Aztreonam: Worldwide overview of the treatment of patients with gram-negative infections

Aztreonam: Worldwide Overview of the Treatment of Patients with Gram-Negative Infections

SHARON A. HENRY, M.D. CECIL B. BENDUSH, M.D, Princeton,

New

Jersey

From E.R. Squibb and Sons, Princeton, New Jersey. Requests for reprints should be addressed to Dr. Sharon A. Henry, E.R. Squibb and Sons, P.O. Box 4000, Princeton, New Jersey 08540.

Multicenter trials were conducted to determine the safety and efficacy of aztreonam in the treatment of patients with gram-negative bacterial infections. A total of 2,821 patients were treated; 2,117 received aztreonam and 704 received control antibiotics. All patients were evaluated for safety and 1,180 of those treated with aztreonam and 428 treated with the control drugs met the criteria for efficacy evaluation. The number of patients treated with aztreonam who were evaluable for efficacy and their microbiologic response rates were: urinary tract infections, 443 (82 percent); lower respiratory tract infections, 217 (79 percent); septicemia, 63 (98 percent); skin/ skin structure infections, 136 (88 percent); intra-abdominal infections, 47 (85 percent); postpartum/gynecologic infections, 21 (100 percent); bone and joint infections, 12 (100 percent); acute uncomplicated gonorrhea, 209 (97 percent); and acute uncomplicated cystitis, 56 (84 percent). Adverse reactions were qualitatively similar to those reported for beta-lactam antibiotics, i.e., mild gastrointestinal upset, rash, eosinophilia, or transient increase in hepatic enzyme parameters. There was an apparent lack of adverse effects on kidney, inner ear, and blood coagulation system. The most frequent adverse effect was phlebitis at infusion site (2.4 percent of patients). Superinfections and colonization with new organisms occurred in 9.4 percent of aztreonam-treated patients and in 7.4 percent of control drug-treated patients; only 40 percent of patients in each group, approximately 4 percent of all patients receiving aztreonam and 3 percent of those receiving control antibiotics, required specific therapy for the superinfection. Overall, results indicated that aztreonam is a safe and effective antibiotic in the treatment of aerobic gram-negative infections, when used either as monotherapy or in combination with other antibiotics. Aztreonam is a novel, totally synthetic antibiotic-the first member in a new family of monocyclic, beta-lactam antibiotics, the monobactams. Excellent in vitro activity has been demonstrated against Escherichia coli, Klebsiella, Proteus mirabilis, indole-positive strains of Proteus species, Neisseria gonorrhoeae (penicillinase and non-penicillinase-producing strains), Serratia, Pseudomonas aeruginosa, and Enterobacter species. The antibiotic has no appreciable activity against gram-positive or anaerobic organisms [l-3]. Its spectrum of activity is similar to that of the aminoglycosides, and its activity in vitro is comparable or superior to that of third-generation cephalosporins such as ceftazidime, moxalactam, and cefotaxime [4]. The stability of aztreonam in vitro to plasmid-mediated and chromosomal beta-lactamases has imparted significant activity against multiply drug-resistant strains of Enterobacteriaceae [5,6]. The minimal inhibitory concentration and minimal bactericidal concentration of this antibiotic are similar, a finding of potential clinical significance [4].

February

8, 1985

The

American

Journal

of Medicine

Volume

78 (suppl

2A)

57

AZTREONAM

TABLE

SYMPOSIUM-HENRY

I

Clinical

and BENDUSH

Research

Trials Program

Number of Patients Evaluated Efficacy Indication or Infection

Antibiotic Treatment

Safety

Aztreonam

Aztreonam Control Aztreonam Control 43

130

64

Intramuscular

134

54

213

105

Intravenous -,

209 56

201 45

268 78

264 75

Intramuscular fntramuscular

Open, multi-drug resistant

68

-

Lower respiratory tract Intra-abdominal

98

37

173

72

ia

17

36

30

After delivery and gynecologic Open multisites

13

9

40

38

urinary

tract*

Gonorrhea Cystitis

473

*A subset of patients efficacy. Fifty-seven

-

-

97

-

963

Intravenous or intramuscular Intravenous or intramuscular Intravenous Intravenous or intramuscular Intravenous or intramuscular

was treated with aminoglycosides; eight patients treated and 119 patients treated with aztreonam in that subset

