Aztreonam in the treatment of serious orthopedic infections

nfe

ztreonam in the Treatment of Serious

C. PRIBYL, M.D. R. SALZER, M.D. J. BESKIN, M.D. R. J. HADDAD, M.D. B. POLLOCK, B.S. R. BEVILLE, A.B. B. HOLMES, B.A. W. J. MOGABGAB, M.D. New

Orleans,

Louisiana

Aztreozam was evaluated in the treatment of a variety of orthopedic infections. Included were 17 patients with osteomyelitis, three with purulent arthropathy with prostheses, and 16 with superficial infections secondary to trauma or surgical procedure. Pathogens were gram-negative bacilli sensitive to aztreonam. Concomitant antibiotics were administered for gram-positive cocci that were present initially or by superinfection. Infecting organisms included Pseudomonas aeruginosa (minimal inhibitory concentration 4 to 16 pglml), Serratia marcescens, Enterobacter cloacae, Enterobacter sakazakii, Morganella morganii, Citrobacter freundii, Proteus vulgaris, Proteus rettgeri, Acinetobacter calcoaceticus and others (all with minimal inhibitory concentrations less than 1 Xl lug/ml). Dosage of aztreonam was 2 to 8 g per day administered intravenously or intramuscularly for five to 52 days. Clinical and bacteriologic responses were adequate in all instances. Recurrences were observed in two individuals with osteomyelitis and one with purulent arthropathy. Adverse clinical or laboratory observations were infrequent and ineonsequential. Several types of infections, such as infections of the bone, which are secondary to traumatic fractures; of the joints, which are frequently associated with prostheses; and of superficial structures, which can be quite extensive and often result from trauma or surgery, present special medical management problems [l-6]. The degree of tissue damage and the resulting decrease in vascularity usually demand a prolonged course of antibacterial therapy [4,6]. In addition, invasion by gram-negative bacilli frequently occurs in these patients [6,7]. Treatment of these infections may be difficult because of the development of antibiotic resistance during prolonged therapy. Antibiotics such as the aminoglycosides can be hazardous due to the high incidence of serious adverse side effects [8]. The new monobactam, aztreonam, has been shown to be particulariy well suited to these problems. It is effective against difficult gram-negative bacilli, is associated with a low incidence of adverse side effects, even with prolonged use 191, and can be administered either alone or in combination with other antibiotics. The efficacy of aztreonam in the treatment of serious gram-negative orthopedic infections was evaluated in a study conducted at Charity, Veterans Administration, and Tulane Medical Center Hospitals in New Orleans from 1982 to 1984.

From the Section of infectious Disease, Department of Medicine. Tulane Universitv School of Medicine, New Orieans, Louisiana. Requests for reprints should be addressed to Dr. W. J. Mogabgab, Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112.

PATIENTS AND METHODS Patients with bone, joint, and superficial infections ranging from ulcerations to deep infected wounds and from purulent arthritis to osteomyelitis took part in the trial. Infections were due to aztreonam-sensitive, gram-negative bacilli as the sole or participating pathogen. Gram-positive cocci, when present, were

February

8, 1985

The

American

Journal

of Medicine

Volume

78

(suppl

24

51

Age/S&x

37iM

25/M

38/M

42/M

60/M

43/M

43/M

61/F

56/M

59lM

61/F

18iM

I

TABLE

Patient

1

2

3

4

5

6

7

8

9

IO

11

12

Tibia (fracture)

(gunshot) Tibia

Site (Cause)

with

(open

Tibia fracture)

Femur

Humerus (fracture)

Treated

x-ray

x-ray,

x-ray

biopsy

Biopsy, clinical

Biopsy, scan

Scan,

Scan

Bone

Scan

Biopsy,

X-ray

Scan

Sequestrectomy x-ray, biopsy Bone biopsy

X-ray

Conficmation

Osteomyelitis

Femur (pathologic fracture, infection)

Fingertip Waft)

Tibia (fracture)

Hip (Girdlestone)

