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Protopic:
An Alternative to Topical Steroids in
the Treatment ofAtopic Dermatitis

Thomas J. Murray III, Pharm. D. Candidate


Introduction
Atopic dermatitis (eczema) is a commonly
found skin disorder present all over the world. It is
a chronic inflammatory skin disease affecting 5-
10% of the population in the U.S. (about 15 million
people). The disease has both genetics and suscep-
tibility to environmental irritants as predisposing
factors. Individuals affected have intense itching,
xerosis, erythematic lesions, rash, exudative ero-
sions and increased vulnerability to cutaneous in-
fections.1,2 Typically the only treatments have been
topical steroids, oral antihistamines and antibiotics
when infection is present. Protopic (topical tac-
rolimus) is a new drug designed to combat atopic
dermatitis.
Protopic, manufactured by Fujisawa, is the
first new drug to treat atopic dermatitis in 40 years.
It was approved by the FDA in December of 2000
and is indicated for short-term and intermittent
long-term therapy in the treatment of patients with
moderate to severe atopic dermatitis in whom the
use of alternative, conventional therapies are
deemed inadvisable because of potential risks, or in
the treatment of patients who are not adequately re-
sponsive to or are intolerant of alternative, conven-
tional therapies.3 This article will address the phar-
macology, clinical trials, dosing, adverse effects
and costs of Protopic therapy.
Pharmacology/Pharmacokinetics


Tacrolimus is the first in a new generation
of topical immunomodulators (TIMs)3. When ap-
plied topically tacrolimus complexes with protein
FKBP-12, found in T-cells. This complex eventu-
ally binds calcineurin and blocks the transcription
of cytokines thus inhibiting further T-cell activation
and a proliferation of the immune response.2'3 Tac-
rolimus may also act by binding to cell surface ster-
oid receptors, inhibiting the release of mast cell me-
diators, downregulate IL-8 receptors and decrease
intracellular adhesion molecule-1 and E-selectin
lesional blood vessel expression. All of this leads
to decreased recognition of antigen and a general
decrease in the entire inflammatory cascade.
The kinetic profile of this drug is essentially
non-existent. It is a topical ointment that does not
reach systemic circulation to any clinically signifi-
cant degree. The average peak blood concentra-
tions of tacrolimus are <1 to 5 ng/mL which are
less than the trough concentrations of 5-20 ng/mL
seen in patients on tacrolimus therapy to prevent
organ rejection.24

Clinical Trials
Tacrolimus was used as monotherapy to
treat atopic dermatitis in two identical randomized,
double-blind, comparative studies. A total of 632
adults (age >15 y/o) were treated for up to 12
weeks or until 1 week after complete resolution of
symptoms. Efficacy was determined by the physi-
cian's global evaluation of clinical response at the
end of the study period. The results of the study
showed that both concentrations of tacrolimus oint-
ment were indeed superior to vehicle alone in treat-
ment of atopic dermatitis. In this study, African
American patients benefited more from the 0.1%
ointment versus the 0.03%, most likely due to a


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lower percutaneous penetration/absorption of topi-
cally applied agents compared with Caucasian pa-
tients. A more compact stratum corneum and
higher epidural lipid content are thought to explain
these racial differences. No other variations in pa-
tient population seemed to affect the outcome of
therapy. Treatment with tacrolimus 0.1% and
0.03% lead to statistically significant healing rates
compared to vehicle alone (see Table 1).5
In a second study, 351 children (2-15 y/o)
were followed in a randomized, double-blind, par-
allel group, 3-arm, intention to treat, vehicle-


Table 1. Adult Response5

Physician's Global Vehicle Protopic Protopic
Evaluation of Clini- Ointment Ointment Ointment
cal Response 0.03% 0.1%
(% Improvement) (N= 212) (N= 211) (N= 209)
100% 2(1%) 21(10%) 20(10%)
>90% 14(7%) 58 (28%) 77(37%)
>75% 30 (14%) 97 (46%) 117 (56%)
>50% 42 (20%) 130 (62%) 152 (73%)


