytial virus [A have been reported to be important. Legionella species are organisms receiving increasing recognition as pathogens that cause nosocomial infections of the lower respiratory tract. These infections occur in specific hosts or clinical situations such as patients who have undergone renal or cardiac transplantation or in an institution with an ongoing outbreak of legionellosis. Sporadic nosocomial Legionella infections are quite unusual, and account for only a small portion of sporadic legionellosis cases reported to the Centers for Disease Control [8]. No pathogen is established in approximately one fourth of patients with nosocomial lower respiratory tract infections [4]. Diagnosis of nosocomial pneumonia is complicated by the fact that critically ill patients at risk of acquiring this infection may have fever, leukocytosis, and an abnormal chest roentgenographic appearance due to concomitant illnesses other than pneumonia. In addition, gram-negative bacilli may be cultured from the sputum of such patients, irrespective of the presence of lower respiratory tract infections [9]. When nosocomial pneumonia is suspected, treatment is usually initiated before culture results have returned from the laboratory. Broad-spectrum antibiotics are necessarily utilized. The necessity for an aminoglycoside in the empiric therapeutic regimen appears to depend on the likelihood that P. aeruginosa is the pathogen. The recent development of novel beta-lactam antibiotics that rival the aminoglycosides in their in vitro activity against P. aeruginosa and other aerobic gram-negative bacilli may obviate the need for aminoglycosides in the treatment of hospital-acquired pneumonia. Ceftazidime is a semi-synthetic cephalosporln that has excellent in vitro activity against gram-negative organisms, including P. aeruginosa [lo]. This report describes our experience with ceftazidime in the treatment of hospital-acquired lower respiratory infections. PATIENTS
ON ADVANCES
AND METHODS
RESULTS
Patients were enrolled in the study exclusively through consuftation with the infectious disease service of Rush-Presbyterian-St. Luke’s Medical Center. Informed consent was obtained from the patient or next of kin. Patients with infections due to P. aeruginosa were particularly sought. Criteria for diagnosis of hospital-acquired pneumonia included fever,
August 9,19&i
Eighteen of the 20 patients showed improvement during treatment with ceftazidime. Eleven patients showed a good response. Seven patients had a favorable clinical response, but the pathogen persisted. Two patients with pneumonia had poor responses to ceftazidime. In these
lb
Ammican Juumd
of Madlci~~
Volume 79 (sup@ U)
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SYMPOSIUM
ON ADVANCES
IN CEPHALOSPORIN
$IID
THERAPY-TRENHOLME
ET AL
P seruginosa
All others
1.56
0.76
Figura 1. Minimal inhibitory concentrations of ceftazidime for isolated pathogens.
6.25
3.13
MIC to Ceftazidime
two patients, ceftazidime was begun before susceptibility results were available. The pathogens isolated from these patients, P. aeruginosa and E. cloacae, respectively, were found to be resistant to ceftazidime. Neither patient showed improvement during treatment with ceftazidime. Therapy was changed to antibiotics to which the organisms were susceptible. The response to ceftazidime related to pathogenic isolates is shown in Table I. Fourteen of the 15 patients with
TABLE I
Response Related to Pathogens in 20 Pstknts with Nosocomlal Lower Reapiratoty Inisctlons Who Received Ceftazidlms*
Pseudomonas aeruginosa Serratia marcescens Staphybcoca~s aureus Enterobacbr aerogenes Enterobacter cloacae Kbbsiilla prteumoniae Klebsiella oxytoca Pseudomonas maltophilia Hemophilus influenzae Proteus mirabilis EacherHh coli TOtal *Nine
34
patients
Augusl
15 4 3 2 2 2 2 1 1 1 1 34
had polymicmbial
9, l@Hi
The
lower
8 1 2 1
1 17 respiratory
AmericanJoumd
-
1
1 1
-
-
1 1
1 1
6 3 1 2
1
1 15
2
infections.