The directed spectrum and potent activity of aztreonam against aerobic gram-negative pathogens, in conjunction with its favorable animal toxicologic and clinical pharmacokinetic profiles, prompted a worldwide evaluation of the drug’s safety and efficacy in a variety of infections. This report presents microbiologic and clinical responses of those patients treated and an assessment of the drug’s safety. PATIENTS

AND METHODS

Patient Population. A total of 2,821 adult patients worldwide were enrolled in multicenter comparative and open noncomparative studies; 2,117 patients received aztreonam and 704 received control antibiotics. Patients with serious gram-negative infections were treated

in multiple-dose

comparative

and

Usual Dosage

Route

78

Serious

noncomparative

studies. Patients with urinary tract, lower respiratory tract, intra-abdominal, and postpartum or gynecologic infections were evaluated in comparative trials. In open trials, patients with the above types of infections as well as those with septicemia, osteomyelitis, septic arthritis, and infections of the skin and skin structures were studied. Clinical trials designed to evaluate the efficacy of aztreonam in the treatment of patients with serious urinary tract infections caused by multiply

Control Drug

1 g three times daily 1 g three times daily 1 g 1 g

with tobramycin were evaluated

Cefamandole

Intramuscular

Cefamandole

Intravenous

Spectinomycin Amoxicillin

Intramuscular Oral

-

0.5 g twice daily-l g three times daily l-2 g three times daily 1 g three times daily l-2 g three times daily l-2 g three times daily

Usual Dosage

Route

1 g three times 1 g three times 2 g 250 mg times -

-

Tobramycin

Intravenous or intramuscular Intravenous

Tobramycin Gentamicin

Intravenous or intramuscular

-

and 13 treated with gentamicin were for efficacy and safety, respectively.

tropenia

(polymorphonuclear

cell

count

below

1 ,000/mm3),

hepatic insufficiency, or history of immediate (anaphylactoid) hypersensitivity reactions to penicillins and/or cephalosporins. Table I presents treatment regimens and total number of patients enrolled. Criteria for Efficacy Evaluation. Response to treatment was considered evaluable if the patient had pretreatment cultures within 48 hours prior to initiation of therapy. Cases in which pretreatment cultures were obtained more than 48 hours

prior

to treatment

were

considered

evaluable

only

ing treatment.

isolated

least

signs and symptoms of infection.

58

February 8, 1985

cephalosporin.

The American Journal of Medicine

for

For urinary tract and moderately severe infections, aztreonam was administered intramuscularly or intravenously at a dosage of 0.5, 1, or 2 g every eight or 12 hours, and, for life-threatening infections, 2 g every six or eight hours. Concurrent use of antibiotics, usually clindamycin, with a spectrum of activity limited to gram-positive and/or anaerobic pathogens was permitted if indicated. Single-dose studies in which patients received 1 g of aztreonam or a control antibiotic were conducted in patients with acute uncomplicated cystitis and uncomplicated gonorrhea. All patients, with the exception of those enrolled in singledose studies, had infections that required hospitalization and antibiotic treatment for a minimum of five days. Generally excluded from study entry were patients with profound neu-

drug-resistant pathogens were also conducted, utilizing an open study design. Pathogens were considered multiply drug-resistant when they demonstrated in vitro resistance to an aminoglycoside and/or to both an aminopenicillin and at or second-generation

three daily

evaluable

in the first specimen

first-

daily

3-5 mgikg per day 3-5 mgikg per day 3-5 nigikg per day -

same pathogen was obtained

one

daily

The

pathogen

had

if the

taken dur-

to be an

aerobic

gram-negative organism susceptible to the assigned study drug in comparative trials or to aztreonam in the open studies.

