3640
Outpatient Treatment of Febrile Episodes
in Low-Risk Neutropenic Patients
with Cancer
Edward B Rubenstein, M.D.,* Kenneth Rolston, M.D.,* Robert S. Benjamin, M.D.,t
John Loewy, Ph.D.,$ Carmen Escalante, M.D.,* Ellen Manzullo, M.D.,*
Pamela Hughes, M.D.,* Betty Moreland, R.N.,§ Andrew Fender, P.A.-C.,*
Kathryn Kennedy, M.S.W.,I( Frankie Holmes, M.D.,t
Linda Elfing, Ph.D.,* and Gerald P. Bodey, M.D."
Background. Hospitalization and intravenous (IV)
broad-spectrum antibiotics are the standard of care for
all febrile neutropenic patients with cancer. Recent work
suggests that a low-risk population exists who might
benefit from an alternate approach.
Methods. A prospective randomized clinical trial
was performed comparing oral ciprofloxacin 750 mg plus
clindamycin 600 mg every 8 hours with IV aztreonam 2 g
plus clindamycin 600 mg every 8 hours for the empiric
outpatient treatment of febrile episodes in low-risk neu-
tropenic patients with cancer.
Results. The oral regimen cured 35 of 40 episodes
(88% response rate), whereas the IV regimen cured 41 of
43 episodes (95% response rate, P = 0.19).Although the
cost of the oral regimen was significantly less than that of
the IV regimen ( P < o.ooo~), it was associated with signifi-
cant renal toxicity ( P < 0.05),which led to early termina-
tion of the study. Overall, combining its safety and effi-
cacy, the IV regimen was superior (P = 0.03).
Conclusions. This prospective study suggested that
outpatient antibiotic therapy for febrile episodes in low-
risk neutropenic patients with cancer is safe and effec-
tive. Better oral regimens are needed. Cancer 1993;
71~3640-6.
Key words: cancer, neutropenia, fever, outpatient antibi-
otic therapy.
Febrile neutropenic patients are routinely admitted to
the hospital for the administration of broad-spectrum
From the Departments of *Medical Specialties, tMedical Oncol-
ogy, IISocial Work, SBiomathematics, and GDivision of Nursing, The
University of Texas M. D. Anderson Cancer Center, Houston, Texas.
Address for reprints: Edward B Rubenstein, M.D.. The Univer-
sity of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boule-
vard, Box 40, Houston, TX 77030.
Accepted for publication January 25, 1993.
intravenous (IV) antibiotic^.'-^ Currently, no studies
have examined the role of outpatient therapy for the
treatment of such patients, despite retrospective reports
indicating that there exists a population with a high
response rate to antibiotic therapy and a low risk of
serious complication^.^^^ One of the challenges of am-
bulatory medicine research is to develop strategies that
move traditionally inpatient problems or therapies to
the outpatient setting. Several recent advances in medi-
cine, including the availability of broad-spectrum beta-
lactam antibiotics with long half-lives and stabilities,
the development of oral antipseudomonal agents, im-
provements in vascular access, and the application of
programmable computerized small-volume infusion
pumps, allowed us to design a study to evaluate the
efficacy of outpatient antibiotic therapy in low-risk fe-
brile neutropenic patients with cancer.
Previous studies of infections in neutropenic pa-
tients with cancer have documented the need for such
patients to be treated with antibiotics that have broad-
spectrum coverage against gram-negative bacilli and
gram-positive organism^.^-^ Aztreonam is a synthetic
monocyclic beta-lactam that is highly active against
gram-negative aerobic organisms, including Pseudo-
monas aerugitiosa, but has no activity against gram-
positive or anaerobic organisms.'0," It has previously
been shown to be effective for the treatment of gram-
negative infections in neutropenic patients with
cancer." Of all the beta-lactam antibiotics, aztreonam is
least likely to be associated with hypersensitivity reac-
tions, even in patients with a history of such reactions to
other beta-la~tams.'~ Clindamycin penetrates tissues
well, particularly the soft tissues, and is active against
staphylococci, streptococci (including Streptococcus
pneurnoniae), and anaerobe^.'^,'^ Therefore, clindamy-
cin is an excellent complement to aztreonam. The com-
Outpatient Antibiotics in Neutropenic FeverlRubenstein et al.
bination has potent broad-spectrum activity that has
been proved to be effective in other clinical settings.16
Ciprofloxacin is highly active against Enterobacter-
iaceae and is the only noninvestigational oral antimi-
crobial agent available in this country with good activ-
ity against P. ~eruginosa.'~The combination of cipro-
floxacin and clindamycin has previously been shown to
have higher bactericidal activity against gram-positive
organisms, particularly against Staphylococcus aureus
