# Abstract

 

## Objectives Administering outpatient parenteral antimicrobial therapy in the community setting (CoPAT) is becoming more common with the increasing emphasis on controlling costs. However, few controlled trials have evaluated this treatment modality. 

## Methods Using data from a recent randomized trial comparing daptomycin with standard therapy (semi-synthetic penicillin or vancomycin, each with initial low-dose gentamicin) for *Staphylococcus aureus* bacteraemia and infective endocarditis (SAB/IE), patient characteristics and outcomes were evaluated. Patients receiving their full course of therapy in the hospital setting were compared with those who received some portion outside of the hospital (CoPAT). 

## Results Among the 200 patients, 51.5% received CoPAT. These patients were generally younger (median age 50 versus 54 years, *P* = 0.028). In the CoPAT group, there tended to be fewer patients with endocardial involvement (8.7% versus 18.6%, *P* = 0.061) and pre-existing valvular heart disease (7.8% versus 15.5%, *P* = 0.120). CoPAT patients received longer therapy courses (mean 25.4 versus 13.5 days, *P* < 0.001) and had higher rates of therapy completion (90.3% versus 45.4%, *P* < 0.001) and clinical success (86.4% versus 55.7%, *P* < 0.001). Persisting or relapsing *S*. *aureus* was less frequent in the CoPAT group (3.9% versus 15.5%, *P* = 0.007) and there were fewer deaths (3.9% versus 18.6%, *P* = 0.001) 6 weeks after the end of therapy. Hospital readmission occurred for 18 of the 103 (17.5%) CoPAT patients. Clinical success rates were similar for CoPAT patients receiving daptomycin (90.0%) or standard therapy (83.0%). 

## Conclusions With proper monitoring, stable patients can complete treatment for SAB/IE as outpatients in the community setting. Daptomycin is an appropriate option for this setting. # Results 

## Patient characteristics Two hundred US patients were included in this analysis, with 103 (51.5%) receiving part of their treatment outside of the hospital setting (CoPAT). The majority of CoPAT patients (69/103, 67.0%) were discharged home without assistance and two others (1.9%) went home with assistance. Nineteen of the 103 CoPAT patients (18.4%) were discharged to a skilled nursing facility, while 13/103 (12.6%) were treated in an assisted-living setting, nursing home or rehabilitation centre. The study database did not systematically record the types of venous access devices used to deliver CoPAT. In general, peripherally inserted central catheters were the preferred means of securing venous access. Compared with patients who received all care in the hospital, CoPAT patients were younger (median age 50 versus 54 years, *P* = 0.028) and tended to have fewer cases of endocardial involvement (8.7% versus 18.6%; *P* = 0.061) as well as less pre-existing valvular heart disease (7.8% versus 15.5%, *P* = 0.120). The two groups had a similar distribution of diagnoses (Figure [1](#)) and a similar distribution of study medications. Baseline demographic, diagnostic and treatment characteristics are shown in Table [1](#). ::::table-wrap

::: caption
Demographics, diagnosis and treatment characteristics by treatment
location
:::

Characteristic CoPAT (*n* = 103) IPAT (*n* = 97) *P*^a^

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Study drug\
daptomycin 50 (48.5%)^b^ 50 (51.5%) 0.687^c^
vancomycin^d^ 30 (29.1%) 23 (23.7%)\
SSP^d^ 23 (22.3%) 24 (24.7%)\
Age (years)\
median 50.0 54.0 0.028^e^
range 21--90 24--91\
Male 60 (58.3%) 59 (60.8%) 0.774
Race\
white 66 (64.1%) 55 (56.7%) 0.070^c^
black 30 (29.1%) 25 (25.8%)\
other 7 (6.8%) 17 (17.5%)\
Weight (kg)\
median 81.7 78.2 0.493^e^
range 49.9--129.0 53.5--131.4\
MRSA 37 (35.9%) 39 (40.6%)^f^ 0.560
CL~CR~ (mL/min)\
median 92.1 86.0 0.064^e^
range 29.4--277.0 17.9--200.8\
CL~CR~ \<50 mL/min 12 (11.7%) 12 (12.4%) >0.999
Evidence of endocardial involvement 9 (8.7%) 18 (18.6%) 0.061
Injection drug use 26 (25.2%) 22 (22.7%) 0.741
Pre-existing valvular heart disease 8 (7.8%) 15 (15.5%) 0.120
Fever on day 4 10 (9.7%) 18 (18.8%)^g^ 0.101
Completed treatment 93 (90.3%) 44 (45.4%) \<0.001
Duration of treatment (days)\
mean (SD) 25.4 (12.34) 13.5 (9.49) \<0.001^h^
range 9--74 1--43\
Days inpatient during treatment\
mean (SD) 10.5 (7.27) 13.5 (9.49) 0.014^h^
range 2--38 1--43\
Days outpatient during treatment\
mean (SD) 14.9 (10.08) 0 NA
range 1--49 ---\
Experienced ≥1 SAE 48 (46.6%) 52 (53.6%) 0.396