controlled study where tacrolimus was used as
monotherapy. Patients were again treated for up to
12 weeks or for 1 week after complete resolution of
symptoms. Even though the evaluation criteria
(improvement of 90%) were stringent, over one-
third of tacrolimus treated patients saw this level of
improvement while the majority of the vehicle oint-
ment group had no appreciable improvement or
were worse off at the end of the study. This study
noted no appreciable difference between varying
patient demographics and effective tacrolimus
treatment. Overall there was a statistically signifi-
cant higher healing rate with tacrolimus over vehi-
cle alone (see Table 2).6
Another study looked at the efficacy and
safety of tacrolimus treatment on refractory facial
lesions in atopic dermatitis following topical ster-
oid discontinuation. This study included 47 pa-
tients (ages 18-63 y/o) with refractory facial atopic
dermatitis, of whom 38 had used topical steroids
for at least 4 weeks before enrollment (Group 1)
and 9 that had not received steroid treatment
(Group 2). All patients received 0.1% tacrolimus
ointment and the severity index and pruritus scores


were assessed as an atopic dermatitis activity index
each week and compared with baseline data. The
data showed that both groups showed excellent im-
provement and Group 1 showed no evidence of a
rebound phenomenon commonly seen when ster-
oids are discontinued in patients with atopic derma-
titis. There were no serious systemic adverse ef-
fects noted in this study and mild burning at the site
of application was the major topical adverse effect
noted, present in 66% of the study population
(although only transient and not occurring past the
third day of treatment on average).
Dosing
Tacrolimus is available in 30g and 60g
tubes of two strengths, 0.03% and 0.1%. The

Table 2. Pediatric Response6

Physician's Global Age 2-15 y/o
Evaluation of Clini- Protopic
cal Response Vehicle Ointment Ointment 0.03%
(% Improvement) (N = 116) (N =117)

100% 4 (3%) 14 (12%)
>90% 8 (7%) 42 (36%)
>75% 18 (16%) 65 (56%)
>50% 31(27%) 85 (73%)


0.03% strength is indicated for the treatment of
atopic dermatitis in children ages 2-15 years. It is
applied as a thin film twice daily with treatment
continuing one week past the resolution of symp-
toms. The 0.1% strength is indicated for those over
15 years of age. It is also applied as a thin film
twice daily with treatment continuing one week
past the resolution of symptoms, this may take
about three weeks.2'3 Also, occlusive dressings
should not be used as this can lead to increased sys-
temic availability of the drug and subsequent un-
wanted side effects.

Adverse Effects
In numerous clinical trials the most com-
monly reported adverse effects were a sensation of
burning upon use of tacrolimus, pruritus, flu-like
symptoms, skin erythema and headache. Two ran-
domized, double-blind, comparative, vehicle con-
trolled studies involving 631 adults with moderate
to severe atopic dermatitis showed that the previ-


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Table 3. Incidence of Adverse Effects with Protopic"

Treatment Group p-value

Vehicle 0.03% 0.1% 0.03% vs. 0.1% vs.
(n = 212) (n = 210) (n = 209) vehicle vehicle

Skin burning 25.8 + 3.43 45.6 3.50 57.7 3.52 <.001 <.001
Pruritus 36.5 3.70 46.1 +3.57 46.1 +3.59 .059 .062
Flu-like symptoms 19.3 + 4.06 23.2 3.28 30.8 3.61 .451 .034
Skin erythema 19.8 + 3.04 24.8 3.07 27.9 3.19 .250 .066
Headache 10.7 2.79 20.0 2.99 19.2 2.99 .022 .036
Skin infection 10.6 + 2.67 12.4 2.50 4.7 + 1.65 .617 .063
Skin Tingling 2.4 + 1.04 3.4+ 1.27 7.6 + 1.91 .522 .015
Acne 1.8 1.30 4.3+ 1.48 7.1 2.02 .213 .028


ously mentioned AE's had a significantly higher
incidence in the tacrolimus treatment groups versus
the vehicle group (see Table 3).8 Although these
AE's were more severe in the tacrolimus groups,
there was a higher rate of completed treatment in
these groups compared to the vehicle groups (see
Table 4).
An open-label, long-term, non-comparative
safety study enrolled 255 children (ages 2-15 y/o)
to assess early discontinuation of therapy in pediat-
ric populations (see Table 5)9. The patients were


Table 4. Adult Discontinuation8

0.03% 0.1%
Vehicle
Tacrolimus Tacrolimus

Number of Patients 212 210 209

Completed Treatment 67(31.6) 149 (71.0) 157 (75.1)

Prematurely Discontin- 145(68.4) 61(29.0) 52 (24.9)
ued Treatment

Adverse Event 26 (12.3) 13 (6.2) 11(5.2)
Lack of Efficacy 95(44.8) 26(12.3) 18(8.6)
Administrative 24 (11.3) 22 (10.4) 23 (11.0)