Hip (Girdlestone mid-treatment) Femur, stump

Patients

years

6 weeks

2-3

15 months

1 month

2 years (open fracture) 4 months

8 months

1 month

2 weeks

2 weeks

3 years

1 month

Duration

with

Bone -biopsy

Aspirate

Bone biopsy

Surgical

Bone biopsy

Bone biopsy

Bone biopsy

Pus

Pus

biopsy Bone

Culture Source

Aztreonam

Escherichia coli, Morganella morganii, Proteus mirabilis Enterobacter cloacae, Staphylococcus aureus

Pseudomonas aeruginosa, Serratia marcescens Klebsiella pneumoniae, Pseudomonas aeruginosa Serratia marcescens

Pseudomonas aeruginosa

Pseudomonas aeruginosa, Enterobacter cloacae Klebsiella pneumoniae

Serratia marcescens Proteus mirabilis Pseudomonas aeruginosa, Citrobacter freundii Serratia marcescens

Organism

>I6

025

0.01

0.02

0.06

0.125

8.0

0.30

.0.125

4.0

>16

6

8

8

6

3

6

8

26

50

11

10

8

6

37

4

3

1 .o 0.06

8

30

41

9

9

Duration (days)

6

8

8

2

3

Dose (g)

16.0

0.5

0.125

4.0

0.007

0.125

MIG Wml)

Treatment

Nonevaluable 14

37

8

5

9

Nonevaluable

7

7

9

11

8

4

Day Culture Negative

Satisfactory

None

Above-knee amputation Day 22

Fair

Satisfactory

Satisfactory

Nonevaluable

Satisfactory

Satisfactory

Satisfactory

Satisfactory

Satisfactory

Satisfactory

Response

on

4 (poor)

16

1

24

3

Nonevaluable

2

24

20

Followup (weeks) bone

Concomitant cefazolin, nafcillin

Enterococcus on Day 8, Serratia marcescens on Day 5 aftertherapy Doing well

Transferred

Also nafcillin for prior Staphylococcus aureus Organism from superficial culture was sensitive Doing well

Staphylococcus aureus at 3rd week of nafcillin therapy Acinetobacter calcoaceticus after therapy, resistant Infection after knee prosthesis

Recurrence

Healing

Comments

AZTREONAM

ET AL

treated concomitantly with appropriate antibiotics. Patients ranged in age from 18 to 73 years. Infection in some of the younger patients and in most of the older patients was complicated by serious concomitant illnesses such as diabetes mellitus, alcohol or drug abuse, or pulmonary, cardiovascular, hepatic, or renal disease. Many of the participating patients had previously failed to respond to such traditional antibiotic therapy as penicillins, cephalosporins, and aminoglycosides. Potential subjects were excluded from the study if they had a history of allergy to penicillin, a positive pregnancy test result, or prior effective treatment with an antibacterial agent, or if their infecting organism proved resistant to aztreonam in vitro. All patients were hospitalized for the duration of treatment. Radiography was used as needed, with clinical monitoring on a daily basis before, during, and after the treatment period until either recovery or stabilization was achieved. The following laboratory determinations were made before, at weekly intervals during, and at the end of therapy: wound cultures, blood cultures, complete blood cell count with differentials, promthrombin and partial thromboplastin times, urinalysis, serum glucose, blood urea nitrogen, creatinine, sodium, potassium, carbon dioxide, calcium, phosphorus, total protein, albumin, alkaline phosphatase, lactate dehydrogenase, serum glutamic-oxaloacetic transaminase, serum glutamicpyruvic transaminase, total bilirubin, and cholesterol levels, and direct and indirect Coombs’ tests. Aerobic culture specimens were obtained by swab, aspiration, or bone biopsy, and anaerobic specimens by deep aspiration through intact skin or tissue and inoculated into an appropriate transport medium. Eoth aerobic and anaerobic blood specimens were collected, and swabs or aspirates were streaked onto 5 percent sheep blood agar plates and incubated at 37.5%. Colony counts were made whenever possible. Disc sensitivity was determined by a modified Kirby-Bauer technique, and minimal inhibitory concentration of aztreonam was determined in Mueller-Hinton agar dilution by spotting 106.0 colony-forming units with a 0.001 ml platinum loop. Aztreonam was administered as a 1 to 2 g intravenous dosage every six, eight, or 12 hours; as a 30-minute infusion; or as a 1 g intramuscular dosage every six, eight, or 12 hours. Additional antibiotics were given for concurrent gram-positive coccal infections as needed. Length of aztreonam therapy varied with type and severity of infection but was minimally five days. Osteomyelitis and infected joints with prostheses were generally treated for a month or longer. Patient Characteristics. A total of 36 patients took part in the study. Features of the 17 patients with relatively longstanding osteomyelitis, including the specific infecting organism for each patient, are given in Table I. The majority of these patients acquired nosocomial infection secondary to trauma, as confirmed by culture of drainage or bone biopsy specimen. These patients with osteomyelitis ranged in age from 18 to 61 years (average age 46), their aztreonam dose ranged from 2 to 8 g per day (average 6.3), and their duration of therapy ranged from four to 50 days (average 21.3). Three patients underwent therapy for purulent arthropathy secondary to joint replacement (Table II). Two of three were

