Antibiotic Therapy in Osteomyelitis in Outpatients

Update on Antibiotics II

0025-7125/88 $0.00

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Antibiotic Therapy of Osteomyelitis in Outpatients Christopher Ingram, MD,* Lawrence J. Eron, MD,* Robin I. Goldenberg, MD, * Allan J. Morrison, jr, MD, * Donald M. Poretz, MD,* Mary E. Alder, RN, BSN,T Lisa K. Harvey, RN, BSN, t lames B. Rising, RPh, T and Sarah B. Sparks, RNt

The clinica~ resolution of osteomyelitis in adults may involve up to 4 to 6 weeks of intravenous antibiotic therapy following initial surgical debridement. Until recently, that usually required 1 to 2 months of hospitalization. Our therapeutic approach has been to emphasize outpatient therapy with both intravenous and oral antibiotics.5-9 Indeed, the "standard of care" has been revised in recent years so that it now is acceptable to deliver the medical portion of the therapy in an outpatient setting. 1.5-9. 1018. 25. 27-30. 33 This is because of both economic considerations and the growing availability of outpatient programs. 3. 4. 18.26.31 But in spite of the widespread use of outpatient therapy, there has been no in-depth review of those factors that determine the suitability of this approach for the different types of osteomyelitis. We therefore reviewed our experience with 481 episodes of the condition to identify the types of bone infection that are especially suited to outpatient therapy and to determine what factors influence prognosis.

MATERIALS AND METHODS Patients with osteomyelitis were included in this analysis if they were treated at least in part as outpatients between 1980 and 1986 at Intracare (Annandale, VA), a clinic for outpatient intravenous antibiotic therapy. Osteomyelitis was defined as an inflammatory condition of bone on plain roentgenogram, radio nuclide scan, computerized tomography, biopsy, or on gross examination of bone. Data were sorted by age, sex, and underlying disease (diabetes mellitus, arthritis, malignancy, chronic steroid use, and From the 'Division ofInfectious Diseases, The Fairfax Hospital, Falls Church; and tIntracare Corporation, Annandale, Virginia Medical Clinics of North America-Vol. 72, No. 3, May 1988

723

724

CHRISTOPHER INGHACW ET AL.

peripheral vascular disease). The types of osteomyelitis were categorized as to their pathogenesis according to previous suggestion 32-caused by hematogenous dissemination, caused by a contiguous septic focus (surgically or traumatically induced), associated with a prosthesis infection, or complicated by vascular insufficiency. Cases were further subdivided into acute (initial therapeutic) episodes and chronic (recurrent therapeutic) episodes. Cultures were obtained from bone, purulent drainage deep within wounds, or blood. All specimens were cultured aerobically and anaerobically and those from wound drainage also were examined microscopically following Gram staining. A positive wound culture was confirmed by the observation of a given organism amidst polymorphonuclear leukocytes. Four hundred eighty-one episodes of osteomyelitis were analyzed, 179 of which were treated with intravenous antibiotics as outpatients and 302 of which were treated with intravenous antibiotics in the hospital and continued as outpatients. Patients were examined at Intracare twice weekly for clinical efficacy, microbiological eradication, persistence, superinfection, or drug toxicity. Clinical efficacy was determined whether or not a pathogen had been isolated only in those patients who received a minimum of 5 days of intravenous antibiotics. Cure was defined as the complete resolution of all signs of bone and wound inflammation for a minimum of 6 months, in combination with microbial eradication where cultures were obtained at the conclusion of therapy; failure as continued inflammation with persistent infection or superinfection requiring further surgical and/or antibiotic therapy. A portion (61 patients) had several entirely distinct episodes of osteomyelitis requiring additional courses of intravenous antibiotics. Each course was analyzed separately. In addition, antibiotic efficacy was determined in 259 patients in whom a culture was obtained at the initiation of therapy and that yielded an organism that was sensitive to the antibiotic administered. Because intravenous antibiotics were followed by step-down to oral antibiotics in most cases, results of the intravenous portion of the antibiotic course were reported either as response (cure or improved) or failure. Statistical analyses were performed by SAS programs FREQ and CATMOND. RESULTS

During the past 6 years, 481 episodes of osteomyelitis in 420 patients were treated with intravenous antibiotic therapy, of which at least a portion was administered in an outpatient setting. There were 321 males and 160 females with a median age of 40 years (range, 2 to 94). The median duration of the total course of intravenous antibiotic therapy (both inpatient and outpatient) was 37 days (range, 1 to 162). The median duration of the outpatient portion of intravenous antibiotic therapy was 28 days (range, 1 to 156), accounting for over 50 per cent of the total intravenous course in 434 episodes and over 75 per cent of the total therapy in 325 episodes. One hundred seventy-nine episodes (37 per cent) were treated solely as outpatients. Where appropriate (that is, if the patient was improved but

725

A"ITIBIOTIC THERAPY OF OSTEO'"lYELITIS IN OUTPATIENTS

Table 1. Types of Osteomyelitis NUMBER OF EPISODES

Hematogenous dissemination Vascular insufficiency Contiguous septic focus Surgical Traumatic Prosthesis infection Device in place Device removed