No. Treatment Days
mean (median) 40.0 (22) 69.4 (84) 68.1(84)


evaluated at baseline, 1 week, and 3, 6, 9, 12
months and 1 week after each time remission was
achieved. Again the major AE noted was burning
and pruritus at the site of application and typically
lasted less than 10 minutes and 1 hour respectively.
Although not specifically assessed there were no


reports of skin atrophy or growth retardation.
Cost of Therapy
The price of a 30 day supply of Protopic
varies between amount used and strength used. A
summary of average retail pharmacy prices can be


Table 5. Pediatric Discontinuation9

No. Patients (%)

Enrolled 255

Prematurely Discontinued 66 (25.9)

Lack of Efficacy 8 (3.1)
Administrative Reason 48 (18.8)
Any Adverse Event 10 (3.9)
Application site irritation 5 (2.0)
Non-application site irritation 5 (2.0)
* Administrative reasons include lost to follow-up, non-compliance, patient
refusal, etc.



found in Table 6.
Summary
Targeting immune cells to prevent
inflammatory response is the new direction of
treatment for atopic dermatitis. Studies show that


Table 6. Costs of Protopic

Strength Amount Cost

0.03% ointment 30 g $ 69.64
0.03% ointment 60 g $134.78
0.1% ointment 30 g $72.74
0.1% ointment 60 g $140.95


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Volume 17, Issues 8-9 June/July 2002







topical tacrolimus is not only effective in treating
this disease, but also lacks the unpleasant adverse
effects commonly seen with topical steroid therapy.
While this may be a costly alternative to other
available medications, overall topical tacrolimus
seems to be an important clinical breakthrough for
the treatment of atopic dermatitis.

References
1. American Academy of Dermatology. Patient
Information: Eczema/Atopic Dermatitis. www.
aad.org/pamphlets/eczema.html, 1999.
2. Clinical Pharmacology 2000. Tacrolimus/
Protopic Monograph.
3. Fugisawa Healthcare, Inc. Full Prescribing In-
formation for Protopic. Dec 2000.
4. Fugisawa Healthcare, Inc. Professional Re-
sources: Prograf Product Monograph. www.
prograf.com/prof/dosageadm.asp#blood
5. Hanifin J, et al. Tacrolimus Ointment for the
Treatment of Atopic Dermatitis in Adult Pa-
tients: Part I, Efficacy. J Am Acad Dermatol
2001;44(Suppl): S28-38.
6. Paller A, et al. A 12-Week Study of Tacrolimus
Ointment for the Treatment of Atopic Dermati-
tis in Pediatric Patients. J Am Acad Dermatol
2001;44(Suppl): S47-57.
7. Kawakami T, et al. Safe and Effective Treat-
ment of Refractory Facial Lesions in Atopic
Dermatitis Using Topical Tacrolimus following
Corticosteroid Discontinuation. Dermatology
2001;203:32-37.
8. Soter N, et al. Tacrolimus Ointment for the
Treatment of Atopic Dermatitis in Adult Pa-
tients: Part II, Safety. J Am Acad Dermatol
2001;44(Suppl): S39-46.
9. Kang S, et al. Long-Term Safety and Efficacy
of Tacrolimus Ointment for the Treatment of
Atopic Dermatitis in Children. JAm AcadDer-
matol;44(Suppl):S58-64


-
Pha rma Note Volume 17, Issues 8-9 June/July 2002


Treating Com-
munity-Acquired Pneumonia
In the Drug Resistant Era

QueTran Hoang, Pharm. D. Candidate


Introduction
Antimicrobial resistance leads to increased
mortality, morbidity, and health care costs. The
emergence of drug-resistant pneumococcal strains
has complicated the management of infections such
as community-acquired pneumonia (CAP). Pneu-
monia currently constitutes the sixth cause of death
and the first cause of infectious death in the United
States.1 Streptococcus pneumoniae is the most
commonly identified cause of CAP, accounting for
9% to 55% of cases of community-acquired pneu-
monia among patients requiring hospitalization. In
the past, several agents have been used as first line
treatment options for this organism in CAP. How-
ever, with extensive usage, in-vitro antimicrobial
resistance has developed.2'3 According to the Na-
tional Committee for Clinical Laboratory Standards
(NCCLS), in cases of pneumonia, S. pneumoniae
should be considered as penicillin susceptible if the
MIC is 0.06 g/mL, as intermediate susceptible if
the MIC is 0.1 to 1.0 g/mL, and resistant if the MIC
is 2.0 g/mL.10 Unfortunately, resistance extends
beyond the 8-lactam antibiotics. Resistance has
been documented to other classes of antibiotic in-
cluding the macrolides and the fluoroqui-
nolones.3'8'16 This article will review the role of 3-
lactam antibiotics, macrolides, and the fluoroqui-
nolones in the treatment of pneumococcal CAP.