co

P

0 B 9 iri co

CD

February

SYMPOSIUM-PRIBYL

8, 1985

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of Medicine

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78

(suppl 24

53

A7XlEONAM

TABLE

SYMPOSIUM-PRIBYL

II-

Purulent

ET AL

Arthritis

Treated

with Aztreonam Treatment Day

Patient

Age/Sex

Site

41/F

18

19

Hip

60/M

Knee

47/M

20

infected

with

Knee

more

than

Cause

Organism Pseudomonas aeruginosa Klebsiella pneumoniae Morganella morganii Proteus mirabilis Pseudomonas aeruginosa (same 2 years prior therapycefsulodin

Total hip arthroplasty

Prosthetic replacement (3 months

prior)

Surgical replacement

one

organism.

MIC (baml)

In these

4.0

0.015

8.0

individuals,

RESULTS Patients with Osteomyelitis. Among the patients with osteomyelitis, Pseudomonas, Serratia, Klebsiella, and Enterobacter werk the most common organisms isolated. Analysis of individual patient response revealed that aztreonam was effective in treatment of susceptible infecting organisms in all patients (Table I). Fourteen of 17 patients in this group became culturenegative within 14 days of starting therapy with aztreonam. One individual (Patient 7) initially demonstrated a sensitive Pseudomonas, but culture of a bone sample obtained during surgery yielded a Pseudomonas with a minimal inhibitory concentration of greater than 16 pgiml. This information prevented an erroneous designation of therapeutic failure. Thirteen patients were cured of their original gram-negative bacterial infection, but superinfections developed later in two (Patients 3 and 4), and, in two others (Patients 2 and lo), recurrences developed at five days and six months, respectively. Patient 6 had a Staphylococcus infection in addition to his Klebsiella pathogen. This 43-year-old man suffered head injuries when a tree

8, 1985

The American

Journal

of Medicine

Culture Negative

4

12

3

Response

New infection group G Streptococcus at I month

Impaired

Recurrence of Proteus mirabilis at 2 weeks, above knee amputation 2 weeks after therapy for Staphylococcus aureus

8 6

52

14

3

15

7

Volume

Comments

Satisfactory

0.015

14.5).

February

Duration (days)

0.60

age ranged from 41 to 61 years (average 49), dose ranged from 3 to 6 g per day (average 4.3), and duration of therapy ranged from 12 to 52 days (average 26.3). The remaining 16 patients had serious infections of superficial structures. As can be seen in Table Ill, the identity of the infecting organisms,. as well as type of injury and associated illness, was indicative of the difficulty in treating them. These patients ranged from 18 to 73 years of age, (average 44), aztreonam dose ranged from 2 to 6 grams per day (average 3.4), and duration of therapy was five to 32 days (average

54

Dose (9)