Total

Acute

Chronic

64 106 257 73 184 54 24 30

60 66 185 58 127 33 16 17

4 40 72 15 57 21 8 13

not yet cured at the end of the intravenous course of antibiotics), oral antibiotics were continued as step-down therapy following discontinuation of intravenous therapy. Step-down to oral antibiotics was used in 235 cases (49 per cent), with a median duration of 21 days (range, 1 to 387). Types Treated The types of osteomyelitis treated in our series are illustrated in Table 1. Osteomyelitis associated with a contiguous septic focus accounted for most of the cases (54 per cent) followed by osteomyelitis associated with vascular insufficiency (22 per cent), with hematogenous dissemination (13 per cent), and with an infected prosthesis (11 per cent) in decreasing order of frequency. Considering all types of osteomyelitis, 344 were acute episodes and 137 were chronic, of which 67 per cent and 25 per cent, respectively, were cured (p < 0.001). Osteomyelitis Acquired by Hematogenous Dissemination. Sixty-four episodes of hematogenously acquired osteomyelitis were treated in 63 patients (Table 2). Sixty of these episodes were acute and four were chronic. As noted in Figure 1, the most common sites of involvement included the axial skeleton and skull, the long bones of the lower extremity, and the foot. Intravenous therapy was begun in the hospital in 44 (73 per cent) of the acute cases. In 16 of the acute cases and in all four chronic cases, intravenous therapy was begun at Intracare without prior hospitalization. Surgical debridement was performed in only one case. An organism was isolated from bone or blood in 25 per cent of cases and from deep within wounds in 14 per cent. Staphylococcus aureus was cultured initially in 17 cases, followed by streptococci in four cases (Table Table 2. Clinical Results of Therapy of Osteomyelitis Acquired by Hematogenous Dissemination I'iUYlBER OF EPISODES (PER CEJ\T)

Acute Chronic Total

Total

Cured

Failed

60 4 64

53 (88) 3 (75) 56 (88)

7 (12) 1 (25) 8 (12)

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CHRlSTOPHER INGRAM ET AL.

Chronic

Acute

cI a vI c I e

(3 )----------,:l:::;=o!~~6:?_

humerus ( 1 ) - - _ _ _ _ __

.l5O:~~------_stern um (1)

vertebrae (11 pelvis (3) -

_ _ _ _ _ _jJ~

I W - - - - - - - - - - - f e m u r (2) carpall metacarpall phal flnx tibia (1)

femur (10) tibia (18) tars all metatarsal I phal anx not specified

(1)

Figure 1. Osteomyelitis hematogenously acquired.

3). Ten of 26 percutaneous aspirations of bone were negative even in the absence of prior antibiotic therapy. In 24 cases, a culture by percutaneous aspiration was not performed and antibiotic therapy was begun empirically. Fifty-six episodes were cured (88 per cent) and eight failed (12 per cent). The cure rate was similar whether the initial culture was positive for S. aureus, was negative, or was not performed (see Table 3). Table 3. Clinical Results of Therapy According to Initial Culture for Hematogenously Acquired Osteomyelitis NUMBER OF EPISODES (PER CENT)

Total Acute S. aureus P. aeruginosa Miscellaneous Streptococci Culture negative No culture Chronic Enterobacteriaceae No culture Culture negative

17 1 1

5

12 24

1 2 1

Cured 16 1 1 3 11 21

(94) (100) (100) (60) (92) (88)

0 2 (100) 1 (100)

Failed 1 0 0 2 1 3

(6) (40) (8) (12)

1 (100) 0 0

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ANTIBIOTIC THERAPY OF OSTEOMYELITIS IN OUTPATIENTS

Table 4. Clinical Results of Therapy of Osteomyelitis Acquired from, a Contiguous Septic Focus NUMBER OF EPISODES (PER CENT)

Total

Acute Surgical Traumatic Chronic Surgical Traumatic Total

185 58 127 72 15 57 257

Cured

Failed

130 44 86 19 6 13 149

55 14 41 53 9 44 108

(70) (76) (68) (27) (40) (23) (58)

(30) (24) (32) (73) (60) (77) (42)

Osteomyelitis Acquired from ci Contiguous Septic Focus. Two hundred fifty-seven cases of osteomyelitis caused by a contiguous septic focus were treated, including 184 resulting from trauma and 73 following elective surgical procedures (Table 4). Sites of involvement are illustrated in Figure 2. The extremities most frequently were infected. Intravenous therapy was begun in the hospital in 120 acute cases (65 per cent) and 34 chronic cases (47 per cent). The remainder were begun at Intracare. Surgical debridement was performed in 40 episodes of acute (22 per cent) and 20 chronic (28 per cent) infections.