Mechanism of Resistance
Bacteria possess a significant number of ge-
netic mechanisms for resistance to antimicrobials.
Three of the proposed mechanisms for resistance
development that are influenced by antimicrobial
usage include acquisition of resistance, emergence
of dormant resistance and selection of resistant sub-
populations. Resistance to penicillin is acquired
through the production of 1-lactamase, altered peni-
cillin-binding proteins (PBPs), and the reduction of
permeability. Penicillin resistance in S. pneumo-
niae is intrinsic and appears to be caused by altered
PBPs. Although the majority of strains with re-


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Volume 17, Issues 8-9 June/July 2002







duced susceptibility to penicillin are susceptible to
certain third-generation cephalosporins, such as ce-
fotaxime or ceftriaxone, intermediate resistance and
resistant strains are increasing. Bacterial resistance
to cephalosporins may be natural or acquired and
may result from one or a combination of factors. A
major mechanism of bacterial resistance to cepha-
losporins is the production of 1-lactamase which
inactivates the drugs by hydrolyzing the 1-lactam
ring. Nevertheless, absence or presence of a 13-
lactamase does not entirely dictate susceptibility or
resistance to a cephalosporin. Bacterial resistance
usually results from both 1-lactamase production
and presence of permeability barriers.4'9'11'12
Resistance to erythromycin from S. pneu-
moniae develops stepwise and is due to two main
mechanisms: one involves the target site modifica-
tion by an enzyme that methylates 23S rRNA, the
erythromycin resistance methylase, and the second
is the presence of a macrolide efflux pump. Efflux
mutants, encoded by mefE, account for approxi-
mately 60-75% of macrolide-resistant strains of S.
pneumoniae in North America.8 This mechanism of
resistance can be overcome with higher serum
erythromycin concentrations. Cross-resistance
does occur among the macrolides, including
azithromycin, clarithromycin, dirithromycin, and
erythromycin. Resistance by the mechanism of ri-
bosomal methylase encoded by ermAM, which oc-
curs mostly in Europe, results in a high grade of re-
sistance that cannot be overcome. Erythromycin,
specifically, exhibits a dissociated type of resis-
tance, in which the presence of erythromycin can
influence in vitro susceptibility testing. For exam-
ple, strains of organisms that are resistant to eryth-
romycin but susceptible to other macrolides may
show resistance to these drugs if erythromycin was
also present. Clindamycin's MIC is used to deter-
mine which macrolide resistance is present. S.
pneumoniae resistance arising from ribosomal me-
thylation is erythromycin resistant and clindamycin
resistant, however, macrolide resistance from the
efflux mechanism can be erythromycin resistant
and clindamycin susceptible. S. pneumoniae
strains, with mefE phenotype and MIC of erythro-
mycin between 1 and 16 g/mL, are resistant to mac-
rolides but susceptible to clindamycin. 3,4,8,11
Fluoroquinolones (FQs) remain a popular
choice of antibiotic for many inpatient and outpa-


tient infections. Some fluoroquinolones possess ex-
cellent antipneumococcal activity. Unfortunately,
with widespread use, resistance to this class of anti-
biotic has also emerged, therefore the Center of
Disease Control (CDC) currently recommends
fluoroquinolones as a second line treatment for
CAP. The organisms become resistant to FQs
through two mechanisms: chromosomal mutations
or alterations in their ability to permeate the bacte-
rial cell wall. Single or multiple mutations in the
genes encoding the bacterial DNA gyrase or topoi-
somerase IV are the specific sites of mutation. S.
pneumoniae shows resistant to FQs through the ef-
flux pump mechanism, which limits intracellular
accumulation of antimicrobials. This is independ-
ent of the FQs resistance caused by the other two
mechanisms and is an energy dependent process.
Cross-resistance among the FQs does exist, there-
fore empiric therapy with FQs should be used with
caution.4,6,10,11,13,16