Satisfactory

landed on his hip. Although his hip did not appear to be injured, subsequently, radiography and gal&m scanning showed osteomyelitis in the hip. Needle aspiration yielded Staphylococcus aureus and then P. aeruginosa. He was treated with second-generation cephalosporins and then cefsulodin. At that time, the bone biopsy specimen contained K. pneumoniae, and therapy was changed to aztreonam. At the end of a week, the infection had responded to the aztreonam, and at six-month follow-up, he remained free of infection. Purulent Arthropathy. All three of the patients with infected total joint prostheses improved clinically (Table II). Although superinfections with other, gram-positive pathogens developed in two patients, their original Pseudomonas infections were effectively eradicated. The third (Patient 19) had an early recurrence two weeks’ after cessation of aztreonam and%ultimately underwent an above-knee amputation (see Patient 5 in Table I). In this 60-year-old man, septic arthritis of the knee led to a total knee replacement in the spring of 1983. Three months later, he presented with a hot, swollen knee, pus drainage, and dehiscence of the surgical wound. He was treated first with apalcillin and then with aztreonam. An above-knee amputation was performed. The stump then became infected with the same organisms as before (P. aeruginosa and E. cioacae). Aztreonam therapy was started again and the infection was cured., Superficial Infections. Despite the kinds of organisms causing these infections, all patients with skin and skin structure or superficial infections improved clinically and became culture-negative. Concomitant antibiotics were necessary in only two instances (Patients 25 and 34). It was particularly interesting that invasions of P. aeruginosa

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AZTREONAM

TABLE

III

Superficial

Infections

Treated

SYMPOSIUM-PRIBYL

ET AL

with Aztreonam Treatment

Site and Type

Cause

Organism

MIC hml)

Dose (9)

Duration (days)

Day Culture Negative

Patient

Age/Sex

21

71/F

Hip cellulitis

Hip replacement

Serratia marcescens

0.125

2

8

11

22

73/M

Aboveknee stumps

Wounds

1.0

3

7

7

Arm

Wound, trauma

Proteus morganii, Enterobacter aerogenes Pseudomonas aeruginosa, Klebsiella pneumoniae Proteus vulgaris, Proteus morganii Pseudomonas aeruginosa, Proteus morganii Serratia marcescens Acinetobacter calcoaceticus Proteus vulgaris Pseudomonas aeruginosa Pseudomonas aeruginosa, Serratia marcescens Pseudomonas aeruginosa Providencia rettgeri, Staphylococcus epidermidis, Enterobacter cloacae Pseudomonas aeruginosa, Staphylococcus aureus, Serratia marcescens

3

16

13

3

28

19

3

24

0.125

3

8.0

23

24

25

18iM

68/M

64lM

26

35/M

27

60lM

28

47/M

29

52lM

30

32/M

31

23lM

32

62/M

Aboveknee stump

Wound

Hip (ORIF)