CoPAT, outpatient parenteral antimicrobial therapy in the community
setting; IPAT, patients receiving their full course of therapy in the
hospital setting; SSP, semi-synthetic penicillin; MRSA,
methicillin-resistant *S. aureus*; NA, not applicable; SAE, serious
adverse event.

^a^Fisher's exact test, unless otherwise specified.

^b^No. (%), unless otherwise specified.

^c^Overall Fisher's exact test for characteristic.

^d^With or without concomitant gentamicin.

^e^Wilcoxon's rank sum test.

^f^*n* = 96 for MRSA.

^g^*n* = 96 for fever (inpatient): fever on day 4 was possible but not
definitive on day 4 for six patients in the inpatient group who were
considered to have not had a fever.

^h^*t*-test.:::: <figure> <p><img src="" /></p> <figcaption>Final diagnosis by CoPAT or IPAT treatment. CoPAT, outpatient parenteral antimicrobial therapy in the community setting; IPAT, patients receiving their full course of therapy in the hospital setting; uBAC, uncomplicated bacteraemia; cBAC, complicated bacteraemia; RIE, right-sided infective endocarditis; LIE, left-sided infective endocarditis.</figcaption> </figure> Other differences between the treatment groups included a trend towards higher baseline CL~CR~ in the CoPAT patients (median 92.1 versus 86.0 mL/min, *P* = 0.064) and a trend towards a lower percentage of CoPAT patients with fever at day 4 of treatment (9.7% versus 18.8%, *P* = 0.101). Among CoPAT patients, baseline characteristics were similar for those receiving either daptomycin or comparator treatment (Table [2](#)). ::::table-wrap
::: caption
Demographic, diagnosis and treatment characteristics by treatment group
among CoPAT patients
:::

Characteristic Daptomycin (*n* = 50) Comparator^a^ (*n* = 53)

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Age (years)\
median 46.5 52.0
range 21--81 25--90
Gender\
male 31 (62.0%)^b^ 29 (54.7%)
Race\
white 26 (52.0%) 40 (75.5%)
black 19 (38.0%) 11 (20.8%)
other 5 (10.0%) 2 (3.8%)
Weight (kg)\
median 82.1 80.0
range 55.0--129.0 49.9--124.8
MRSA 18 (36.0%) 19 (35.8%)
CL~CR~ (mL/min)\
median 108.1 86.4
range 29.4--246.9 31.0--277.0
CL~CR~ \<50 mL/min 4 (8.0%) 8 (15.1%)
Evidence of endocardial involvement 4 (8.0%) 5 (9.4%)
Injection drug use 14 (28.0%) 12 (22.6%)
Pre-existing valvular heart disease 3 (6.0%) 5 (9.4%)
Fever on day 4 3 (6.0%) 7 (13.2%)
Completed treatment 46 (92.0%) 47 (88.7%)
Duration of treatment (days)\
mean (SD) 25.9 (13.31) 25.0 (11.46)
range 11--74 9--57
Days inpatient during treatment\
mean (SD) 10.7 (7.06) 10.3 (7.52)
range 5--38 2--35
Days outpatient during treatment\
mean (SD) 15.2 (10.08) 14.7 (10.18)
range 2--46 1--49
Final diagnosis\
uBAC 10 (20.0%) 17 (32.1%)
cBAC 27 (54.0%) 24 (45.3%)
RIE 11 (22.0%) 8 (15.1%)
LIE 2 (4.0%) 4 (7.5%)
Experienced ≥1 SAE 23 (46.0%) 25 (47.2%)

CoPAT, outpatient parenteral antimicrobial therapy in the community
setting; MRSA, methicillin-resistant *S. aureus*; uBAC, uncomplicated
bacteraemia; cBAC, complicated bacteraemia; RIE, right-sided infective
endocarditis; LIE, left-sided infective endocarditis; SAE, serious
adverse event.

^a^Comparator treatment was semi-synthetic penicillin/gentamicin or
vancomycin/gentamicin.