In addition,

Volume 78 (suppl 2A)

the

patient

had

to exhibit

the

usual

clinical

AZTREONAM

In determining the drug’s ability to eradicate susceptible organisms, if the patient’s infection was caused by more than one susceptible pathogen, the effect on, or eradication of, each pathogen was assessed independently. The microbiologic response also provided a measure of the drug’s effectiveness in treating specific types of infection. In this regard, a patient with infection caused by a single pathogen that was eradicated by antibiotic therapy was considered to have a microbiologic cure, whereas a patient with polymicrobial infection involving two or more susceptible pathogens was considered to have a microbiologic failure unless all of the pathogens were eradicated. Patients who were considered as having microbiologic cures sometimes became reinfected with the same causative organism following therapy (cure with relapse) or a new organism (cure with reinfection). For urinary tract infections, a cure with relapse was considered failure of therapy. Superinfections resulted when culture specimens, taken during therapy from the same site as the original infection revealed a new organism, usually resistant to the treatment antibiotic. For patients with urinary tract infections who were required to have pretreatment pathogen counts of 105/ml of urine or more, microbiologic cure required an organism count of 1 04/ ml or less in urine culture specimens obtained on Days 2 to 4 of treatment and Days 5 to 9 following completion of therapy. In single-dose studies of acute uncomplicated cystitis, microbiologic response was judged on the basis of results of urine culture specimens obtained five to nine days following treatment. Two positive pretreatment blood culture specimens were required to confirm a diagnosis of septicemia. Microbiologic cure of septicemia required two negative blood culture specimens, obtained during and/or following completion of therapy. For all infections other than urinary tract and septicemia, microbiologic cure was judged on the basis of elimination of the original pathogen from specimens obtained on last treatment day and/or during the post-therapy period. If a specimen was unavailable because the infection, e.g., skin infection, pneumonia, had been resolved, the patient was considered microbiologically cured. All patients had a clinical and microbiologic (post-therapy) evaluation within two weeks after the end of treatment. Long-term (six months) follow-up evaluation was requested and obtained in some patients with osteomyelitis/septic arthritis. The patient’s clinical (symptomatic) response to test antibiotic therapy was judged on the basis of the investigator’s assessment of clinical course. Clinical cure required the resolution of all infection signs and symptoms under study. Partial clinical cure indicated a substantial or temporary improvement in these signs and symptoms, and clinical failure indicated the absence of any significant improvement. In this report, clinical cure and partial clinical cure are referred to collectively as favorable clinical response. Unevaluable Patients. Efficacy was not evaluated if pretreatment cultures did not grow a susceptible aerobic gramnegative pathogen, if additional antibiotics active against the causative pathogen were administered concomitantly, if treatment was prematurely discontinued for reasons other than microbiologic or clinical failure, or if culture was not repeated at appropriate time intervals.

February

8, 1985

TABLE

II

SYMPOSIUM-HENRY

Overall Clinical Response

Primary Diagnosis

and BENDUSH

and microbiologic

Number of Evaluable Patients

Favorable Clinical Response* (percent)

Microbiologic Cure (percent)

209

94

97

56

93

84

443

98

82

217

93

79

136

95

88

Single dose Acute, uncomplicated gonorrhea Acute, uncomplicated cystitis Multiple dose Urinary tract infection Lower respiratory tract infection Skin/skin structure infection Postpartum and gynecologic infection In&a-abdominal infection Septicemia Bone/joint infection