of Mmdklm
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infections associated with P. aeruginosa showed improvement with ceftazidime. The only failure occurred in a patient whose P. aeruginosa isolate was initially resistant to ceftazidime. Four of the five patients with lower respiratory infections due to organisms other than P. aeruginosa improved during therapy. Nine patients with polymicrobial lower respiratory infections, including eight with P. aeruginosa, improved with treatment. Three patients had positive blood culture results: one with E. coli, one with Staphylococcus aureus, and one with P. aeruginosa; all improved with treatment. Eight possible complications were noted in the 20 patients who received ceftazidime. In two patients, ceftazidime was discontinued because of possible side effects. In both patients, renal failure developed. The first patient had recently undergone mitral valve replacement and had chronic congestive heart failure. On the eighth day of therapy, azotemia developed, presumably due to inadequate renal perfusion. The dosage of ceftazidime was reduced to 3 g per day prior to its discontinuation two days later. Azotemia progressed to renal failure requiring peritoneal dialysis. Two weeks after ceftazidime was discontinued, eosinophils were noted in the patient’s urine. The second patient was a 72-year-old man who had recently undergone coronary artery bypass surgery. The postoperative course was complicated by hypotension, a possible cerebrovascular accident, and pneumonia due to P. aeruginosa. The pneumonia was treated with piperacillin and tobramycin for two weeks. Eight days after cessation of treatment, the lower respiratory infection relapsed. P. aer-
19 (auppl2A)
SYMPOSIUM
uginosa susceptible to ceftazidime was isolated from bronchoscopic specimens. Following treatment with ceftazidime at a dosage of 4 g per day, the patient showed improvement. However, on the 13th day, the patient had respiratory arrest with associated hypotension. The patient’s renal function deteriorated thereafter, and he required dialysis. Ceftazidime was stopped three days after the respiratory arrest. Persistence of organisms was seen in the sputum of seven patients who had a favorable therapeutic response. Persistent isolates included six P. aeruginosa, one S. aureus, one E. aerogenes, and one Proteus mirabilis. Three of the isolates of P. aeruginosa were resistant to ceftazidime at the end of therapy. An additional P. aeruginosa isolate became resistant to ceftazidime during therapy and was associated with a relapse. Sputum specimens from this patient before therapy yielded P. aeruginosa serotype 11 (Bacto P. aeruginosa antiserum set; Difco). The minimal inhibitory concentration of ceftazidime for the organism was 3.13 &ml. This patient improved during therapy, but on the 13th day of ceftazidime therapy, a superinfection appeared to develop. Bronchoscopic specimens revealed a P. aeruginosa serotype 11 resistant to ceftazidime (minimal inhibitory concentration = 256 M/ml). Five patients became colonized with new organisms that were resistant to ceftazidime. These included Citrobacter diversus, C. freundii, P. maltophilia, Flavobacterium meningosepticum, and Candida albicans. These isolates were not believed to be clinically significant.
TABLE II
IN CEPHALOSPORIN
THERAPY-TRENHOLME
ET AL
Treatment of Nosocomial Pneumonia with Investigational Antibiotics: RushPresbyterian-St. Luke’s Medical Cantar Number of Palienfs
Favorable
Ciinlcai ROylOllS
P. aeni-
Antibiotic Amikacin [12] Cefotaxime [13] imipenem Ceftazidime
P. aeru-
flinosl
8vemii
6 2 2 13
15 7 6 18
flinosa 5 2 2 12
Ovanil 13 7 6 16
teen had a favorable response to ceftazidime; one of the 14 had a relapse. The excellent clinical response of patient8 with infections associated with P. aeruginosa correlate8 with the high degree of susceptibility of P. aeruginosa to ceftazidime. The median minimal inhibitory concentration of ceftazidime for the pseudomonal isolates in our study was 1.56 ccg/ml (Figure 1). All of the isolates of P. aeruginosa were susceptible to tobramycin and amikacin. Our studies of patients with nosocomial pneumonia at Rush-Presbyterian-St. Luke’s Medical Center are summarized in Table II [12,13]. Studies that evaluated amikacin, cefotaxime, and imipenem were performed with patients who were similar to those utilized in the analysis of ceftazidime. The overall response of patients with hospital-acquired pneumonias to treatment with the four agents was similar. However, the number of infections associated with P. aeruginosa was low in the prior studies because infections with this organism were not specifically sought as they were in the ceftazidime study. Results of treating nosocomial pneumonia with ceftazidime that have been published in the medical literature are shown in Table III [14-l 61. The results of the present study are included. Overall, there have been 69 patients with nosocomial pneumonia who have received ceftazi-