and S. piieunroiiiae, than does ciprofloxacin alone."
We compared the efficacy of oral clindamycin and
ciprofloxacin with that of IV clindamycin and az-
treonam in regard to the standard response rates
achieved with inpatient therapy. The safety and effi-
cacy of these regimens were compared with each other,
and the overall safety and efficacy of outpatient ther-
apy and the costs associated with each regimen were
calculated.
Materials and Methods
Patients
All patients were recruited from the outpatient clinics at
the University of Texas M. D. Anderson Cancer Center.
Eligible patients included those with solid tumors and
leukemia. All patients had fevers (> 38.3"C), chemo-
therapy-induced neutropenia (absolute neutrophil
count [ANC], I1000/mm3), and a preexisting central
venous catheter (CVC). They needed to stay within 30
miles of the cancer center. Exclusion criteria included:
previous anaphylactic reactions or hypersensitivity to
the quinolones, aztreonam, or clindamycin; age
younger than 16 years; pregnant or nursing state;
shock; renal insufficiency (serum creatinine, > 2.5 mg/
dl or creatinine clearance, < 50 ml/min); infections
caused by microorganisms known to be resistant to the
study drugs at the time of randomization; and impaired
hepatic function (aspartate aminotransferase/alanine
aminotransferase levels > fourfold normal). Also ex-
cluded were those patients who had significant comor-
bidity (e.g., systolic blood pressure, < 90 mm Hg; un-
controlled hypercalcemia; altered sensorium; respira-
tory rate, > 30/min; or serum sodium, < 128 mg/dl).
The protocol was approved by the University of Texas
M. D. Anderson Cancer Center Surveillance Commit-
tee, and written informed consent was obtained from
all patients before therapy.
Study Design and Treatment Protocol
The patients were seen and examined in the Ambula-
tory Treatment Center. The baseline evaluation in-
cluded a physical examination; a complete blood count;
3641
multichannel biochemical profile; serum electrolyte lev-
els; prothrombin and partial thromboplastin times; uri-
nalysis; chest roentgenogram; blood cultures (one from
the CVC and one from a peripheral vein); and urine,
throat, sputum, and wound cultures when appropriate.
Eligible patients were randomized to receive either oral
ciprofloxacin 750 mg plus oral clindamycin 600 mg
every 8 hours or IV aztreonam 2 g plus IV clindamycin
600 mg every 8 hours. The study population was strati-
fied to include an equal number of patients with leuke-
mia in each treatment regimen. The patients were given
their first dose in the Ambulatory Treatment Center
and observed for a minimum of 2 hours. If there were
no adverse reactions, the patients in the oral treatment
arm were given a 7-day supply of medication and dis-
charge instructions and scheduled to return the follow-
ing day to see one of the physician-investigators.
The patients receiving the IV regimen were met at
home by a nurse from a local home infusion therapy
company (Vitalcare of America, Houston, TX). The pa-
tients were connected by their CVC to a Y set attached
to two infusion pumps (CADD PLUS, Pharmacia Del-
tec, Minneapolis, MN), each of which held a l -day sup-
ply of the antibiotic. The patients receiving the intrave-
nous regimen returned to the Ambulatory Treatment
Center on day 2 for follow-up by one of the physician-
investigators. On day 3, both groups were seen at home
by nurses from the home infusion therapy company.
Data sheets, which included vital signs, a brief physical
examination, and adverse effects, were completed by
the nurse and transmitted by telephone facsimile to the
principal investigator.
All patients were then seen every other day in the
Ambulatory Treatment Center by one of the physician-
investigators and, on the other days, by the home infu-
sion therapy nurse until they met the criteria for treat-
ment success or failure. Blood was drawn for routine
cultures on the patient's return if fever persisted at
home. Cultures were repeated, if initially positive, on
every return visit until they became negative or until
the patient was considered a treatment failure. Com-
plete blood counts were done every other day, and bio-
chemical studies were done on day 7 or on the last day
of treatment and whenever clinically indicated. A re-
cord of all study-related charges was kept to collect data
regarding the cost of outpatient therapy.
Diagnostic Criteria
The patients were considered to have bacteremia when
at least one positive blood culture was obtained, except
for coagulase-negative staphylococci, for which at least
two positive blood cultures were required. Standard
diagnostic criteria were used for cellulitis, urinary tract
3642 CANCER June 2, 2993, Volume 71, No. 11