21 47 63 12

100

100

87 95

85 98

100

100

*Twenty-five patients were not assigned a clinical response by the investigator. RESULTS In acute uncomplicated cystitis, Escherichia coli was the most frequently isolated pathogen. Eighty-four percent of the isolates were eradicated following a single, 1 g dose of aztreonam. Ninety-seven percent of Neisseria gonorrhoeae strains were eradicated from patients with acute uncomplicated gonorrhea. Microbiologic eradication rates in multiple-dose studies ranged from 65 percent for Pseudomonas species to 100 percent for Hemophilus. The response rates for other organisms, i.e., Enterobacter, Klebsiella, and Serratia, were in the range of 90 percent. The microbiologic cure rates in patients treated with aztreonam (Table II) varied between 79 percent for lower respiratory tract infections to 100 percent for postpartum and gynecologic and bone and joint infections. Table II also depicts the corresponding overall high clinical response rates. Urinary Tract Infections. In comparative trials, patients were randomly assigned to treatment in a two-to-one ratio, and 212 of those who received aztreonam and 75 of those treated with cefamandole were evaluated. The two treatment groups were comparable with respect to type of infection. Approximately 50 percent had recurrent infection and complicating underlying conditions, i.e., structural abnormality or presence of a urethral catheter. Overall microbiologic cure rate was 87 percent for the 212 aztreonam-treated patients compared with 75 percent for the 97 patients treated with cefamandole (p CO.01). The difference is especially noteworthy since none of the patients treated with cefamandole had infections due to Pseudomonas. Incidence of reinfection (i.e., lo5 or more

The

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AZTREONAM

TABLE

SYMPOSIUM-HENRY

III

and BENDUSH

Microbiologic Eradication Rates by Pathogen: Urinary Tract Infections in Comparative Studies Cefamandole

Aztreonam

Pathogen Escherichia Klebsiella Proteus Pseudomonas

Number 1371157 32136 29131 15124

Percent a7 89 94 63

Number

Percent

50166 8110 10/14

76 80 71 -

colony-forming units of a new organism in five- to nine-day post-therapy culture) was 6 percent for aztreonam and 14 percent for cefamandole. Table Ill depicts the comparative eradication rates for pathogens isolated from patients treated with aztreonam and those treated with cefaman‘dole. Favorable clinical response was ach.ieved in 99 percent of patients with both treatment regimens. A total of 106 other patients in an open study of urinary tract infections had an overall microbiologic cure rate of 70 percent, with reinfection occurring in 7 percent, and a favorable clinical response occurring in 97 percent. Fiftyseven percent of patients had upper urinary t&t involvement and 64 percent had underlying complicating factors. An additional 68 patients with infections due to mukiply drug-resistant pathogens were evaluated for response to aztreonam therapy. Fifty-four percent had recurrent infection, and underlying complicating factors were present in 85 percent. Eighty-eight percent were microbiologically cured. Relapse occurred in one patient, reinfection in three, and 95 percent had a favorable clinical response. Overall, 83 percent of 470 pathogens isolated from all patients with serious urinary tract infections were eradicated following multiple-dose therapy. Fifty of the 470 pathogens were isolated from patients with infeCtions caused by multiple drug-resistant organisms. Microbiologic eradication was achieved for 87 percent (34) of P. aeruginosa isolates, 100 percent (eight) of Enterobacter species, and 89 percent (eight) of E. coli isolates. TABLE

IV

Microbiologic Eradication Rates by Pathogen: Lower Respiratory Tract Infections in Comparative Studies

Aztreonam Pathogen Enterobacter Escherichia Hemophilus Klebsiella Proteus Pseudomonas Serratia