COMMENTS This study indicates that ceftazidime is an effective treatment for patients with hospital-acquired lower respiratory tract infection. Sixteen patients with pneumonia and two with tracheobronchitis improved during therapy with ceftazidime. Two failures were seen in patients whose pathogens were initially resistant to ceftazidime. An additional patient had relapsed infection when resistance to ceftazidime developed during treatment. Fifteen patients were infected with P. aeruginosa. Four-
TABLE III
ON ADVANCES
Treatment of Nosocomial Pneumonia with Wftazidima: Results of Major Studies Favorable Number oi Patients
Gozzard et al [14] Mandell et al [15] Franciole et al [16] Clumeck et al [17] Scutly et al [18] Present study Total
P. aetuflinou
lIvenil
6 4 9 4 2 13 38
7 17 11 11 5 16 69
CiiniceiAecpoeee P. aeruflineea 6 4 8 3 1 12 34 m
Auguol 9.1985
8vemii 7 15 9 9 4 16 80 W)
Comment, Failures: H. infiuenzae, S. aureus Emergence of resistance: P. aeruginosa, S. aureus Failures: susceptible P. aeruginosa, E. coli, S. aureus Failure: sus&ptible P. aeruginosa Failures: resistant E. cloacae, P. aeruginosa
The Amariclnr Joumai of Madkina
Volume 79 (auppl2A)
35
SYM~~~IU~
or4 ADVANCES
IN CE~HALOS~~~~IN
THERAPY-TFIENH~LME
ET AL
dime; 38 had pneumonia associated with P. aeruginosa. Favorable response rates were observed in 88 percent of patients with nosocomial pneumonia. Ninety percent of patients with infections associated with P. aeruginosa had a favorable response. The excellent therapeutic results with ceftazidime must be tempered by the possibility of emergence of resistance. Ceftazidime’s relative lack of in vitro activity against S. aureus may also be of concern. Nevertheless, published studies evaluating ceftazidime in the treatment of infections with S. aureus have shown favorable results [19]. Side effects attributed to ceftazidime were generally mild. The development of renal failure in two patients is
1.
5. 6.
7.
6.
9.
10.
36
Gross PA, Neu HC, Aswapokee P, et al: Deaths from nosocomial infections: experience in a university hospital and community hospital. Am J Med 1960; 66: 219. Garibaldi RA, Britl MR, Coleman MI, Reading JC, Pace NL: Risk factors for postoperative pneumonia. Am J Med 1961; 70: 677. Eickhoff TC: Pulmonary infections in surgical patients. Surg Clin North Am 1960; 60: 175-163. Centers for Disease Control: National Nosocomial Infections Study Report: Annual Summary 1979. Atlanta: Centers for Disease Control, March 1962. Kapila R, Lintz 01, Tecson FT, Z&kin L, Louda DB: A nosocomial outbreak of influenza A. Chest 1977; 71: 576. Tuxen DV, Cade JF, McDonald MI, Buchanan MRC, Clark FtJ, Pain MCF: Herpes simplex virus from the lower respiratory tract in adult respiratoty distress syndrome. Am Rev Respir Dis 1962; 126: 416. Mathur U, Bentley DW, Hall CB: Concurrent respiratory syncyiial virus and influenza A infections in the institutionalized elderly and chronically ill. Ann Intern Med 1960; 93: 49-52. England AC, Fraser DW, Plikaytis DB, Tsai TF, Starch G, Broome CV: Sporadic legionelbsis in the United States: the first thousand cases. Ann Intern Med 1961; 94: 164. Johanson WG, Pierce AK, Sanford JP, et al: Nosocomial respiratory infections with gram-negative bacilli. Ann Intern Med 1972; 77: 701. Jones R, Barry A, Thornsbeny C, et al: Ceftaziiime, a Pseudomonas-active cephalceporin: in vitro antimicrobial activity evaluation including recommendations for discdiiusion sus-
Auguet
9,1966
The Amerkan
Journal
of Medklns
Vofume
of interest. The molecular structure of ceftazidime is similar to that of cephaloridine. Each has a pyridine side chain at position 3 of the dihydrothiazine moiety. Although cephaloridine has been implicated in antibiotic-induced acute tubular necrosis, no association between the pyridine side chain and renal failure has been documented. Published studies of ceftazidime have not shown an increase in nephrotoxicity in comparison with other cephalosporins
PI. This study provides support for the use of ceftazidime as the sole agent in the treatment of patients with hospitalacquired pneumonias. The conclusions of this article are limited, however, to patients who are not neutropenic.
ce&ibilii 11.
12.
13.
14: 15.
16.
17.
16.
19.
tests.