infections, sinusitis, pneumonia, vascular access site in- Table 1. Demographic and Clinical Characteristics of
fection, pharyngitis, and fever of unknown rigi in.^,^,'^ Patients Studied
Oral Intravenous
Evaluation of Response and Toxicity Characteristic reeimen reeimen
Assessable episodes 40 43
The response to therapy was evaluated by an investiga- Age ( Y O
tor who was not involved in the patient's care. All pa- Median 52* 39*
tients with negative cultures remained in the study for a Range 16-73 17-74
minimum of 5 days, including 4 consecutive afebrile Sex (men/women) 20/20 18/25
Solid tumors 27 34
days. Those with positive cultures were treated for at
Sarcoma 10 17
least 7 days (10 days for bacteremias) until their cul- Breast cancer 9 11
tures returned to negative and they were afebrile for a Melanoma 6 4
minimum of 4 consecutive days. Patients with positive Other 2 2
cultures who remained febrile (without a downward Hematologic malignancies 13 9
trend) after 3 days were removed from the study, Leukemia (acute/chronic) 6 (5P) 5 (5/Q
treated with appropriate therapy (based on the culture Lymphoma 5 4
results), and considered treatment failures. Those with Myeloma 2 0
negative cultures, if they were still febrile on day 5, ANC (at randomization)
were removed from the study and considered treatment < 100 (per mm3) 24 25
101-500 (per mm3) 13 15
failures. These decisions were made independently of
501-1000 (per mm3) 3 3
the patient's ANC. Response was defined as the disap-
ANC: absolute neutrophil count.
pearance of all clinical and laboratory evidence of in-
* P > 0.05.
fection when the antibiotics were discontinued. Relapse
was defined as the same infection reappearing within 7
days after the discontinuation of therapy. The patients
were monitored for superinfection and toxicity using May 1990. Thirteen episodes were not evaluable (nine
standard riter ria.^*^,'* in the oral regimen and four in the IV regimen) for the
following reasons: withdrew consent (three), lack of
fever (two), lack of preexisting CVC (two), inappropri-
Statistical Considerations ate drug dosing (two), inability to keep outpatient fol-
low-up appointments (two), candidemia (one), and liv-
The sample size for this study was estimated from pre- ing outside the study area (one). The remaining 83 epi-
vious studies at the University of Texas M. D. Anderson sodes form the basis of this report. The demographic
Cancer Center because there are no published data of and clinical characteristics of the study patients are
clinical trials reporting an expected response rate for shown in Table 1, and there were no statistically signifi-
outpatient antibiotic therapy to our kn~wledge.~,~,'* As- cant differences between the two groups with regard to
suming a response rate similar to that of inpatient ther- age, gender, or underlying neoplasm. In 49 episodes
apy (80%), the study was designed to enroll 63 patients (59%), the patients were profoundly neutropenic
per treatment arm to ensure that outpatient therapy (ANC, < 100/mm3). In 28 episodes, the patients were
would not be 20% worse (i.e., 60%) in either treatment moderately neutropenic (ANC, 101-500/mm3), and in
arm at a level of significance alpha = 0.05 and 80% 6 episodes, they were mildly neutropenic (ANC, 501-
power using a two-sided chi-square test. Interim analy- 1000/mm3).
ses were planned at accrual levels of 20, 40, 60, and 80 Ninety-five percent of the patients receiving the IV
patients. If the response rate in either regimen was sig- regimen responded to therapy compared with 88% be-
nificantly worse than 80% or if either regimen showed ing treated by the oral regimen ( P = 0.19, Table 2 ) . Six
unacceptable toxicity, the study would be terminated. patients were admitted to the hospital who were receiv-
Comparisons between proportions were done using a ing the oral regimen: three who did not respond to out-
Pearson chi-square test or Fisher exact test when appro- patient antibiotics and three who had toxicity. None of
priate. the patients receiving the IV regimen required admis-
sion ( P = 0.01). No patients had septic shock or died of
Results uncontrolled infection. The median duration of therapy
during the IV regimen was 8 days (range, 5-16 days),
Seventy-eight neutropenic patients with 96 febrile epi- and during the oral regimen, it was 7 days (range, 3- 16
sodes were enrolled on this study from January 1989 to days).
Outpatient Antibiotics in Neutropenic Fever/Rubensfein ef al. 3643