Acute

Chronic

skull/mandible clavicle (1) sternum (4)

:1--------skul/lmandlble (3)

(13) . - - - - - - 1 - ;

_ _~_~'_"""'--------- clavicle

(1)

--------u~5 -=:JOl.""C>,",

t \ , - - - - - - - - h u m e r u s (1)

vertebrae (10) on----In\---------vertebra e (4)

pelvis (3)

\

carpa/lmetacarpa/lpha/anx (3) femur (13)

femur (9)

_ - - - - - - - - - tibia (13) tibia

(14)---------~·1f1

tarsa/lmetatarso/lpha/anx (94)~ not specified

(2)

/tarsa/lmetBtarsa/lPha/anx (33) not specified (1)

Figure 2. Osteomyelitis acquired from a contiguous septic focus.

728

CHRISTOPHER INGRAM ET AL.

Table 5. Clinical Results of Therapy According to Initial Culture in Contiguous Focus Osteomyelitis

NUMBER OF EPISODES (PER CENT)

Total Acute S. aureus Enterobacter P. aeruginosa Streptococci Anaerobes Miscellaneous Culture negative No culture Chronic S. aureus Enterobacteriaceae P. aeruginosa Streptococci Anaerobes Culture negative No culture

53 23 33 7 5 3 28 38 22 5 12 1 1 14 18

Cured 37 12 22 5 4 2 19 28

(70) (52) (67) (71) (80) (67) (68) (74)

7 (32) 1 (20) 1 (8) 1 (100) 0(0) 3 (22) 6 (33)

Failed 16 11 11 2 1 1 9 10

(30) (48) (33) (29) (20) (33) (32) (26)

15 (68) 4 (80) 11 (92) 1 (100) 11 (78) 12 (67)

An organism was isolated from bone in 10 per cent of cases and from deep within wounds in 52 per cent of cases (Table 5). In 42 cases, initial cultures were negative (16 per cent). In 56 cases, cultures could not be performed because there was no wound drainage, so therapy was empirical. Of the acute cases, S. aureus initially was isolated in 51 cases, followed by Pseudomonas aeruginosa in 36, and Enterobacteriaceae in 29 cases (see Table 5). In the chronic episodes, S. aureus was cultured in 22 cases, followed by P. aeruginosa in 13, and Enterobacteriaceae in 9 cases. In both acute and chronic osteomyelitis, the majority (greater than 90 per cent) of Pseudomonas infections occurred following trauma, frequently due to plantar nail punctures. Eight cases of polymicrobial infections were noted. A small portion of both acute (28 episodes) and chronic (14 episodes) cases had cultures that initially were negative. These were more likely to occur in cases of trauma. Overall, 58 per cent of episodes were cured. Those that failed were located predominantly in the distal lower extremities. Of the 185 acute episodes, 130 were cured (70 per cent) and 55 failed (30 per cent) (see Table 4). This compared favorably with the clinical results in the 72 chronic episodes, of which 19 were cured (27 per cent) and 53 (73 per cent) failed (p < 0.001). Osteomyelitis Associated with Vascular Insufficiency. We treated 106 cases of osteomyelitis associated with vascular insufficiency (Table 6). Vascular insufficiency was associated with diabetes mellitus in 81 per cent of cases and with vasculitis or peripheral vascular disease (without diabetes mellitus) in 19 per cent of cases. Intravenous therapy was begun in the hospital in 67 cases (63 per cent) and at Intracare in 39 (37 per cent). Surgical debridement was performed in 33 episodes (31 per cent), of which 23 were acute and 10 chronic. Sites

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ANTIBIOTIC THERAPY OF OSTEOMYELITIS IN OUTPATIENTS

Table 6. Clinical Results of Therapy of Osteomyelitis Associated with Vascular Insufficiency NUMBER OF EPISODES (PER CENT)

Acute Chronic Total

Total

Cured

Failed

66 40 106

25 (38) 5 (12) 30 (28)

41 (62) 35 (88) 76 (72)

of involvement predominantly were in the distallower extremities (Fig. 3). All episodes involving the bones of the hands were acute, while those involving the axial skeleton and especially the tibia and fibula were more likely to be chronic. An organism was isolated from bone in 24 cases (4 per cent) and from deep within wounds in 73 cases (69 per cent) (Table 7). The bacteria cultured initially in the acute cases included S. aureus (25 cases), Streptococcus group B (7), Enterobacteriaceae (17), P. aeruginosa (6), and anaerobes (3). Fifteen cases were polymicrobial infections. There were four cases in which cultures were negative. In 13 acute episodes, no cultures were taken and therapy was begun on an empirical basis. Chronic episodes were caused by S. aureus (10), Enterobacteriaceae (13), P. aeruginosa (3), Streptococcus group B (4), and anaerobes (2). Eight episodes were polymicrobial. There were four cases in which cultures were negative. In 8 cases, cultures could not be performed and therapy was begun on an empirical basis. Acute

Chronic

humerus ( 1 ) - - - - - - - _ ~~-----''i\\_---------

vertebrae (5)

1

carpal/metacarpal/phalanx (5)

tibia

( 1 ) - _ _ _ _ _ _ _ _ __

tarsal/metatarsal/phalanx (59)-----."

I I _ - - - - - - - - - - - - t l b l a (2) __________ tars aI/ metatarsal/ phalanx (33)

Figure 3. Osteomyelitis associated with vascular insufficiency.