J Antimkxob
Chemother
1961;
6 (suppl
B):
Bauer AW, Kirby WMM, Sherris JC: Antibiotic susceptibility testing by a standardized single-disc method. Am J Clin Pathol 1966; 45: 493. Trenholme GM, McKellar PP, Riera N, Levin S: Arnikacin in the treatment of gram-negative pneumonia. Am J Med 1977; 62: 949-953. Karakusis PH, Feczko JM. Goodman LJ, et al: Clinical effkxcy ol cefotaxime in serious infections. Antimicrob Agents Chemother 1962; 21: 119-124. Gozzard DI, Geddes AM, Fanell ID, et al: Ceftazidime-a new *extended-spectrum cephalosporin. Lancet 1962; I: 1152. Mandell LA, Nicolle LE, Ronad AR, et al: A multicentre prospective randomized trial comparing ceftazidime with cefazolin/ tobramycin in the treatment of hospitalized patients with nonpneumococcal pneumonia. J Antimicrob Chemother 1963; 12 (suppl A): 9. Francioli P, Clement M, Geroulanos S, et al: Ceftaziiime in severe infections: a Swiss multicentre study. J Antimicrob Chemother 1963; 12 (suppl A): 139. Clumeck N, Laethem YV, Bon% B, Jaspar N, Butzler JP: Use of ceftazidime in the therapy of serious infections, including those due to multiresistant organisms. Antimicrob Agents Chemother 1963; 24: 176. Scully BE, Neu HC: Clinical efficacy of ceftazidime: treatment of serious infection due to multiresistant Pseudomonas and other gram-negative bacteria. Arch Intern Med 1964; 144: 57. Foord RD: Ceftazidime: aspects of efficacy and tolerance. J. Antimicrob Chemother 1963: 12 (suppi A) 399.
79 (euppl2A)
Patients with hospital-acquired lower respiratory infections pose both diagnostic and therapeutic challenges. Such Infections are commonly seen In critically Ill patients. When nosocomlal pneumonia Is suspected, treatment Is generally inltlated wlth broad-spectrum antibiotics before culture results become available. The usual therapeutic regimen includes an aminoglycoside with or without a beta-la&am agent. In a clinical efficacy study of a single agent, ceftazldlme, in the treatment of 20 adults wlth hospital-acquired lower respiratory infection, 18 patients showed clinical improvement with ceftazidime therapy and pathogens were eradicated In 11. Therapeutic failures occurred in two patients who received empiric therapy prior to the isolation of pathogens resistant to ceftazidlme. The median minimal inhlbitory concentration of ceftazidime for the Isolated pathogens was 0.78 pglml. Of the 15 patients infected with Pseudomonas aeruglnosa, 14 showed a favorable clinical response. Therapy-limiting side effects occurred In two patfents and bacfltary resistance developed in one patient. The efficacy and safety of ceftazidlme in the treatment of hospital-acquired pneumonias were comparable to results previously demonstrated for amikacin, cefotaxime, and imipenem in studies conducted at our institution. In studies reported In the literature, 44 of 51 patients (88 percent) with nosocomial pneumonia who were treated with ceftazidlme had a favorable clinical response to therapy. The patients Included in these studles were nelther neutropenic nor commonly bacteremlc, and none had cystic fibrosis. Ceftazidime appears to be a useful agent in the treatment of selected patlents with nosocomial pneumonias, including those due to P. aeruginoea.
GORDON M. TRENHOLME, M.D. JOHN C. POTTAGE, Jr., M.D. PETER H. KARAKUSIS, M.D. Chicago,
Illinois
From Rush-Presbyterian-St. Luke’s Medical Center, Department of Medicine, Section of Infectious Disease, Chicago, Illinois. Requests for reprints should be addressed to Dr. Gordon M. Trenholme, Rush-Presbyterian-St. Luke’s Medical Center, Department of Medicine, Section of Infectious Diseases, 1753 West Congress Parkway, Chicago, Illinois 60612.