Wound, Richards screw

Middle finger Elbow ulcer Heel Ear concha Tibia

Leg wound Leg wound

Wound

arthritis Cast abrasion Laceration, graft Trauma

Trauma Trauma

33

32/M

Thigh

Gunshot

34

16/M

Leg

Trauma

35

39/F

Thigh

Trauma

36

30/F

Hip

Trauma

Pseudomonas aeruginosa Pseudomonas aeruginosa, Enterobacter cloacae

February

Response

Comments

Satisfactory

Staphylococcus aureus Day 4 after therapy

Improved

8.0 8.0

Satisfactory

Arm amputated during therapy

7

Satisfactory

Staphylococcus aureus Day 7, cephapirin added

IO

10

Satisfactory

Serratia marcescens

3

5

4

Satisfactory

0.007

2

7

7

Satisfactory

8.0

6

9

6

4.0

3

9

a

8.0

3

19

22

Satisfactory

0.02

8

32

7

Satisfactory

0.03 0.008 0.015 4.0 0.015

Satisfactory

0.125

>16

22

0.5

3

9

5

Satisfactory

4.0

6

24

8

Improved

Nonevaluable 7

>16 0.125

8.0

6

14

13

Satisfactory

8.0

6

12

6

Satisfactory

>I6

8, 1985

Concomitant cefazolin

Concomitant nafcillin, vancomycin; 4-month recurrencePseudomonas aeruginosa

6

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AZTREONAM

SYMPOSIUM-PRIBYL

ET AL

with minimal inhibitory concentration levels as high as 4 to 16 ,ug/ml were eradicated as easily as were other gramnegative bacilli with minimal inhibitory concentration levels less than 1.O ,ug/liter. More than two weeks of aztreonam therapy was necessary only in four patients. Adverse Reactions. There were very few complications or adverse side effects associated with aztreonam therapy. Only two patients had to be withdrawn from therapy due to adverse reactions. A rash and eosinophilia developed in one patient on the fourth treatment day. When treatment was stopped, both the rash and the eosinophilia resolved quickly. Fever and anemia, secondary to multiple surgical procedures, developed in the second patient. Aztreonam therapy was stopped and blood transfusions given, and the patient quickly became afebrile. Three patients had transient elevation of their liver enzyme levels and one patient had elevated uric acid levels; all resolved spontaneously after the usual course of therapy. COMMENTS Orthopedic infections caused by gram-negative organisms are frequently difficult to treat because of resistance to many antibiotics and the necessity for prolonged therapy [4-6,8]. A fine line exists between adequate dose and increased risk of adverse side effects and between sufficient duration of treatment and development of resistant

organisms [8,10]. Inaccessibility of the site of infection to adequate antibiotic levels is frequently the basis of the problem. In this short-term study, the majority of patients were cured of their gram-negative bacterial infections by aztreonam. It was not surprising that the highest percentage of cures (100 percent) occurred in those with superficial and so% tissue infection. What was unexpected, and was of considerable interest, was that aztreonam proved effective in the management of all types of infection due to P. aeruginosa. With the inclusion of cases of osteomyelitis and purulent arthropathy with prostheses, the high rate of success achieved was not anticipated. The absence of serious adverse side effects provides a strong recommendation for the use of aztreonam in situations similar to those presented herein, in which doses must be high and treatment periods prolonged. In order to appreciate the full potential of this unique antibiotic, adequate bacterial information must be obtained prior to and throughout the course of treatment. If, in addition to gram-negative bacilli, there are gram-positive pathogens, appropriate concomitant therapy can be administered. In patients receiving long-term treatment, superinfection with gram-positive cocci can be expected in some instances. This, too, can be handled easily with an appropriate antibacterial agent.

REFERENCES 1.

2.

3.

4.

5.

56

Mogabgab WJ, Haddad R-J, Longnecker SL, et al: Third-generation beta-lactam antibiotics for treatment of orthopedic infections. Clin Ther 1982; 5: 21-33. Chapman SW: Osteomyelitis. In: Reese RE, Douglas RG, eds. A practical approach to infectious diseases. Boston: Little, Brown, 1983; 615-640. Roberts NJ: Joint infections. In: Reese RE, Douglas RG, eds. A practical approach to infectious diseases. Boston: Little, Brown, 1983; 595-614. Cierny G, Mader J: Adult chronic osteomyelitis. In: Reese RE, Douglas RG, eds. A practical approach to infectious diseases. Boston: Little, Brown, 1983; 1557-l 564. Cierny G, Mader J: The surgical treatment of adult osteomyelitis. In: Evarts CMc, ed. Surgery of the musculoskeletal sys-

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6, 1965

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Journal

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8. 9.

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tern, voi 4(10). New York: Livingston, 1983; 15-35. Bucholz HW, von Foester G, Heinert K: Management of infected prostheses. Orthopedics 1984; 7: 1620-l 625. Mogabgab WJ: Treatment of skin and soft-tissue infections with cefsulodin. Rev Infect Dis 1984; G(suppl 3): S721S727. Karam GH: Ahtibiotic review for the orthopedic surgeon. Orthopedics 1984; 7: 1546-1552. Sykes RB, Bonner DP, Bush K, et al: Monobactams-monocyclic p-lactam antibiotics produced by bacteria. J Antimicrob Chemother 1981; 8(suppl E): 1-16. Pottage JC Jr, Karakusis PH, Trenholme GM: Cefsulodin therapy for osteomyelitis due to Pesudomonas aeruginosa. Rev Infect Dis 1984; G(suppl 3): S728-S733.

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