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CIIRISTOPHER INGI\A'v1 ET AL

Table 7. Clinical Results of Therapy According to Initial Culture in Osteomyelitis Associated with Vascular Insufficiency [\C~IBER

OF EPISODES (PER CENT)

Total Acute S. aureus En terobacteriaceae P. aeruginosa Streptococcus, group B Anaerobes Miscellaneous Culture negative No culture Chronic S. aureus Enterobacteriaceae P. aeruginosa Streptococcus, group B Anaerobes Miscellaneous Culture negative No culture

Cured 14 4 0 1 2 1 1 5

25 17 5 3 3 5 4 13

(56) (24) (33) (67) (20) (25) (39)

1 (10)

10 11 2 4 2 1 5 7

1 (20) 3 (43)

Failed 11 13 5 2 1 4 3 8

(44) (76) (100) (67) (33) (80) (75) (61)

9 (90) 11 (100) 2 (100) 4 (100) 2 (100) 1 (100) 4 (50) 4 (57)

Overall, 28 per cent of cases complicated by vascular insufficiency were cured. Of the 66 acute cases, 25 were cured (38 per cent) and 41 failed (62 per cent) (Table 6). These results were superior to the 40 chronic cases, of which 5 were cured (12 per cent), and 35 failed (88 per cent) (p < 0.01). All failures were infections of the foot or ankle. Osteomyelitis Associated with Infected Prosthetic Devices. Fifty-four cases of osteomyelitis associated with prosthetic devices were treated, including 24 cases associated with a device that remained in place and 30 cases where the device was removed during treatment (Table 8). The devices included 20 compression plates; 28 pins, screws, or wires; and 6 total joint replacements. Intravenous therapy was begun in the hospital in 37 cases (67 per cent). . Positive cultures were obtained directly from infected prostheses (2 Table 8. Clinical Results of Therapy of Osteomyelitis Associated with Prosthesis Infection NUMBER OF EPISODES (PER CENT)

Total Acute Device Device Chronic Device Device Total

in place removed in place removed

33 16 17

21 8 13 54

Cured

Failed

21 10 11 7 3 4 28

12 6 6 14 5 9 26

(64) (63) (64) (33) (38) (31) (52)

(36) (37) (35) (67) (62) (69) (48)

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A1\TlIlIOTIC THERAPY OF OSTEU\IYELlTIS IN OUTPATlDJTS

Table 9. Clinical Results of Therapy According to Initial Cultures in Osteomyelitis Complicated hy a Prosthetic Device '.;LT~IHER

Acute S. aureus S. epidennidis Enterobacteriaceae P. aeruginosa Anaerobes Miscellaneous Culture negative 1\10 culture Chronic S. aureus Enterobacteriaceae P. aeruginosa Streptococci Culture negative No culture

OF EPISODES (PER CE'.;T)

Total

Cured

Failed

11 4 6 5 1 2 4

7 (64) 3 (75) 3 (50) 3 (60) 1 (100) 1 (50) 3 (75) 1 (100)

4 1 3 2

8

2 (25)

2 4 2 4 1

1 (25) 3 (75) 1 (100)

(36) (25) (50) (40)

1 (50) 1 (75)

6 2 3 2 1

(75) (100) (75) (100) (25)

cases) or from deep within wounds (38 cases). The low frequency of isolation of organisms from prostheses that were removed may have been because of prior antibiotic therapy. Again, S. aureus was the most common organism in both the acute (ll) and chronic (8) cases, accounting for 38 per cent of culture positive cases (Table 9). P. aeruginosa and Enterobacteriaceae together also accounted for 38 per cent of culture positive cases. S. epidermidis was cultured from only 7 acute cases. Culture negative cases accounted for 21 per cent of all prosthetic device infections. Considering all cases, we cured 52 per cent. Of acute episodes, 21 were cured (64 per cent) and 12 failed (36 per cent). This compares with 7 chronic cases cured (33 per cent) and 14 failed (67 per cent) (p = 0.05). The cure rates were similar in this selected series whether the prosthetic device remained in place or was removed. Bacteriology Whether considering acute or chronic episodes of osteomyelitis, the most common pathogens were S. aureus, Enterobacteriaceae, and P. aeruginosa (Table 10). Culture negative cases accounted for 15 per cent of acute and 17 per cent of chronic episodes. S. aureus was isolated in 42 per cent of bone biopsies and 38 per cent of wound cultures. When a single pathogen was isolated in an acute episode, a cure was noted in 67 per cent of cases, compared with 19 per cent in chronic episodes. Polymicrobial infections were identified in 28 acute and in 18 chronic episodes, usually in association with vascular insufficiency or a contiguous septic focus. Gram positive cocci (particularly S. aureus) and anaerobic organisms accounted for over 70 per cent of isolates in polymicrobial infections. Sites of polymicrobial infection mainly were in the distal lower extremities, complicated by vascular insufficiency. Treatment of polymicrobial infections resulted in 43 per cent cured in acute cases and 5 per cent cured in chronic

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CHRISTOPHEH INGRAYI ET AL.