60

Tobramycin

Number

Percent

Number

Percent

11113 20121 12112 24125 717 20129 515

85 95 100 96 100 69 100

717 516 818 819 317 6/l 2 II2

100 83 100 89 43

February 8, 1985

The American Journal of Medicine

2

Overall microbiologic cure rates were 84 percent and 93 percent, respectively, for 47 patients with acuje uncomplicated cystitis treated with a single 1 g intramuscular dose of aztreonam and 42 who received a IO-day course of amoxicillin 250 mg orally three times daily. In this comparative study, reinfection rates were comparable for aztreonam and a!noxicillin, 9 and 10 percent, respectively. Favorable clinical response was achieved in 93 percent of aztreonam-freated patients and in 97 percent of those receiving amoxicillin. Lower Respiratory Tract Infections. In comparative trials, 98 aztreonam-treated patients and 37 tobramycintreated patients were evaluated (two-to-one random treatment assignment ratid). Pneumonia was present in 90 percent of those who received aztreonam and in 89 percent of those receiving tobramycin. Patient demographics were similar, with a mean patient age of 67 years and comparable sex ratio for both groups. Underlying conditions predisposing to development of pulmonary infection, e.g., emphysema, chronic bronchitis, congestive heart failure, pulmonary neoplasm, need for mechanical ventilatory assistance, were present in 61 percent of patients treated with aztreonam and in 70 percent of those who received tqbramycin. The.microbiologic cure rate was 86 percent with aztreonam and 73 percent with tobramycin. The reinfection rate and relapse rate were both 4 percent with aztreonam, and 5 percent and 3 percent, respectively, with tobramycin. Table IV presents the microbiologic eradication rates achieved in comparative studies. Favorable clinical response was observed in 94 percent of those who received aztreonam and in 77 percent who received tobramycin. In open studies, 119 patients with gram-negative pulmonary infections were evaluated for their response to aztreonam. Eighty-six of them (72 percent) had pneumonia. Underlying conditions predisposing to infection included emphysema (32 percent), chronic bronchitis (32 percent), bronchiectasis (17 percent), congestive heart failure (16 percent), pulmonary neoplasm (2 percent), and the need for mechanical ventilation (1 percentj. Ten additional patients had cystic fibrosis. The microbiologic cure rate for all patients was 73 percent. Reinfection occurred in 3 percerit and relapse in 9 percent, and a favorable clinical response occurred in 92 percent. Overall, therapy with aztreonam resulted in eradication of 81 percent of 255 pathogens. Intra-Abdominal Infections. Forty-seven patients with in&a-abdominal infection were evaluated for response to aztreonam. Twenty-one participated in the open studies and 18 in the comparative trial. Many had “mixed” infections caused by two or more pathogens; thus, clindamycin was frequekitjy used for anaekobic coverage. In comparative trials, 18 patients receiving aztreonam and 17 receiving tobramycin were evaluated. The intraabdominal infections were peritonitis, treated with aztre-

Volume 78 (suppl 2A)

AZTREONAM

onam in 11 patients and with tobramycin in 11; abdominal infection (not otherwise specified), treated with aztreonam (six) and tobramycin (four); peritonitis and a perforated appendix, treated with aztreonam (one) and tobramycin (two). The overall microbiologic cure rates were 83 percent and 65 percent for those treated with aztreonam and tobramycin, respectively. Table V presents the comparative pathogen eradication rates. Favorable clinical responses were obtained in 78 percent and 88 percent of the aztreonam-treated and tobramycin-treated patients, respectively. In the open study, infections included intra-abdominal abscess in seven patients; peritonitis plus intra-abdominal abscess in five; peritonitis in four; cholecystitis in two; and other intra-abdominal infections with or without wound infections in three. Overall microbiologic cure rate was 81 percent. No cases of reinfection or relapse occurred with any of the treatment regimens; 93 percent of patients responded favorably. Therapy with aztreonam resulted in microbiologic eradication of 88 percent of 67 pathogens isolated from all patients. Postpartum and Gynecologic Infections. Response to aztreonam was assessed in 21 patients, 13 of whom participated in comparative drug trials, and eight in open studies. Response to treatment with the control drug gentamicin was evaluated in nine patients. Endometritis precipitated by cesarean section was the most common infection, accounting for 15 of 21 (71 percent) cases treated. Other infections included pelvic inflammatory disease (three cases), and pelvic abscess, endoparametritis, and vaginal cuff cellulitis (one case each). Overall microbiologic cure rate was 100 percent. Microbiologic cure rate was 78 percent for the nine patients treated with gentamicin in the comparative studies, of which eight patients had endometritis, and one had pelvic inflammatory disease. All 26 pathogens isolated from 21 patients treated with aztreonam were eradicated. Comparative eradication rates for aztreonam and gentamicin are shown in Table VI. Favorable clinical response was achieved in 100 percent of those treated with aztreonam and in 67 percent of those treated with gentamicin. Relapses and reinfections did not occur. Skin/Skin Structure, Infections. There were 136 patients with a variety of skin infections: 48 with cellulitis, 35 with wound infections, 11 with cutaneous abscess, 13 with burn wound infections, nine with ulcers, and 23 with miscellaneous unspecified infections. Overall microbiologic cure rate was 88 percent. Ninety-one percent of 185 pathogens were eradicated, and for the predominant pathogens, the microbiologic eradication rates were 83 percent (58) for P. aeruginosa; 90 percent (31) for P. mirabilis; 93 percent (27) for E. coli; 94 percent (17) for Enterobacter