32
August
9,1995
The Amerkan
Journal
Patients with hospital-acquired pneumonia present both a diagnostic and a therapeutic challenge. Pneumonia is the third most common hospitalacquired infection and the most common infectious cause of death in hospitalized patients [l]. This infection has been associated with a number of risk factors, including advanced age, male sex, obesity, respiratory intubation, surgery, hospitalization in an intensive care unit, and antibiotics [2]. Fifty percent of nosocomial pneumonias occur in surgical patients [3]. Upper abdominal and thoracic surgery, surgical procedures of more than four hours’ duration, preoperative stay of more than seven days prior to surgery, and the severity of underlying diseases have been found to be independent risk factors for development of pneumonia in surgical patients [2]. Nosocomial lower respiratory infections appear to be related to introduction of organisms into the lower respiratory tract following intubation
of Medicine
Volume
79 (suppl2A)
SYMPOSIUM
IN CEPHALOSPORIN
THERAPY-TRENHOLME
ET AL
purulent sputum with microorganisms present on a gramstained specimen obtained from the lower respiratory tract, and roentgenographic evidence of a new or progressive pulmonary infiltrate. Criteria for diagnosis of tracheobronchitis were similar except that infiltrates were not present on chest roentgenography. Twenty patients received ceftazidime for hospital-acquired lower respiratory infections. Eighteen patients had pneumonia; two had tracheobronchitis. All of the patients had severe underlying conditions. No patient was neutropenic or had acute leukemia. Seven had recently undergone cardiovascular or abdominal surgery. Thirteen of the 20 patients were receiving mechanical ventilation at the time of diagnosis. Eighteen patients had received broad-spectrum antibiotics prior to ceftazidime. The mean age of patients was 66 years (range 24 to 86). The mean and range of the total white blood cell count and temperature prior to therapy were 14,600/mm3 (4,806 to 23,500/mm3) and 102.2”F (100 to 104°F). Ceftazidime was administered by intravenous infusion. One patient with renal insufficiency received 1 g of ceftazidime twice daily. Another patient received 2 g twice a day. A third patient initially received 6 g daily, but the dose was reduced to 3 g when renal failure developed. Seventeen patients received 2 g three times daily. The duration of therapy ranged between four and 17 days (mean 12.0 days). Initial susceptibilii studies were based on a standardized disk-testing method using 30 w disks of ceftazidime [ll]. Figure 1 shows the minimal inhibitory concentration of ceftazidime for the organisms isolated in our 26 patients. The median minimal inhibitory concentration of ceftazidime for the isolates was 0.78 &ml. Minimal inhibitory concentrations were determined by the broth dilution technique. The inoculum was IO* colony-forming units/ml. The response of patients to treatment with ceftazidime was classified as good, fair, or poor. A good response was defined as clinical and bacteriologic improvement. Clinical improvement was based on roentgenographic resolution of pulmonary infiltrates, defervescence, and a decrease in the amount and purulence of sputum. The bacteriologic response was based on the disappearance of the pathogen on repeated culture. A fair response was defined as clinical improvement with persistence of the pathogen. A poor response was defined as absence of clinical improvement regardless of bacteriologic response. Parameters assessed before therapy included a complete history and physical examination, complete blood cell count, platelet count, urinalysis, determination of blood urea nitrogen, serum creatinine, total protein, albumin, total bilirubin, cholesterol, alkaline phosphatase, glutamic oxalacetic transaminase, glutamic pyruvic transaminase, and lactate dehydrogenase levels, and direct Coombs’ test. These studies were repeated weekly and at the conclusion of therapy.
or aspiration. An inability to clear these organisms from the lower respiratory tract may result in either tracheobronchitis or pneumonia. The most common etiologic organisms are coagulase-positive staphylococci and aerobic gram-negative bacilli such as Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, and Enterobatter species [4]. Less common causes include anaerobic bacteria, viruses, and Legionella. Various viruses consistently account for a substantial number of nosocomial pneumonias, particularly in pediatric units. However, among adults, Hemophilus influenzae [5], Herpes simplex [S] and respiratory syncytial virus [A have been reported to be important. Legionella species are organisms receiving increasing recognition as pathogens that cause nosocomial infections of the lower respiratory tract. These infections occur in specific hosts or clinical situations such as patients who have undergone renal or cardiac transplantation or in an institution with an ongoing outbreak of legionellosis. Sporadic nosocomial Legionella infections are quite unusual, and account for only a small portion of sporadic legionellosis cases reported to the Centers for Disease Control [8]. No pathogen is established in approximately one fourth of patients with nosocomial lower respiratory tract infections [4]. Diagnosis of nosocomial pneumonia is complicated by the fact that critically ill patients at risk of acquiring this infection may have fever, leukocytosis, and an abnormal chest roentgenographic appearance due to concomitant illnesses other than pneumonia. In addition, gram-negative bacilli may be cultured from the sputum of such patients, irrespective of the presence of lower respiratory tract infections [9]. When nosocomial pneumonia is suspected, treatment is usually initiated before culture results have returned from the laboratory. Broad-spectrum antibiotics are necessarily utilized. The necessity for an aminoglycoside in the empiric therapeutic regimen appears to depend on the likelihood that P. aeruginosa is the pathogen. The recent development of novel beta-lactam antibiotics that rival the aminoglycosides in their in vitro activity against P. aeruginosa and other aerobic gram-negative bacilli may obviate the need for aminoglycosides in the treatment of hospital-acquired pneumonia. Ceftazidime is a semi-synthetic cephalosporln that has excellent in vitro activity against gram-negative organisms, including P. aeruginosa [lo]. This report describes our experience with ceftazidime in the treatment of hospital-acquired lower respiratory infections. PATIENTS
ON ADVANCES
AND METHODS
RESULTS
Patients were enrolled in the study exclusively through consuftation with the infectious disease service of Rush-Presbyterian-St. Luke’s Medical Center. Informed consent was obtained from the patient or next of kin. Patients with infections due to P. aeruginosa were particularly sought. Criteria for diagnosis of hospital-acquired pneumonia included fever,
August 9,19&i
Eighteen of the 20 patients showed improvement during treatment with ceftazidime. Eleven patients showed a good response. Seven patients had a favorable clinical response, but the pathogen persisted. Two patients with pneumonia had poor responses to ceftazidime. In these
lb
Ammican Juumd
of Madlci~~
Volume 79 (sup@ U)
33
SYMPOSIUM
ON ADVANCES
IN CEPHALOSPORIN
$IID
THERAPY-TRENHOLME
ET AL
P seruginosa
All others
1.56
0.76
Figura 1. Minimal inhibitory concentrations of ceftazidime for isolated pathogens.