Table 10. Clinical Results of Therapy According to Organism Treated NUMBER OF EPISODES (PER CENT)

Total Acute S. aureus Enterobacteriaceae Pseudomonas species Others Culture negative No culture Chronic S. aureus En terobacteriaceae Pseudomonas species Others Culture negative No culture

106 46 44 35 48 74 40 19 18 11 24 28

Cured

Failed

74 19 26 21 34 55

32 27 18 14 14 19

(70) (41) (59) (60) (71) (75)

10 (25) 1 (5) 2 (11) 1 (9) 8 (33) 12 (43)

(30) (59) (41) (40) (29) (25)

30 (75) 18 (95) 16 (89) 10 (91) 16 (67) 16 (57)

cases, results less favorable than the above cure rates for monomicrobial infections (p = 0.01). Considering all types of osteomyelitis, results of therapy varied with the initial isolate. Infections caused by S. aureus were cured in 60 per cent of cases, compared with those caused by Enterobacteriaceae (30 per cent cured) or P. aeruginosa (46 per cent cured) (p < 0.001). When the initial culture result was negative or when a culture was not obtainable, cures were noted in 57 and 66 per cent of cases, respectively. Superinfection was noted in 23 cases, a mean of 24 days into therapy (range, 7 to 50 days). The most frequent superinfecting pathogens were Enterobacteriaceae (10), followed by Staphylococcus aureus (5), enterococcus (3), and P. aeruginosa (2). After a superinfection occurred, only one case was cured while all of the others failed (22). Antibiotic Therapy Cefazolin was used most frequently (151 courses), followed by ceftriaxone (138), aminoglycosides (91), cefoperazone (61), and clindamycin (47). Clinical results in 259 patients were analyzable for the intravenous portion of their antibiotic therapy (Table ll). The total in Table II exceeds this number because in 29 patients, two different antibiotics were administered consecutively becatIse of adverse drug reactions. In these patients, the Table 11. Clinical Results of Therapy with Intravenous Antibiotic Regimens NUMBER OF EPISODES (PER CENT)

Total Cefazolin Ceftriaxone Clindamvcin Cefoper~zone Aminoglycoside

69 82 16 39 53

Response 62 71 13 26 36

(90) (87) (81) (67) (68)

Failure 7 11 3 13 17

(10) (13) (19) (33) (32)

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Al'\TIBIOTIC THERAPY OF OSTEO'vIYELITIS IN OUTPATIE:-.!TS

drugs were evaluated independently as if they were two different antibiotic courses. Response rates were observed to be 90 per cent for cefazolin, 87 per cent for ceftriaxone, 81 per cent for clindamycin, 67 per cent for cefoperazone, and 68 per cent for aminoglycosides. There were many more S. aureus infections treated by the first three antibiotics and P. aeruginosa infections treated by the last two antibiotics (p < 0.001). The percentage of cases caused by S. aureus did not differ among the first three antibiotics (81 per cent for cefazolin, 63 per cent for ceftriaxone, 77 per cent for clindamycin) but was significantly higher than for cefoperazone (11 per cent) or aminoglycosides (4 per cent) (p < 0.01). Conversely, the percentage of cases caused by P. aeruginosa was similar for cefoperazone (46 per cent) and aminoglycosides (62 per cent) compared with zero for the other three antibiotics (p < 0.001). The relative number of chronic cases did not differ among the five antibiotic groups, nor were differences among the groups detectable with respect to the pathogenic types of osteomyelitis, with one exception. There were more cases complicated by vascular insufficiency in the ceftriaxone group (38 per cent), compared with cefazolin (16 per cent), clindamycin (21 per cent), cefoperazone (23 per cent), or aminoglycosides (15 per cent) (p < 0.01). Step-down therapy from intravenous to oral antibiotics was administered in 235 of the 494 episodes (165 acute and 70 chronic). The organism most commonly treated was S. aureus (33 per cent) followed by culturenegative (31 per cent), Enterobacteriaceae (17 per cent), streptococci (8 per cent), and S. epidermidis (6 per cent). The median duration of oral therapy was 14 days (range, 1 to 150) in the acute cases and 28 days (range, 7 to 387) in chronic cases. The clinical results in patients who received oral step-down therapy were similar to those who did not (results not shown). Because the reason for step-down to oral antibiotics was incomplete response to intravenous antibiotics, no valid analysis of oral step-down therapy could be accomplished, because no comparable control group was available.

Table 12. Adverse Reactions to Intravenous Antibiotics Given to Outpatients NUMBER DISCONTINUED

Laboratory Abnormality Leukopenia Thrombocytopenia Elevated serum creatinine Prolonged prothrombin time Liver enzyme abnormality Eosinophilia Adverse Reaction Rash Nausea or vomiting Diarrhea Disulfiram-like reaction Fever

TOTAL NUMBER

OR DOSE ALTERED

39

6 2 3

3 10 1

o

6

3

19 6 18

9 2 4

54

2

19

9

o 2

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CIlRISTOPHEB 1"'(;HA'\1 ET AL.

Adverse Reactions Onc hundred fifty-six adverse reactions and/or laboratory abnormalities were noted in 146 patients (Table 12). Antibiotics werc changed or doses altered because of adverse reactions or laboratory abnormalities in 17 and 23 cases, respectively. Positive Clostridium difficile toxin assays were not detected in any patients with diarrhea.