February

8, 1985

TABLE

V

SYMPOSIUM-HENRY

and BENDUSH

Microbiologic Eradication Rates by Pathogen: Aztreonam versus Aminoglycosides in Intra-Abdominal Infections

Pathogen

Aztreonam

Tobramycin

lOill 313 414 515 314 011 l/l

IO/15 2l3 515 0 112 0 111

Escherichia Proteus Klebsiella Enterobacter Pseudomonas Citrobacter Serratia

species; 92 percent (13) for K. pneumoniae; 100 percent (11) for Serratia marcescens; and 100 percent (seven) for Citrobacter species. Microbiologic relapse occurred in one patient. Favorable clinical response was achieved in 95 percent of all patients treated. Bone and Joint Infections. Microbiologic cure and favorable clinical response were achieved in all 12 patients treated with aztreonam: five with osteomyelitis, seven with septic arthritis. The pathogens eradicated inciuded: seven P. aeruginosa, two E. coli, one Enterobacter cloacae, one K. pneumoniae, one P. mirabilis, one S. marcescens, and one Hemophilus species. Relapse occurred in two patients with osteomyelitis. One of them had a polymicrobial infection caused by E. coli and Pseudomonas and had relapse of E. coli infection 15 days after completion of treatment. The second patient had an E. cloacae infection and had relapse approximately six months after completion of treatment. There were no reinfections. Septicemia. Efficacy of aztreonam in the treatment of septicemia caused by aerobic gram-negative pathogens was evaluated in 66 patients. The most common source of septicemia was the urinary tract. Microbiologic cure was achieved in 98 percent of patients. Microbiologic eradication was achieved for 97 percent of the 74 clinical isolates, which included 100 percent (28) of E. coli, (five) P. mirabilis, (seven) P. aeruginosa, (five) Enterobacter species, and 91 percent (11) of K. pneumoniae. None of the patients had microbiologic relapse, and reinfections developed in two. Favorable clinical response was achieved in TABLE

VI

Microbiologic Eradication Rates by Pathogen: Aztreonam versus Aminoglycosides in Post-Delivery and Gynecologic Infections

Pathogen

Aztreonam

Escherichia Klebsiella Proteus Enterobacter Pseudomonas

The American

-

616 616 414 212 l/l

Journal

of Medicine

Volume

-

Gentamicin 515 113 213 0 Oil

78 (suppl

2A)

61

AZTREONAM

SYMPOSIUM-HENRY

TABLE VII

and SENDUSH

Microbiologic Response of Acute Uncomplicated Go?orrhea* Infection Number of Patients*

Females Aztreonam Cure Failure Spectinomycin Cure Failure Males Aztreonam Cure Failure Spectinomycin Cure Failure ‘Patients

Urethra

Cervix

57 0

80 0

12 0

1 0

81 0

100

53 1

85 3

8 2

0 1

86 4

96

-

2 1

0 1

121 7

95

4 0

4 0

108 3

97

128 122 5

-

111

-

106 2 at one or more

-

Rash Nausea Diarrhea Miscellaneous gastrointestinal Local reactions

Mreonam (n = 1,771)

Control (n = 370)

1.5 0.8 0.7 0.3

1.4 1.4 0.5 -

2.4

-

in percent.