6.25
3.13
MIC to Ceftazidime
two patients, ceftazidime was begun before susceptibility results were available. The pathogens isolated from these patients, P. aeruginosa and E. cloacae, respectively, were found to be resistant to ceftazidime. Neither patient showed improvement during treatment with ceftazidime. Therapy was changed to antibiotics to which the organisms were susceptible. The response to ceftazidime related to pathogenic isolates is shown in Table I. Fourteen of the 15 patients with
TABLE I
Response Related to Pathogens in 20 Pstknts with Nosocomlal Lower Reapiratoty Inisctlons Who Received Ceftazidlms*
Pseudomonas aeruginosa Serratia marcescens Staphybcoca~s aureus Enterobacbr aerogenes Enterobacter cloacae Kbbsiilla prteumoniae Klebsiella oxytoca Pseudomonas maltophilia Hemophilus influenzae Proteus mirabilis EacherHh coli TOtal *Nine
34
patients
Augusl
15 4 3 2 2 2 2 1 1 1 1 34
had polymicmbial
9, l@Hi
The
lower
8 1 2 1
1 17 respiratory
AmericanJoumd
-
1
1 1
-
-
1 1
1 1
6 3 1 2
1
1 15
2
infections.
of Mmdklm
Volume
infections associated with P. aeruginosa showed improvement with ceftazidime. The only failure occurred in a patient whose P. aeruginosa isolate was initially resistant to ceftazidime. Four of the five patients with lower respiratory infections due to organisms other than P. aeruginosa improved during therapy. Nine patients with polymicrobial lower respiratory infections, including eight with P. aeruginosa, improved with treatment. Three patients had positive blood culture results: one with E. coli, one with Staphylococcus aureus, and one with P. aeruginosa; all improved with treatment. Eight possible complications were noted in the 20 patients who received ceftazidime. In two patients, ceftazidime was discontinued because of possible side effects. In both patients, renal failure developed. The first patient had recently undergone mitral valve replacement and had chronic congestive heart failure. On the eighth day of therapy, azotemia developed, presumably due to inadequate renal perfusion. The dosage of ceftazidime was reduced to 3 g per day prior to its discontinuation two days later. Azotemia progressed to renal failure requiring peritoneal dialysis. Two weeks after ceftazidime was discontinued, eosinophils were noted in the patient’s urine. The second patient was a 72-year-old man who had recently undergone coronary artery bypass surgery. The postoperative course was complicated by hypotension, a possible cerebrovascular accident, and pneumonia due to P. aeruginosa. The pneumonia was treated with piperacillin and tobramycin for two weeks. Eight days after cessation of treatment, the lower respiratory infection relapsed. P. aer-
19 (auppl2A)
SYMPOSIUM
uginosa susceptible to ceftazidime was isolated from bronchoscopic specimens. Following treatment with ceftazidime at a dosage of 4 g per day, the patient showed improvement. However, on the 13th day, the patient had respiratory arrest with associated hypotension. The patient’s renal function deteriorated thereafter, and he required dialysis. Ceftazidime was stopped three days after the respiratory arrest. Persistence of organisms was seen in the sputum of seven patients who had a favorable therapeutic response. Persistent isolates included six P. aeruginosa, one S. aureus, one E. aerogenes, and one Proteus mirabilis. Three of the isolates of P. aeruginosa were resistant to ceftazidime at the end of therapy. An additional P. aeruginosa isolate became resistant to ceftazidime during therapy and was associated with a relapse. Sputum specimens from this patient before therapy yielded P. aeruginosa serotype 11 (Bacto P. aeruginosa antiserum set; Difco). The minimal inhibitory concentration of ceftazidime for the organism was 3.13 &ml. This patient improved during therapy, but on the 13th day of ceftazidime therapy, a superinfection appeared to develop. Bronchoscopic specimens revealed a P. aeruginosa serotype 11 resistant to ceftazidime (minimal inhibitory concentration = 256 M/ml). Five patients became colonized with new organisms that were resistant to ceftazidime. These included Citrobacter diversus, C. freundii, P. maltophilia, Flavobacterium meningosepticum, and Candida albicans. These isolates were not believed to be clinically significant.