Pharmacokinetics
Amoxicillin has extended antibacterial ac-
tivity to the gram-negative organisms and closely
related to ampicillin. It has a more complete ab-
sorption than ampicillin, 74-92% absorption from a
single dose, which results in higher serum concen-
trations. With a more complete absorption, less
drug remains in the intestinal tract, and the fre-
quency of diarrhea is decreased. Peak serum con-
centrations of amoxicillin are generally reached 1-2
hours after oral administration.6'11 12
Several cephalosporins such as cefuroxime,
cefotaxime, cefepime, or ceftriaxone are also rec-
ommended for the treatment of CAP.6'7 These
agents have better coverage against S. pneumoniae
compared to other cephalosporins. The bioavail-
ability of cefuroxime is increased when taken with
food. The variable absorption rate of this drug ac-
counts for the high incidence of gastrointestinal
side effects. Cefotaxime is unique among the
cephalosporins since it is metabolized through
deacetylation by the liver to a biologically active
metabolite, desacetylcefotaxime. Desacetylcefo-
taxime in combination with cefotaxime can have
synergistic or addictive effects. Ceftriaxone has the
longest half-life of the 8-lactams. It is unique
among the cephalosporins in that it is one of two
cephalosporins that has a dual hepatic and renal ex-


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Volume 17, Issues 8-9 June/July 2002







Table 1. Overview of Pharmacokinetic Properties

F tin Cmax
Drugs Dose (%) (urs) max Excretion Protein binding
(%) (hours) (mg/L)
Cephalosporins
Cefuroxime 750 mg 50 1.3 4.1 Urinary 35%
Ceftriaxone 1 gm ---- 8.5 132 Dual 83-96%
Cefepime 1 gm ---- 2.0 29.6 Urinary 20%
Cefotaxime 1 gm ---- 1.2 37.9 Urinary 35%

Macrolides
Erythromycin 500 mg 15-45 2 3.0 Biliary 80%
Clarithromycin 500 mg 50 3-5 2.4-3.5 Biliary 42-50%
Azithromycin 500 mg 34 10-40 0.336 Biliary 52%

Fluoroquinolone
Ciprofloxacin 500 mg 85 3-7 2.0 Urinary 35%
Levofloxacin 500 mg 99 7.4 5.2 Urinary 24-38%
Moxifloxacin 400 mg 90 12 Urinary 50%
Gatifloxacin 400 mg 98 8.4 3.4 Urinary 20%

Penicillin
Amoxicillin 500 mg 74-92 0.7-1.4 Urinary 17-20%
F = bioavailability, Cma maximal concentration, t/2= half-life, < 95% protein binding considered insignificant, dual = biliary + urinary


cretion.3, 6 11
Macrolide agents have some activity for or-
ganisms with penicillin MIC values of 2.0 mg/L,
this may be due to the high degree of macrolide
penetration into respiratory secretions. Most mac-
rolide resistance in North America is due to an ef-
flux mechanism. The efflux mechanism is associ-
ated with substantially lower MIC values than the
ribosomal mechanism.6 Clarithromycin and
azithromycin have a broader coverage and are bet-
ter tolerated compared to erythromycin. Erythro-
mycin is well absorbed from the gastrointestinal
tract (GIT). Erythromycin is excreted primarily in
the bile. The normal serum half-life is 1.4 hours
and serums levels are maintained for 6 hours.
Clarithromycin is also well absorbed from the GIT
with a bioavailability of 50% with steady state usu-
ally reached after five doses. Clarithromycin tis-
sue-serum ratio is greater than erythromycin but
less than azithromycin. It is extensively metabo-
lized in the liver and excreted really. Azithromy-
cin is more stable than erythromycin at gastric pH.
It has an extensive uptake from the circulation into
intracellular compartments, followed by a slow re-
lease. Azithromycin is eliminated unchanged in the
feces with no metabolite. It has a mean tissue half-


)hcrmalinto


life of 2-4 days, which allows a 5-day
CAP.3 '8, 12


regimen for


Antipneumococcal fluoroquinolones (FQs)
such as moxifloxacin, levofloxacin, or gatifloxacin
penetrate well into the lung, often achieving levels
higher than serum levels at sites such as the epithe-
lial lining fluid and alveolar macrophages. FQs
have longer serum half-lives, which allows for once
daily dosing and higher peak levels. FQs are bacte-
ricidal antibiotics and display a concentration-
dependent killing effect. They also exhibit a post-
antibiotic effect.12 Table 1 reviews the pharma-
cokinetics properties of the FQs and other agents
recommended for the treatment of CAP.