Table 2. Response Rate

Oral regimen Intravenous regimen

No. of No. of No. of No. of

Type of episode episodes responses (Yo) episodes responses (YO) P value
Documented infection
Bacteremia 7 5 8 7
Urinary tract 4 3 3 3
Soft tissue/skin 3 3 2 2
Head and neck 2 2 3 3
Total 16 13 (81) 16 15 (94) 0.30
Fever of unknown
origin 24 22 (92) 27 26 (96) 0.46
Total 40 35 (88) 43 41 (95) 0.19

In 51 episodes, the cause of fever could not be de- count is shown in Table 4. Of the episodes with initial
termined. Despite this, 26 of 27 episodes treated using ANC less than 100/mm3, 45 of 49 had an increase to
the IV regimen and 22 of 24 episodes treated with the more than 100/mm3 when antibiotics were discontin-
oral regimen responded to antibiotic therapy. In 32 epi- ued. The patients had a lower response rate when their
sodes (39%), infections could be documented, 28 of ANC did not change than when they increased. None
them by microbiologic cultures. The responses in sin- of the patients were receiving granulocyte colony-
gle-organism infections are shown in Table 3. A variety stimulating factor. Six patients were receiving granulo-
of gram-positive and gram-negative infections were cyte-macrophage colony-stimulating factor (four in the
successfully treated by both regimens. There were four IV regimen), and there did not appear to be any differ-
polymicrobial infections, two on each regimen, which ence in response rates associated with the use of this
were cured with outpatient therapy. These included growth factor.
bacteremias caused by S. epidermidis, Acinetobacter Treatment failures during the oral regimen in-
species, Escherichia coli, and Proteus species. The re- cluded a patient with acute leukemia and €. cloacae-
sponse rate for patients with solid tumors was 89% and caused bacteremia who became afebrile within 24
94% for the oral and IV treatment arms, respectively. hours but had a new fever on day 5 (cultures negative)
The response rate for the patients with leukemia was and was successfully treated as an inpatient with a com-
67% for the oral regimen and 100% for the IV regimen bination of cefoperazone and sulbactam. The second
(P = 0.27). failure occurred in a 20-year-old man with sarcoma
The response to antibiotics related to the neutrophil who had Xanthomonas maltophila-induced bacteremia.
His bacteremia resolved after his CVC was changed,
and therapy was switched to oral trimethoprim and
Table 3. Response by Infecting Organism sulfamethoxazole. Two other patients with fevers of un-
known origin were admitted and responded to IV antibi-
Oral Intravenous
otics.
Single organism No. of NO. of No. of No. of
infections episodes responses episodes responses
Staphylococcus epiderinidis 1 1 3 2 Table 4. Response Related to Neutrophil Count
S. uureus 1 1 3 3 Intravenous
Enterococcus sp 3 2 2 2 Initial Oral regimen regimen
Total gram-positive 5 4 8 7 neutrophil
Acinetobacter sp 1 1 1 1 count NO. of Yo NO. of O/o

- (/mm3) Trend episodes response episodes response

Enterobacter sp 2 1 -

Xanthonionas maltophila 2 1 - - < 100 Total 24 83 25 100

Pseudonioiias aenigiriosa - - 1 1 Unchanged 2 50 2 100
Pseudomonas sp 1 1 - - Increased 22 87 23 100
Serratia iiiarccscetis 1 1 - - 101-999 Total 16 94 18 89
Klebsiella pneunioniae - - 1 1 Unchanged 2 100 1 100
Hemophilus sp 1 1 - - Increased 0 100 16 100
Total gram-negative 8 6 3 3 Decreased 4 75 1 100
3644 CANCER June 1, 1993, Volume 71, No. 11