TABLE II
IN CEPHALOSPORIN
THERAPY-TRENHOLME
ET AL
Treatment of Nosocomial Pneumonia with Investigational Antibiotics: RushPresbyterian-St. Luke’s Medical Cantar Number of Palienfs
Favorable
Ciinlcai ROylOllS
P. aeni-
Antibiotic Amikacin [12] Cefotaxime [13] imipenem Ceftazidime
P. aeru-
flinosl
8vemii
6 2 2 13
15 7 6 18
flinosa 5 2 2 12
Ovanil 13 7 6 16
teen had a favorable response to ceftazidime; one of the 14 had a relapse. The excellent clinical response of patient8 with infections associated with P. aeruginosa correlate8 with the high degree of susceptibility of P. aeruginosa to ceftazidime. The median minimal inhibitory concentration of ceftazidime for the pseudomonal isolates in our study was 1.56 ccg/ml (Figure 1). All of the isolates of P. aeruginosa were susceptible to tobramycin and amikacin. Our studies of patients with nosocomial pneumonia at Rush-Presbyterian-St. Luke’s Medical Center are summarized in Table II [12,13]. Studies that evaluated amikacin, cefotaxime, and imipenem were performed with patients who were similar to those utilized in the analysis of ceftazidime. The overall response of patients with hospital-acquired pneumonias to treatment with the four agents was similar. However, the number of infections associated with P. aeruginosa was low in the prior studies because infections with this organism were not specifically sought as they were in the ceftazidime study. Results of treating nosocomial pneumonia with ceftazidime that have been published in the medical literature are shown in Table III [14-l 61. The results of the present study are included. Overall, there have been 69 patients with nosocomial pneumonia who have received ceftazi-
COMMENTS This study indicates that ceftazidime is an effective treatment for patients with hospital-acquired lower respiratory tract infection. Sixteen patients with pneumonia and two with tracheobronchitis improved during therapy with ceftazidime. Two failures were seen in patients whose pathogens were initially resistant to ceftazidime. An additional patient had relapsed infection when resistance to ceftazidime developed during treatment. Fifteen patients were infected with P. aeruginosa. Four-
TABLE III
ON ADVANCES
Treatment of Nosocomial Pneumonia with Wftazidima: Results of Major Studies Favorable Number oi Patients
Gozzard et al [14] Mandell et al [15] Franciole et al [16] Clumeck et al [17] Scutly et al [18] Present study Total
P. aetuflinou
lIvenil
6 4 9 4 2 13 38
7 17 11 11 5 16 69
CiiniceiAecpoeee P. aeruflineea 6 4 8 3 1 12 34 m
Auguol 9.1985
8vemii 7 15 9 9 4 16 80 W)
Comment, Failures: H. infiuenzae, S. aureus Emergence of resistance: P. aeruginosa, S. aureus Failures: susceptible P. aeruginosa, E. coli, S. aureus Failure: sus&ptible P. aeruginosa Failures: resistant E. cloacae, P. aeruginosa
The Amariclnr Joumai of Madkina
Volume 79 (auppl2A)
35
SYM~~~IU~
or4 ADVANCES
IN CE~HALOS~~~~IN
THERAPY-TFIENH~LME
ET AL
dime; 38 had pneumonia associated with P. aeruginosa. Favorable response rates were observed in 88 percent of patients with nosocomial pneumonia. Ninety percent of patients with infections associated with P. aeruginosa had a favorable response. The excellent therapeutic results with ceftazidime must be tempered by the possibility of emergence of resistance. Ceftazidime’s relative lack of in vitro activity against S. aureus may also be of concern. Nevertheless, published studies evaluating ceftazidime in the treatment of infections with S. aureus have shown favorable results [19]. Side effects attributed to ceftazidime were generally mild. The development of renal failure in two patients is
1.