February

Number

Percent

sites.

Aztreonam Safety in Multidose Studies*

Reaction

62

Pharynx

90

61 of 64 (95 percent) patients (clinical response was not reported by the investigator for two patients). Acute Uncomplicated Gonorrhea. A total of 410 cases of acute uncomplicated gonorrhea were evaluated. Twohundred nine patients (81 women, 128 men) were randomly assigned to receive treatment with a single 1 g intramuscular dose of aztreonam and 201 (90 women, 111 men) received a single 2 g intramuscular dose of spectinomycin. Sites of infection and microbiologic response rates are shown in Table VII. Thirty men treated with aztreonam and 27 treated with spectinomycin had infections from penicillinase-producing strains of N. gonorrhoeae, and in all of these patients, the organism was eradicated. No woman had infection due to penicillin-resistant strains. A favorable clinical response occurred in 94 percent of patients treated with either aztreonam or spectinomycin. Aztreonam administered intramuscularly was well tolerated. Safety. Safety was evaluated in all 2,821 patients who received either aztreonam (2,117) or a control drug (704). Clinically apparent adverse effects reported by the investi-

*Numbers

Rectum

with Eradication

81

with infections

TABLE VIII

Patients

Site

6, 1965

The American

Journal

of Medicine

Volume

gator as related or possibly related to therapy were analyzed. In addition, laboratory test results obtained during or following treatment with study drugs were analyzed for occurrence of significant changes (marked deviations) when compared with the normal value for the investigator’s laboratory or the patient’s pretreatment (baseline) value. Adverse Reactions. In single-dose studies, 346 patients were treated with aztreonam. and 339 were treated with control drugs. Seventy-five of the patients were treated with amoxicillin for 10 days, 264 with spectinomytin. Adverse reactions were reported in six of 339 (1.7 percent) aztreonam-treated patients, nine of 75 (12 percent) receiving amoxicillin, and two of 264 (0.8 percent) treated with spectinomycin. There were three reports of nausea and vomiting and four of miscellaneous reactions with aztreonam; two reports of rash, two of diarrhea, one of nausea and vomiting, and five of miscellaneous other reactions observed with amoxicillin. There was one case of rash and one of local reaction at the injection site reported with spectinomycin. In multiple-dose studies, the incidence of adverse reactions was evaluated in 1,771 patients treated with aztreonam and in 370 treated with the control drugs cefamandole, gentamicin, and tobramycin. The results are presented in Table VIII. Pain and phlebitis at the intravenous injection site occurred in 2.4 percent of aztreonam-treated patients. The incidence compares favorably with the 5 to 40 percent incidence of venous irritation reported with cephalosporins [6]. Rash occurred in 1.5 percent of patients treated with aztreonam, comparable to the incidence with control drug therapy. A history of allergy to penicillin and/or cephalo-