DISCUSSION For the past decade, a novel approach to the therapy of osteomyelitis increasingly has become accepted: to discharge patients from the hospital following initial surgical debridement and to continue intravenous antibiotics in an outpatient setting. I. 5-9. ](i-II<, 25, 27-30, 3:J Indeed, of all types of infections treated with intravenous antibiotics in outpatients, osteomyelitis is the most common, During this time we have treated 481 episodes of osteomyelitis, with the majority of patients' intravenous therapy rendered as outpatients,5-9 This approach reduces costs of hospitalization and returns the patient to a home environment with a more normal lifestyle, 3, 4, lH, 26, :Jl However, this approach has never been studied systematically in depth for the different types of osteomyelitis. Our results of such a selected group of patients span the clinical and bacteriological spectrum of osteomyelitis. Of all patients treated, osteomyelitis due to a contiguous septic focus was the most frequent type (54 per cent), followed by osteomyelitis complicated by vascular insufficiency (22 per cent), that caused by hematogenous dissemination (13 per cent), and cases associated with an infected prosthetic device (11 per cent). These results are comparable to results reported previously in hospitalized patients in whom osteomyelitis due to a contiguous septic focus was noted in 47 per cent, complicated by vascular insufficiency in 34 per cent, and that caused by hematogenous dissemination in 19 per cent. 32 While osteomyelitis associated with an infected prosthesis was not included in the review, it generally constitutes only a few per cent of all orthopedic infections, [5 There are several factors that may determine the outcome of therapy: the type of osteomyelitis, its relative chronicity, and the pathogenic bacteria,'32 Cases of hematogenously acquired osteomyelitis, most often acute cases caused by S. aureus, were cured in 88 per cent of cases compared with the results for osteomyelitis associated with a contiguous septic focus (58 per cent), prosthesis infection (52 per cent), or vascular insufficiency (28 per cent) (p < 0,001). Results were similar whether antibiotic therapy was based on a positive culture or was empiric. The percentage of cases caused by S. aureus was not significantly different for osteomyelitis caused by hematogenous dissemination, but compared with the other pathogenic types, the relatively large number of acute versus chronic episodes in this group may have been a factor in producing the high cure rate. Our results are consistent with previous experience. 12, 23, :32 Acute episodes of this type were cured in 82 per cent of cases while chronic episodes were cured in 60 per cent. 32 Osteomyelitis secondary to a contiguous septic focus from trauma as

ANTIBIOTIC THEHAPY OF OSTEO\IYELlTlS 1'1 OUTPATlEI\TS

735

well as from elective surgery was more likely to be acute than chronic in our outpatients. Acute episodes were more frequently cured than chronic (70 and 27 per cent, respectively) (p < 0.001), similar to the figures (60 and 25 per cent, respectively) reported previously.32 An organism was isolated from bone in only 10 per cent of cases and from deep within wounds in 52 per cent of cases caused by a contiguous septic focus. This may reflect our reluctance to biopsy bone through or near an adjacent infected focus. When cultures were performed, S. aureus was the most frequently recovered pathogen, followed by P. aeruginosa and Enterobacteriaceae. P. aeruginosa especially was common following trauma, including plantar nail punctures, as previously has been reported. 14, 21, 22 The results of therapy of acute episodes were similar whether therapy was directed against pathogens such as S, aureus, p, aeruginosa, or Enterobacteriaceae, or was empirical either because no pathogen was isolated following a culture or because no culture was performed. This also was true of the therapy of chronic cases, except where p, aeruginosa was involved, in which case the cure rates were much worse (p < 0.001), The favorable results of the therapy of acute episodes of osteomyelitis caused by either hematogenous dissemination or a contiguous septic focus contrast sharply with the outcome of therapy of cases complicated by vascular insufficiency, This was not because of differences between the two groups with respect to the pathogenic organisms or the chronicity of disease (except for osteomyelitis caused by hematogenous dissemination, as previously mentioned), Here cure rates of 38 and 12 per cent were observed for acute and chronic episodes, respectively, as previously has been reported. 19, 32,34 Cure was much more likely in those acute episodes caused by S, aureus (56 per cent) than in those caused by Enterobacteriaceae or p, aeruginosa (18 and 17 per cent, respectively) (p < 0,001), Surgical debridement was performed in only 31 per cent of this group, reflecting two factors, First, this selected series of patients included those not likely to need further debridements during the outpatient phase of their intravenous antibiotic therapy, Second, there was reluctance to subject patients with circulatory impairment to surgical incisions because of their decreased powers of healing, This point also explains our paucity of bone cultures, Osteomyelitis associated with infected prosthetic devices is notoriously difficult to cure, Our rather high cure rate in acute and chronic infections (64 and 33 per cent, respectively) may reflect our ability to extend intravenous antibiotic therapy in outpatients without prolonging hospitalization~ and possibly our practice of using step-down therapy to oral antibiotics for protracted periods of time, The inclusion here of a relatively large number of cases of infected prosthetic devices, compared with other series,15 emphasizes our belief that this type of osteomyelitis especially may be benefitted by continuing parenteral antibiotic therapy in outpatient settings following discharge from the hospital. The prognosis for therapy of osteomyelitis also depends on the pathogenic organism, S. aureus was, as reported in other series, the most common pathogen. 10, 12, 13, 23, 32 Our overall cure rate for S. aureus osteomyelitis (60 per cent) was superior to that for infections caused by Enterobacteriaceae (30 per cent), or p, aeruginosa (46 per cent) when matched