Clinical Studies
A prospective, open-labeled, multicenter,
randomized, and actively controlled study enrolled
590 patients to compare the safety and efficacy of 7
to 14 days of levofloxacin treatment versus ceftri-
axone and/or cefuroxime axetil for the treatment of
CAP in adults. S. pneumoniae was the most com-
mon pathogen and was isolated from 63 sputum
specimens (15% of patients that were clinically
evaluated). After 5-7 days of therapy, levofloxacin
had a higher success rate of 96% compared to the


Volume 17, Issues 8-9 June/July 2002


1


I I I I I I I I i i







ceftriaxone and/ or cefuroxime axetil success rate
of 90%. Levofloxacin eradicated 100 % of S. pneu-
moniae while ceftriaxone and/or cefuroxime axetil
eradicated 85% of the pathogen. Tolerability was
similar in both groups with mild gastrointestinal
symptoms being the most common. Even though
levofloxacin shows an eradication rate of 100% for
S. pneumoniae in this study, in areas with high rates
of pneumococcal resistance, local sensitivity pat-
terns need to be seriously considered. More re-
cently, reserved use status of levofloxacin is recom-
mended based on levofloxacin-resistant S. pneumo-
niae that was cross-resistant to newer fluoroqui-
nolones.18
An international multicenter, randomized,
prospective, double blind study compared the effi-
cacy and safety of two oral moxifloxacin regimens
and oral clarithromycin in the treatment of commu-
nity-acquired pneumonia. S. pneumoniae was 42%
of the isolated pathogens. A total of 678 patients
were randomized to receive either moxifloxacin
200 mg qd, 400 mg qd, or clarithromycin 500 mg
bid for ten days. Patients were evaluated for clini-
cal and bacteriological response. Clinical success
rate after 3-5 days post-therapy was 93.9% for pa-
tients treated with moxifloxacin 200 mg, 94.4%
with 400 mg moxifloxacin, and 94.3% with
clarithromycin. After 21-28 days of study treat-
ment, clinical success rate of 200 mg moxifloxacin
was 90.7%, 92.8% with 400 mg moxifloxacin, and
92.2% with clarithromycin. The bacteriological
success rate for S. pneumoniae was 95% (200 mg
moxifloxacin), 90.5% (400 mg moxifloxacin), and
91.7% (clarithromycin). Adverse events from this
study are similar among the treatment groups. This
study indicates that moxifloxacin is as effective and
well-tolerated as clarithromycin. Bacteriological
success rate is slightly higher in the moxifloxacin-
treated patients than the clarithromycin-treated pa-
tients. Data from this study and other in vitro data
have demonstrated moxifloxacin has a spontaneous
mutation frequency in S. pneumoniae of 1 x 10-9,
two orders lower than other quinolones.
An open-labeled, randomized study evalu-
ated the efficacy of azithromycin as monotherapy
for the treatment of CAP in adults.14 Azithromycin
was administered to 414 patients: 202 comparative
trial and 212 non-comparative trial. The azithromy-
cin in each group was administered as 500 mg IV


for 2-5 days, then followed with 500 mg PO for 7-
10 days. The comparative trial was a multicenter,
parallel group, randomized, open-labeled study
with 202 patients received azithromycin compared
to 201 patients treated with cefuroxime at 750 mg
IV every 8 h for 2-7 days, followed by cefuroxime
axetil at 500 mg PO every 12 h for a total of 7-10
days of therapy. In the non-comparative trial, pa-
tients were given the same dosing regimen as the
comparative trial. Eighty-nine isolates of S. pneu-
moniae were detected, in which 15% had reduced
susceptibility to penicillin and 5% had reduced sus-
ceptibility to azithromycin. Six patients with the
reduced susceptibility S. pneumoniae were treated
with azithromycin. Eradication rate for azithromy-
cin in both trials combined was 64 of 67 (96%).
The study demonstrated that initial azithromycin
therapy had fewer side effects and comparable if
not superior efficacy as cefuroxime therapy. Evi-
dence from this study indicated that cephalosporins
and macrolides still have a role in the treatment of
CAP in the pneumococcal resistance era.
In a prospective, multinational, multicenter,
double-blind, comparative study, 411 patients with
suspected pneumococcal CAP were randomized 1:1
to receive either moxifloxacin 400 mg/d or amox-
icillin 1000 mg tid for 10 days.15 Ninety-eight of
362 patients that were able to be evaluated were
positive for pneumococcal pneumonia. The clinical
success rate at end of therapy (EOT) was 91.5% for
moxifloxacin and 89.7% for amoxicillin; at follow
up, 89.4% for moxifloxacin and 89.3% for amox-
icillin. In both groups, five patients with pneumo-
coccal pneumonia in each group had a bacteriologic
response failure. Both of these drugs are well toler-
ated with similar number of adverse events. This
study demonstrated that moxifloxacin 400 mg once
daily for 10 days is as effective and well tolerated
as high dose amoxicillin, 1000 mg tid for ten days,
for the treatment of pneumococcal pneumonia. Ta-
ble 2 summarizes the above studies.