5. 6.
7.
6.
9.
10.
36
Gross PA, Neu HC, Aswapokee P, et al: Deaths from nosocomial infections: experience in a university hospital and community hospital. Am J Med 1960; 66: 219. Garibaldi RA, Britl MR, Coleman MI, Reading JC, Pace NL: Risk factors for postoperative pneumonia. Am J Med 1961; 70: 677. Eickhoff TC: Pulmonary infections in surgical patients. Surg Clin North Am 1960; 60: 175-163. Centers for Disease Control: National Nosocomial Infections Study Report: Annual Summary 1979. Atlanta: Centers for Disease Control, March 1962. Kapila R, Lintz 01, Tecson FT, Z&kin L, Louda DB: A nosocomial outbreak of influenza A. Chest 1977; 71: 576. Tuxen DV, Cade JF, McDonald MI, Buchanan MRC, Clark FtJ, Pain MCF: Herpes simplex virus from the lower respiratory tract in adult respiratoty distress syndrome. Am Rev Respir Dis 1962; 126: 416. Mathur U, Bentley DW, Hall CB: Concurrent respiratory syncyiial virus and influenza A infections in the institutionalized elderly and chronically ill. Ann Intern Med 1960; 93: 49-52. England AC, Fraser DW, Plikaytis DB, Tsai TF, Starch G, Broome CV: Sporadic legionelbsis in the United States: the first thousand cases. Ann Intern Med 1961; 94: 164. Johanson WG, Pierce AK, Sanford JP, et al: Nosocomial respiratory infections with gram-negative bacilli. Ann Intern Med 1972; 77: 701. Jones R, Barry A, Thornsbeny C, et al: Ceftaziiime, a Pseudomonas-active cephalceporin: in vitro antimicrobial activity evaluation including recommendations for discdiiusion sus-
Auguet
9,1966
The Amerkan
Journal
of Medklns
Vofume
of interest. The molecular structure of ceftazidime is similar to that of cephaloridine. Each has a pyridine side chain at position 3 of the dihydrothiazine moiety. Although cephaloridine has been implicated in antibiotic-induced acute tubular necrosis, no association between the pyridine side chain and renal failure has been documented. Published studies of ceftazidime have not shown an increase in nephrotoxicity in comparison with other cephalosporins
PI. This study provides support for the use of ceftazidime as the sole agent in the treatment of patients with hospitalacquired pneumonias. The conclusions of this article are limited, however, to patients who are not neutropenic.
ce&ibilii 11.
12.
13.
14: 15.
16.
17.
16.
19.
tests.
J Antimkxob
Chemother
1961;
6 (suppl
B):
Bauer AW, Kirby WMM, Sherris JC: Antibiotic susceptibility testing by a standardized single-disc method. Am J Clin Pathol 1966; 45: 493. Trenholme GM, McKellar PP, Riera N, Levin S: Arnikacin in the treatment of gram-negative pneumonia. Am J Med 1977; 62: 949-953. Karakusis PH, Feczko JM. Goodman LJ, et al: Clinical effkxcy ol cefotaxime in serious infections. Antimicrob Agents Chemother 1962; 21: 119-124. Gozzard DI, Geddes AM, Fanell ID, et al: Ceftazidime-a new *extended-spectrum cephalosporin. Lancet 1962; I: 1152. Mandell LA, Nicolle LE, Ronad AR, et al: A multicentre prospective randomized trial comparing ceftazidime with cefazolin/ tobramycin in the treatment of hospitalized patients with nonpneumococcal pneumonia. J Antimicrob Chemother 1963; 12 (suppl A): 9. Francioli P, Clement M, Geroulanos S, et al: Ceftaziiime in severe infections: a Swiss multicentre study. J Antimicrob Chemother 1963; 12 (suppl A): 139. Clumeck N, Laethem YV, Bon% B, Jaspar N, Butzler JP: Use of ceftazidime in the therapy of serious infections, including those due to multiresistant organisms. Antimicrob Agents Chemother 1963; 24: 176. Scully BE, Neu HC: Clinical efficacy of ceftazidime: treatment of serious infection due to multiresistant Pseudomonas and other gram-negative bacteria. Arch Intern Med 1964; 144: 57. Foord RD: Ceftazidime: aspects of efficacy and tolerance. J. Antimicrob Chemother 1963: 12 (suppi A) 399.
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