Table 5. Characteristics of Patients With Acute Renal Failure

Duration of Intervention in
ciprofloxacin Baseline/peak final addition to
Age before ARF Other nephrotoxic serum creatinine (mg/ discontinuation of
(yr) Sex Underlying disease (days) drugs dl) and type of ARF ciprofloxacin
67 M Large cell lymphoma 5 Cispla tin 1.0/9.0/1.0 oliguric None
Cisplatin interferon
60 F Metastatic melanoma 3 NSAID 0.7/ 16.8/ 1.5 anuric Hemodialysis for 4 days
73 M Malignant fibrohistiosarconia 11 Cispla tin 1.0/2.1/1.3 nonoliguric None
1.0/8.6/0.9
63 F* Retromritoneal sarcoma 6 None Nonolieuric None
ARF: acute renal failure; NSAID: nonsteroidal antiinflammatory drug
’ Patient with one kidnev.

The single microbiologic failure during the IV regi- cost

men occurred in a woman who was persistently febrile
even though her S. epidermidis-caused bacteremia
cleared. She became afebrile when her regimen was
changed to oral trimethoprim and sulfamethoxazole.
The other treatment failure during the IV regimen oc-
curred in a man who never became afebrile until he was
receiving a nonsteroidal antiinflammatory drug for tu-
mor fever.
Toxicity
The serious toxicity was limited to the oral regimen and
led to the early termination of this study. Four episodes
of acute renal failure occurred, one of which was mild
and did not require admission to the hospital. These
episodes are summarized in Table 5. One patient with a
history of Clostridium dificile-induced colitis had a re-
currence while receiving the oral regimen. One patient
receiving the IV regimen had a superinfection with oral
candidiasis. There were no relapses in either regimen.
No patients had hepatic or hematologic toxicity.
The IV regimen was more expensive than the oral regi-
men (Table 6). The median cost of pharmaceuticals in
the oral regimen was $202 per patient, whereas in the
IV regimen, the median cost of pharmaceuticals and
infusion therapy equipment was $4672 per patient.
Nursing costs were higher in the IV regmen ($665 per
patient) compared with $190 per patient in the oral regi-
men. The median cost of therapy in the IV regimen was
$7336 per patient (range, $5065-$16,081). The median
cost of therapy in the oral regimen was $2302 per pa-
tient (range, $1105-$65,701; P < 0.0001, by Wilcoxon
rank-sum test).
Discussion
Outpatient antibiotic therapy has been shown to be a
safe and effective alternative to hospitalized care for the
treatment of selected patients with a variety of infec-
tion~.’~-’~Outpatient parenteral antibiotics have also
been shown to be more cost-effective than hospitalized
care and to lead to an improved quality of Our