^b^No. (%), unless otherwise specified.:::: 

## Patient outcomes Among CoPAT patients, clinical success rates were similar regardless of study medication, with 45/50 (90.0%) daptomycin patients and 44/53 (83.0%) comparator patients experiencing clinical success. For IPAT patients, clinical success was observed in 26/50 (52.0%) daptomycin patients and 28/47 (59.6%) comparator patients. Thus, it is justified to combine the treatment groups for analysis of outcomes. CoPAT patients received longer courses of study antibiotics with a mean of 25.4 days (range 9--74 days) compared with 13.5 days (range 1--43) in the IPAT group (*P* < 0.001), and a higher proportion of CoPAT patients completed therapy as part of the study (90.3% versus 45.4%, *P* < 0.001). CoPAT patients received a mean of 14.9 days of therapy outside the hospital setting (Table [1](#)). The shorter duration of study treatment for IPAT patients was influenced by early discontinuations: there were 53 (54.6%) versus 10 (9.7%) in the CoPAT group. The most common reason for discontinuation was adverse events, which accounted for 25/53 (47.2%) IPAT and 8/10 (80.0%) CoPAT patient discontinuations. The adverse events responsible for discontinuation, including rash, infection, renal failure and creatine phosphokinase elevation, are listed in Table [3](#). IPAT patients whose study participation was terminated prior to the end of therapy received subsequent antibiotic therapy as appropriate, but specific information regarding types and duration of additional therapy was not part of the study database. ::::table-wrap
::: caption
Adverse events leading to discontinuation
:::

```
                                       CoPAT (*n* = 8)^a^   IPAT (*n* = 25)^a^
```

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Anaphylactic reaction 0 1
Skin^b^ 4 4
Red man syndrome 0 1
Diabetic gastroparesis 1 0
Vomiting not otherwise specified 0 1
Blood creatine phosphokinase increased 1 2
Cardiovascular^c^ 0 4
Hypoxia 0 1
Infection^d^ 0 3
Fever 0 2
Renal failure 2 3
Sepsis 0 2
Thrombocytopenia 0 1

^a^Number of discontinuations due to an adverse event.

^b^Skin includes dermatitis bullous, dermatitis medicamentosa,
erythematous rash, vesicular rash and rash not otherwise specified.

^c^Cardiovascular includes cardiac arrest (two patients),
cerebrovascular accident and circulatory collapse.

^d^Infection includes osteomyelitis not otherwise specified,
staphylococcal pneumonia and staphylococcal bacteraemia.:::: A higher rate of clinical success at the test-of-cure visit was observed among CoPAT patients (89/103, 86.4%) compared with that among IPAT patients (54/97, 55.7%) (*P* < 0.001). Four of the 103 CoPAT patients (3.9%) experienced persisting or relapsing *S*. *aureus* infection, compared with 15/97 IPAT patients (15.5%, *P* = 0.007). Fewer deaths occurred in the CoPAT group (4/103, 3.9%) compared with those in the IPAT group (18/97, 18.6%; *P* = 0.001) (Table [4](#)). ::::table-wrap
::: caption
Clinical outcomes for CoPAT patients versus IPAT patients
:::

Clinical outcome 6 weeks after end of therapy CoPAT^a^ (*n* = 103) IPAT (*n* = 97) *P*^b^

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Clinical success 89 (86.4%)^c^ 54 (55.7%) \<0.001
Failure 10 (9.7%) 26 (26.8%)\
Non-evaluable 4 (3.9%) 17 (17.5%)\
Death 4 (3.9%) 18 (18.6%) 0.001

CoPAT, outpatient parenteral antimicrobial therapy in the community
setting; IPAT, patients receiving their full course of therapy in the
hospital setting.

^a^Inpatients who were partly treated outside a hospital.

^b^Fisher's exact test.

^c^No. (%).:::: 

## Escalation of care Twice as many CoPAT patients (22/103, 21.4%) were transferred to a higher level of care during their course of treatment compared with those transferred among IPAT patients (10/97, 10.3%), a difference that reached statistical significance (*P* = 0.036) (Table [5](#)). Hospital readmission was required for 18 of the 103 (17.5%) CoPAT patients. As shown in Table [6](#), the reasons for hospital readmission were diverse. Four patients (22.2% of the readmissions and 3.9% of CoPAT patients) were readmitted for reasons related to their initial infection, including osteomyelitis or relapsed SAB. Problems related to provision of treatment in the post-acute care setting led to the readmission of three patients, two of whom relapsed with iv drug use (IVDU) and one of whom developed *Clostridium difficile* colitis. Other medical conditions leading to readmission included pneumonia in three patients and a myriad of other conditions, including unknown reasons, which were each experienced by a single patient. Of the 18 CoPAT patients readmitted to the hospital during the study, half subsequently returned to treatment in the CoPAT setting. ::::table-wrap
::: caption
Escalation of care and patient location at last dose of study drug
:::