Recommendations
According to the CDC guidelines for the
treatment of out-patient CAP in the pneumococcal
era, patients with mild to moderate CAP should be
treated empirically with a macrolide (azithromycin,
erythromycin, or clarithromycin), or an oral antip-
neumococcal 8-lactam such as cefuroxime axetil


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Volume 17, Issues 8-9 June/July 2002







Table 2. Summary of Clinical Trials of the Recommended Agents for the Treatment of CAP
Duration
Reference Study design N Study Regimen (days) Clinical Success (%)
(days)
File et al.13 MC, PR, R, 590 1. LEVO 500 mg IV or PO QD 7-14 5-7 days post therapy success:
OL 2. CEFX (parenterally) 1 or 2 gm QD LEVO: 96%
or BID and or cefuroxime axetil CEFX: 90%
(orally) 500 mg BID Bacteriologic eradication:
LEVO: 98%
CEFX: 85%
Hoeffkenetal.1 MN,MC, R, 678 1. MOXI 200 mg QD 10 3-5 days post therapy:
PR, DB 2. MOXI 400 mg QD MOXI200mg: 93.9%
3. CLAR 500 mg BID MOXI400mg: 94.4%
CLAR: 94.3%

Plouffe et al.14 OL, R,C 414 1. AZI 500 mg IV daily x 2-5 days, 7-10 10-14 days post therapy:
followed by 500 mg PO QD AZI: 77% cured rate
2. CEFU 750 mg q8h for 2-7 days, CEFU: 74% cure rate
followed by cefuroxime axetil
500 mg PO Q 12h
Petitpretz et al.15 MN, MC, DB, 411 1. MOXI 400 mg PO QD 10 MOXI: 91.5
R 2. AMOX 1,000 mg PO TID AMOX: 89.7
LEVO= levofloxacin, CEFX= ceftriaxone, AZI azithromycin, CEFU= cefuroxime, MOXI moxifloxacin, CLAR: clarithromycin, AMOX= amoxicillin,
MC= multicenter, PR= prospective, R= randomized, OL= open-labeled, C= controlled, MN= multinational, DB= double blinded.


(500 mg BID) or a high dose amoxicillin (500 mg
TID).6 Due to an increasing rate of resistance to
the fluoroquinolones and its broad spectrum of cov-
erage, the guidelines recommend to reserve the an-
tipneumoccocal FQs as an alternative for those who
are allergic to other agents, or who have failed
other regimens, or those with highly drug resistant
pneumococci (penicillin MIC>4). Because of the
toxicities observed in juvenile animals, the FQs are
not approved for children. For children younger
than 5 years old, a 1-lactam is the best choice. For


intermediate susceptible strains of pneumococcus
(MIC< 1 g/mL), 1-lactam antibiotics are still effec-
tive. In the absence of immediate hypersensitivity
reactions, penicillin can be safely administered in
high doses to overcome the intermediate suscepti-
ble pathogen.4'6'9
Erythromycin has a limited antimicrobial
spectrum of activity and poorly tolerated due to
gastrointestinal side effects. Azithromycin and
clarithromycin have a better profile but are more
expensive. About 5% of penicillin-resistant S.


Table 3. Adverse Drug Reactions
Hepatic
Drugs Diarrhea Nausea Hypersensitivity Headache Phototoxicity Eets

Cefuroxime 4-10.6% 2-7% 5% rarely ----- 1%
Ceftriaxone 2-4% <1% <1% <1% ----- 3%
Cefepime 2% 2% 4% 1% --
Cefotaxime 1% 1% 2% <1% ----- <1%
Erythromycin 7-15% 4-7% 1% <1% ----- 4.7%
Azithromycin 5-7% 4.3% 1.9% <1% ----- 1-2%
Clarithromycin 2% 3% 1% 2% ----- <1%
Ciprofloxacin 2-10% 2-10% 1-4% 1-2% <1% 2%
Levofloxacin 2-4% 2-4% 2% 1% <1% 2%
Gatifloxacin 3% 2% 1-4% 1% 1% 2.5%
Moxifloxacin 1-2% 1-2% .05-1% <1% <1% 2%
Amoxicillin 9-17% 8% 1.4-10% rarely ----- rarely

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Volume 17, Issues 8-9 June/July 2002