76

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AZTREONAM

sporins was present in 134 of 2,117 patients treated with aztreonam and, of these, only one patient (0.7 percent) had a possible IgE-mediated urticariai rash, thought to be a hypersensitivity reaction. Diarrhea occurred in less than 1 percent of patients during either aztreonam or control drug therapy. One case of Clostridium difficile-associated diarrhea occurred in an aztreonam-treated patient, who had received previous antibiotic therapy. Laboratory Test Results: Marked Deviations. Incidences of marked deviations in hematologic parameters (hemoglobin, hematocrit) were comparable, approximately 7 percent for aztreonam and the control antibjotics cefamandole and aminoglycosides. However, in the comparative studies, which utilized cefamandole as the control drug, eosinophilia occurred more frequently in the control group. Incidence of marked deviations in eosinophil counts was approximately 11 percent for aztreonam and 20 percent for cefamandole. Table IX shows the incidence of marked deviations in selected clinically important laboratory results (serum creatinine, hepatobiliary, and coagulation parameters). Incidence of elevated hepatic transaminases in aztreonam-treated patients was similar to that for control drugs and to that reported in the literature for other beta-lactam antibiotics [7]. The incidence of marked elevations of liver function test results in aztreonam-treated patients was similar to that for control drugs. Generally, in comparative studies, elevations in the range of two to three times the upper limit of normal or baseline were in the range of up to 4 to 6 percent for aztreonam and control, and the values tended to return to or toward baseline during or after treatment. The incidence of patients with marked elevations of serum creatinine, defined as an increase of 0.5 mg/dl or greater if the entry value was 3 mg/dl or less, in association with aztreonam therapy (5 percent) was significantly lower than that with control aminoglycosides (13 percent) and was comparable to that observed with cefamandole (7 percent). Discontinuation of Therapy. Overall incidence of patients for whom therapy was discontinued for adverse reactions in aztreonam multidose studies was approximately 2 percent, usually due to rash. Superinfections. Superinfections (i.e., the finding of organisms other than the original pathogen at infection site during the course of antibiotic therapy) were noted in 1,771 (9.7 percent) of the aztreonam-treated patients and in 365 (7.4 percent) of the control-treated patients. Only approximately 40 percent of patients in each group required specific therapy. In the aztreonam group, the most common organisms identified were enterococci, and in the control group, gram-negative organisms were the most common. Pseudomonas species accounted for 41 percent of the superinfecting organisms.

February

8, 1985

SYMPOSIUM-KENRY

and BENDUSH

The effectiveness and safety of aztreonam were evaluated in patients with a wide variety of aerobic gram-negative infections. Overall clinical and microbiologic response rates were in the range of 90 to 100 percent and 80 to 100 percent, respectively. In comparative aztreonam clinical trials, microbiologic cure rates achieved with aztreonam were similar to those achieved with cefamandole, spectinomycin, amoxicillin, tobramycin, and gentamicin. Overall microbiologic eradication rate for all pathogens was 66 percent. infections due to P. aeruginosa are particularly difficult to treat, and aztreonam therapy resulted in a microbiologic eradication rate of 69 percent, which is similar to the historic response rate for other anti-Pseudomonas drugs such as the aminoglycosides [8]. Overall incidence of adverse reactions and marked deviations in laboratory test parameters (including hepatobiliary and coagulation test results) reported with administration of aztreonam were generally low. Findings were comparable to those observed in the control groups with the exception of serum creatinine values. Significantly more patients treated with aminoglycosides had increased serum creatinine levels indicative of nephrotoxicity. Potential for nephrotoxicity and ototoxicity with aminoglycosides, however, has been well established. In a study of 3,370 patients treated with gentamicin, the reported incidence of drug-related renal toxicity was 4.1 percent and incidence of ototoxicity was 2.4 percent [9]. A similar incidence of ototoxicity (2.3 percent) with gentamitin administration was reported in another publication [I 01; no ototoxicity was reported with administration of aztreonam. Prior to initiation of the extensive clinical trials described herein, the potential for subclinical renal injury with aztreonam was assessed. Sensitive tests, including urinary excretion of N-acetyl-P-glucosaminidase, alanine amino peptidase, and beta*-microglobulin, as well as serum creatinine and urinary creatinine clearance determinations were conducted in normal volunteers, and the results Of these tests were within normal limits. In conclusion, aztreonam has been effective treatment for a variety of infections caused by susceptible aerobic gram-negative pathogens, ranging from acute uncomplicated cystitis to serious complicated urinary tract infections: lower respiratory tract infections, including pneumonia; septicemia; bone and joint infections; intra-abdominal infections, including peritonitis; gynecologic infections; and acute gonorrhea1 infections. Adverse effects were infrequent and comparable to control agents with the dosage regimens employed. Aztreonam appears to be a useful new antibiotic with a side-effects profile similar to other beta-lactam antibiotics.

The American

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78

(suppl 2

AZTREONAM

SYMPOSIUM-HENRY

and BENDUSH

REFERENCES 1.

2.

3.

4.

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