Table 6. Costs Associated With Outpatient Therapy

Oral regimen Intravenous regimen

Variable Median Ranxe Median Ranxe P* value

Clinic visits, laboratory charges, and supplies $1325 $621-4371 $1473 $804-4676 0.33
Pharmaceuticals 202 146-407 4672 3,431-9884 < 0.0001
Physician fees 308 143-9262 295 111-698 0.55
Home nursing visits 190 95-855 665 95-1520 < 0.0001
Hospital charges? 7228 353 1-55,185 NA NA NA
Total $2302 $1105-65,701t $7336 $5065-16,081 < 0.0001
NA: not applicable.
* Wilcoxon rank-sum test
t As a result of failure/morbidity of outpatient therapy
t Includes the cost of hemodialvsis.
Outpatient Antibiotics in Neutropenic FeverlRubenstein et al.
study is the first prospective trial demonstrating the suc-
cess of this approach in febrile neutropenic patients to
our knowledge. We did not compare inpatient with
outpatient therapy with the same antibiotic regimen
because hospitalization exposes patients to hospital
flora and increases the risk of superinfection with resis-
tant bacteria and fungi.30
The combined response rate of 92% for both treat-
ment regimens was higher than that reported in many
of the larger inpatient clinical trials but similar to that of
a low-risk group of febrile neutropenic patients treated
from 1979-1984 at the National Cancer Institute, in
which a subgroup of 590 febrile neutropenic episodes
was retrospectively analyzed and no obvious foci of
infection could be determined.4 In 331 episodes, the
duration of neutropenia was less than 7 days, and these
patients were categorized as being at low risk for sec-
ondary or superinfections. The initial empiric antibiotic
regimen was successful in 315 episodes (95%) com-
pared with 30 cases (32%) in 93 episodes categorized as
high risk (duration of neutropenia, > 14 days).
Others recently developed a model to determine
risk assessment in this patient p ~ p u l a t i o n . ~ Their
,~~
work indicated that patients with serious comorbidity,
inpatients who have fevers while neutropenic, and out-
patients without comorbidity but with uncontrolled
cancer had a much higher risk of subsequent complica-
tions than do clinically stable outpatient^.^^ Their con-
clusion was that ”low risk patients are an appropriate
population in which to study less intensive treatment
strategies” (page 3 16).
With the availability of agents such as the newer
quinolones, oral therapy has become a reasonable alter-
native to IV therapy for treating infections in patients
with cancer; however, in this study, it was associated
with a greater than expected renal toxicity. This may
have been the result of several factors: the high dose of
ciprofloxacinused, subclinical dehydration, preexisting
diminished renal function because of age or chemother-
apy, or a nephrotoxic interaction between ciprofloxacin
and clindamycin. Recently, reports of acute renal fail-
ure associated with doses of ciprofloxacin as low as 250
mg twice daily have appeared in the medical litera-
t ~ r e . ~ However,
’-~~ in a previous clinical trial at our in-
stitution that used ciprofloxacin 750 mg every 8 hours
in hospitalized patients with cancer receiving intrave-
nous fluids, only one episode of transient renal insuffi-
ciency occurred during 46 episodes of infection.35Fur-
thermore, a recent study demonstrated the reduced ab-
sorption of orally administered ciprofloxacin in patients
receiving chemotherapy and suggested using a higher
dose of ciprofloxacin than traditionally recommended
for serious infection^.^^ Therefore, the dose does not
appear to be the only factor associated with nephrotoxi-
3645
city. We cannot exclude an interaction between cipro-
floxacin and known nephrotoxins, such as cisplatin, be-
cause two of the four patients with acute renal failure
had received this drug. However, seven patients receiv-
ing the oral regimen who did not have nephrotoxicity
had also received this drug. We might have detected
renal insufficiency earlier by more frequent determina-
tions of renal function and prevented the more serious
nephrotoxicity seen in this study.
There was a significant difference in major toxicity
between the IV and oral regimens (P < 0.05) and a
difference in efficacy whose significance could not be
determined because it would have required us to enroll
276 patients per treatment group to detect a difference
between a 95% response rate and an 88% response rate
with 80% power and a significance of P = 0.05.37Com-
bining safety and efficacy, the IV regimen overall was
superior to the oral regimen (P = 0.03) but more costly
( P < 0.0001). Future studies could allow those patients
who did not respond to oral antibiotics the benefit of IV
therapy without the costs of hospitalization.
The reported response rates with inpatient empiric
antibiotic therapy in febrile neutropenic patients range
from 70--85Y0.*,~*~ Although we successfully treated 76
of the 83 episodes with the empiric regimens and kept
patients out of the hospital for 77 episodes, this ap-
proach should not be considered the new standard of
care. None of our patients had complicated gram-nega-
tive bacteremias or gram-negative bacterial pneumo-
nias, a group of patients with a well-documented lower
response rate to antibiotic the rap^.^,^' Nevertheless, the
criteria chosen for eligibility for this study identified a
group of patients for whom outpatient IV antibiotic
therapy with careful monitoring is an appropriate alter-
native to hospitalized care. Despite the superiority of IV
therapy in this study, the 88% response rate associated
with oral ciprofloxacin and clindamycin is the first re-
ported result of outpatient oral antibiotics to our knowl-
edge and suggests that future studies should look at
subpopulations who would benefit from less toxic oral
regimens. Consequently, we have designed a new
study utilizing the same IV regimen, but with a modi-
fied oral regimen, and are currently enrolling patients.
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