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for confounding variables of thc chronicity and type of osteomyelitis (p < 0.001). Our less favorable results for antibiotic therapy of polymicrobial osteomyelitis are consistent with previous experience. 24 Only 43 per cent of our patients with acute discase and 5 per cent with chronic disease w.ere cured when they had polymicrobial infections, results less favorable than the cure rates associated with monomicrobial osteomyelitis (p < 0.01). This also may reflect the type of osteomyelitis (complicated by vascular insufficiency) associated with polymicrobial infections and the attendant lower cure rates. In chronic osteomyelitis, sinus tract or wound cultures are not considered to be accurate unless they reveal S. allrells. 24 \Ve prefer to base treatment on bone cultures but many times it would have placed thc patient at risk to obtain them. Therapeutic decisions therefore were based on cultures obtained from deep within wounds even when those cultures revealed gram negative bacilli or were negative. These patients responded to antibiotics as well as those with blood, bone, or wound cultures positive for S. aurellS. In culture negative cases or in those cases in which gram negative bacilli were cultured from wounds, our antibiotic choice usually covered S. allrellS along with the gram negative bacillus through the use of an aminoglycoside or third-generation cephalosporin. Finally, the relative chronicity of the osteomyelitis influences the prognosis. Chronic osteomyelitis is a much more difficult disease to treat. The low cure rate for chronic osteomyelitis (25 per cent) compares poorly with that for acute episodes (67 per cent) when matched for confounding variables of pathogenic organism and the type of osteomyelitis (p < 0.001). \Ve extensively utilized cephalosporins with longer serum half-lives such as cefazolin, cefoperazone, and ceftriaxone. Clindamycin was used in anaerobic infections and in those individuals allergic to penicillins or cephalosporins. Aminoglycosides and cefoperazone were used to treat infections caused by resistant gram negative bacilli, especially P. aeruginosa. \Vhile it appeared that cefilzolin, ceftriaxone, and clindamycin were more effective than cefoperazone and aminoglycosides, the patients treated in each group were not evenly matched for pathogenic organism or the type of osteomyelitis. The former group (cefilzolin, ceftriaxone, and clindamycin) involved more infections caused by S. allrellS and the latter, more infections caused by P. aerllginosa. Because infections caused by S. allrellS responded more readily than those caused by P. aeruginosa, results with the different antibiotics were comparable only within two separate groups: cehlzolin, ceftriaxone, and clindamycin on the one hand, and cefoperazone and aminoglycosides on the other. When the data were stratified in this way, there were no significant differences among the antibiotics within each group. The excess of cases complicated by vascular insufficiency (with the attendant poorer prognoses) in the ceftriaxone group may have spuriously lowered the efficacy rate for this antibiotic. Furthermore, it was not possible to determine the cure rates for the 259 analyzable courses of intravenous antibiotics because many of them were followed by step-down to oral antibiotics. \Ve therefore analyzed efficacy of the intravenous portion of the antibiotic course in terms of "response" or failure. "Response" in manv cases such as those associated

Al':TIBlOTIC TIIER\PY OF OSTE()\1i ELlTIS 1'1 Ol'TP,-\TIE'\TS

7:37

with vascular insufficiency or infection of a prosthetic device may have reflected control of the infE'ction without completely curing it. Although not curative, the prolonged course of oral antibiotics following iutravenous therapy lllay preserve hmction of a limb or may postpone amputation by suppressing infection in these patients. In the future, oral antibiotic therapy with the new fluorinated quinolones may reduce the need for outpatient intravenous antibiotics. 2. 11 The same types of patients reviewed herein likely will be recipients of this new therapeutic approach and this information concerning patient selection, management, and prognosis may be applicable.