Characteristic CoPAT (*n* = 103) IPAT (*n* = 97)

______________________________________________________________________

Transferred to higher level of care at any time during treatment 22 (21.4%)^a--c^ 10 (10.3%)
No. times readmitted to hospital to complete treatment with study drug\
one 17 (16.5%) NA
two 1 (1.0%) NA
Returned to outpatient care after readmission 9 (50.0%)^d^ NA
Reasons readmitted\
factors relating to initial infection 4 (22.2%) NA
other conditions^e^ 11 (61.1%) NA
issues relating to provision of treatment at home 3 (16.7%)^f^ NA
Location for last dose of study drug\
for patients who completed treatment 93 (90.3%) 44 (45.4%)
in hospital setting 8 (7.8%)^g^ 44 (45.4%)
as an outpatient 85 (82.5%) 0
for patients who prematurely discontinued treatment 10 (9.7%) 53 (54.6%)
in hospital setting 2 (1.9%)^g^ 53 (54.6%)
as an outpatient 8 (7.8%) 0

CoPAT, outpatient parenteral antimicrobial therapy in the community
setting; IPAT, patients receiving their full course of therapy in the
hospital setting; NA, not applicable.

^a^No. (%).

^b^*P* = 0.036, Fisher's exact test.

^c^One patient had increased level of care within post-acute care but
was not readmitted to hospital. Three patients had escalation of
inpatient care prior to post-acute care.

^d^Based on the 18 patients who were readmitted to hospital.

^e^Underlying disease or new problems not related to the initial
infection. See Table [6](#).

^f^One patient was readmitted twice for the same problem related to
delivery of treatment at home. See Table [6](#).

^g^Patients readmitted to hospital.:::: ::::table-wrap
::: caption
Patient status and factors related to hospital readmission among CoPAT
patients
:::

Characteristic CoPAT patients (*n* = 103)

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No. of post-acute care patients readmitted^a^ 18/103 (17.5%)^b^
Reasons for readmission\
Factors relating to initial infection (*n* = 4)\
osteomyelitis 2/18 (11.1%)
relapsed *S. aureus* bacteraemia 1/18 (5.6%)
embolic stroke 1/18 (5.6%)
Other conditions (*n* = 11)\
pneumonia 3/18 (16.7%)
urinary tract infection 1/18 (5.6%)
fever of unknown origin 1/18 (5.6%)
gout 1/18 (5.6%)
seizures (history of seizure disorder) 1/18 (5.6%)
sarcoid 1/18 (5.6%)
gastroparesis 1/18 (5.6%)
left against medical advice 1/18 (5.6%)
unknown 1/18 (5.6%)
Issues relating to receipt of treatment at home (*n* = 3)\
drug use 2/18 (11.1%)
*C. difficile* colitis 1/18 (5.6%)
Study drug\
daptomycin 9/50 (18.0%)
vancomycin 4/30 (13.3%)
semi-synthetic penicillin 5/23 (21.7%)
Final diagnosis\
uBAC 2/27 (7.4%)
cBAC 10/51 (19.6%)
RIE 6/19 (31.6%)
LIE 0/6
Intravenous drug user\
no 11/77 (14.3%)
yes 7/26 (26.9%)

CoPAT, outpatient parenteral antimicrobial therapy in the community
setting; uBAC, uncomplicated bacteraemia; cBAC, complicated bacteraemia;
RIE, right-sided infective endocarditis; LIE, left-sided infective
endocarditis.

^a^One patient was readmitted twice for reasons relating to treatment at
home.

^b^No. (%).:::: IVDU was associated with an increased risk of hospital readmission for CoPAT patients, with 7/26 (26.9%) IVDU patients requiring readmission, compared with 11/77 (14.3%) non-IVDU patients requiring readmission. The use of iv drugs during therapy was documented in two of the seven readmitted IVDU patients. Also of note was the fact that a higher proportion of patients with right-sided IE (6/19, 31.6%), though not statistically significant, required hospital readmission compared with those with other final diagnoses (Table [6](#)). Five of the six readmitted patients with right-sided IE were iv drug users (four complicated right-sided IE and one uncomplicated right-sided IE).


Extracted trial result:
Outcome: early discontinuations (binary)
Intervention: some portion of therapy outside of the hospital (CoPAT)
Comparator: full course of therapy in the hospital setting
Intervention events: 10
Intervention group size: 103
Comparator events: 54
Comparator group size: 97