REFERENCES 1. Antoniskis A, Anderson BC, Van Volkinhurg EL et al: Feasihility of outpatient self~ administration of parenteral antibiotics. West J Med 12/):203-206, 197/) 2. Desplaccs "l, Glltman L, Carlet L et al: TIlt' new quinolones and their combinations with other agents I()r therapy of severe infections. J Antimicroh Chemother 17(Suppl A):2,s39, 19/)6 3. Eisenberg ]I'd, Kitz DS: Sa\'ings from outpatient antihiotic therapy I()r osteomyclitis. Economic analysis of a therapeutic strategy. JAMA 2.5.5: 1.58:3-1.588, 1986 4. Eisenbcrg JI\J, KolheT H, Finkler SA: Economic analysis of a new drtlg. Potential savings in hospital operating costs hom the use of a once-daily regimen of a parenteral cephalosporin. Hev Infect Dis 6(Suppl ,1):5909-5923, 19/)4 .5. Eron LJ: Intravenous antibiotic administration in outpatient settings. Infect Dis 14:4-9, 1984 6. Eron LJ: The therapy of osteomyelitis in outpatient settings. Cutis 36(5A): 1.5-20, 198.5 7. Eron LJ: Home health care. Asepsis 7: 1.5-1Il, 198.5 8. Eron LL Park CH, Hixon DL, et al: CeftriaxOJ1t' therapy of bone and soh tissue infections in hospital and outpatient settings. Antimicroh Agents Chemother 23:7.11-737, 19/)3 9. Emn LJ, Goldenberg HI, Porctz DM: Combined ceftriaxonc and surgical therapy for osteomyelitis in hospital and outpatient settings. Am J Surg 141l:1-4, 1984 10. Gerszten E. Allison '.1], Dalton HP: An epidemiological study of lOO consecutive cases of osteomyelitis. South .\[ed J 6:3::36.5-367, 1970 11. Giamarellou H, Daphinis E. et al: Expericnce with ciprofloxacin in the treatment of various infections caused mainlv hy Pseudomonas aeruginosa. Drugs Exp Clin Hcs 11: 3.31-3.56. 198.3 P Gillespie \VJ, '\[ayo KM: The management of acute haematogenous osteomyelitis in the antibiotic era. J Bone Joint Surg (Br) 63-13:126-131, 19S1 13. Glove SC, I\1cKendrick '.[W, Padfield C, et al: Acute osteomyelitis in a district general hospital. Lancet 1:609-611, 1982 14. Greene XE, Bruno J: Pseudomonas inlections of the I()ot after puncturt' wounds. South Med J 7:3:146-149, 1980 1.5. Harris WH: Total joint replacement. N Engl J '\[ed 297:6.50-6.31, 1979 16. Kind AC, \Villiams D:'II, Persons G, et a1: Intravenous antibiotic therapy at home. Arch Intern Med 1.39:413-41.5. 1979 17. Kind AC, \Villiams D"l, Gibson J: Outpatient intravenous antibiotic therapy. Postgrad Mcd 77:lO.3-1ll, 198."5 18. Kunkel 1\1], Iannini 1'13: Cel(JIlicid in a once-daily regimen /(JI' lreatment of osteomyelitis in an ambulatory setting. He\' Infect Dis 6(Suppl 4):.586.5-.5869, 1984 W. Le Frock JL, Blais F, Schell HF, et al: Ce/()xitin in the treatment of diabetic patients with lower extremity infections. Infect Surg 4:361-:374, HJ83 20. l\1ackowiak PA, Jones SR Smith J\V: Diagnostic value of sinus tract cultures in chronic osteomyelitis. JA.\[A 2:39:2772-277.5, 1978 21. Miller EH, Semlan D\V: Gram negative osteomyelitis following puncture wounds of the foot. J Bone Joint Surg (Am) .57A:.5:3.5-.537, 197.3

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22. Minnefor AB, Olson MI, Carver OH: Pseudomonas osteomyelitis following puncture wounds of the foot. Pediatrics 47:598, 1971 23. O'Brien T, Mc.\llanus F, .'.Iacl'\auley PH, et al: Acute haematogenous osteomyelitis. J Bone Joint Surg (Br) 64:450-4.53, 1982 • 24. Pichichero ME, Friesen HA: Polymicrobial osteomyelitis: Report of three cases and review of the literature. Rev Infect Dis 4:86-96, 1982 25. Poretz OM. Eron LI. Goldenberg RI, et al: Intravenous antibiotic therapy in an outpatient setting. JAMA 248:336-339, 1982 26. Poretz OM, Wollard J, Eron LJ, et al: Outpatient use of ceftriaxone: A cost benefit analysis. Am J Med 77:77-83, 1984 27. Rehm SI. Weinstein AJ: Home intravenous antibiotic therapy: A team approach. Ann Intern Med 99:388-392, 1983 28. Smego RA: Home intravenous antibiotic therapy. Arch Intern Med 145:1001-1002, 1985 29. Stiver HG, Telford GO, Massey AM, et al: Intravenous antibiotic therapy at home. Ann Intern Med 89:690-693, 1978 30. Stiver HG, Trosky SK, Cote DD, et al: Self-administration of intravenous antibiotics: An efficient cost-effective home care program. Can Med Assoc J 127:207-211, 1982 3l. Tanner DJ: Health care cost-containment in a changing health care world. Drug Intelligence ClinPharm 19:291-292, 1985 32. Waldvogel FA, Medoff G, Swartz MN: Osteomyelitis: A review of clinical features, therapeutic considerations and unusual aspects. N Engl J Med 282:198-206, 260-266, 316-322, 1970 33. Williams ON, Gibson JA, Kind AC: Outpatient intravenous antibiotic therapy. J Antimic rob Chemother 14:102-104, 1984 34. Wilson KH, Kauffman CA: Oral antibiotic treatment for osteomyelitis of the foot in diabetic patients. South Med J 78:223-224, 1985 3299 Woodburn Road Annandale, VA 22003 (Lawrence J. Eron, MD)