Table 4. Drug interactions with the FQs12
Gatifloxacin Moxifloxacin Levofloxacin Ciprofloxacin
Antacids Yes Yes Yes Yes
Vitamins/minerals Yes Yes Yes Yes
Theophylline No No No Yes
NSAIDs No No Yes Yes?
Warfarin No No No Yes
Digoxin No No No No
Drugs with prolong QT interval Yes Yes Yes N/A


pneumoniae are resistant to macrolides in vitro.
When choosing an agent for the treatment of pneu-
mococcal pneumonia, one not only need to con-
sider the coverage spectrum, but also the cost of
therapy and the tolerability profile.
Finally, all clinicians are advised of recently
adopted supplemental MIC breakpoints for non-
meningeal sources of S. pneumoniae to both cefo-
taxime and ceftriaxone. Resistant isolates are now
defined as MIC's = 4 mcg/cc. All labs should im-
plement this change immediately. Based on the
new MIC's, ceftriaxone is expected to be 96-97%
effective against all strains of S. pneumoniae.

Adverse Reactions
The side effects of the antimicrobial agents
are summarized in Table 3. Gastrointestinal distur-
bance is common among the antibiotics. Phototox-
icity is common in the fluoroquinolones family.12

Drug Interactions
The absorption of all FQs can be interfered
by the co-administration of divalent or trivalent
cation-containing agents such as aluminum, magne-
sium, iron, calcium, and zinc containing products.
A summary of relevant drug interactions is pro-
vided on Table 4. Drugs that are metabolized by the
cytochrome P450 isoenzyme family can be altered
as some of the macrolides are inhibitors of this sys-
tem. Concomitant administration of clarithromycin
and carbamazepine can cause an elevation of car-
bamazepine levels. Other potential interactions in-
clude theophylline, caffeine, digoxin, triazolam, er-
gotamine, cyclosporine, warfarin, valproate, mida-
zolam, and terfenadine. With the 8-lactam antibiot-
ics, caution should be noted with drugs that have
potential for nephrotoxicity such as chlorampheni-
col, aminoglycosides, or cyclosporine, etc...

Cost


A summary of the average cost of the above
antimicrobial agents for outpatient treatment of
CAP is provided in Table 5.
Summary
S. pneumoniae is the most common cause of
CAP worldwide. Drug therapy for the treatment of
CAP in the era of pneumococcal resistance was re-
viewed including its mechanisms of resistance to
the most commonly used antibiotics. For the treat-
ment of penicillin susceptible and intermediate re-
sistant (MIC<1) pneumococcus, amoxicillin and


Table 5. Cost Comparison for 10 days Treatment


Agents
Erythromycin
Clarithromycin (Biaxin)
Azithromycin (Zithromax)
Levofloxacin (Levaquin)
Ciprofloxacin (Cipro)
Moxifloxacin (Avelox)
Gatifloxacin (Tequin)
Amoxicillin
Cefuroxime axetil (Ceftin)


Dose
250 mg QID
500 mg BID
500 mg QD
500 mg QD
500 mg BID
400 mg QD
400 mg QD
1 gm TID
500 mg BID


Cost
$11.95
$95.12
$115.84
$95.08
$118.77
$101.85
$92.45
$28.70
$169.95


cephalosporins are an appropriate choice. Mac-
rolides are a reasonable alternative, however, resis-
tance has also increased rapidly in this class within
the last decade but can be overcome with higher
dosing. For highly resistant strains (MIC>2), a
fluoroquinolone should be used, although cost of
therapy and risk of increasing resistance should se-
riously be taken into consideration. As drug resis-
tance rapidly rising, more studies are recommended
for evaluation of the most appropriate regimen in
the era of pneumococcal resistance.

References
1. Barlett JG, Mundy LM. Community acquired


Pha ma Nte Vlume17, ssue 8-9JuneJuly200


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Volume 17, Issues 8-9 June/July 2002







Pneumonia. NEnglJMed 333: 1618-24, 1995.
2. Bochud, PY et al. "Community- acquired Pneu-
monia: A Prospective Study." Medicine March
2001; 80(2).
3. Amsden, GW. "Pneumococcal Macrolide Re-
sistance- Myth or Reality." Journal of Antim-
icrobial Chemotherapy 1999; 44:1-6.
4. Heffelfinger, JD et al. "Management of Com-
munity-Acquired Pneumonia in the Era of
Pneumococcal Resistance" A report from the
Drug-Resistant Streptococcus Pneumoniae
Therapeutic Work Group. Archives of Internal
Medicine May 22,2000; 160: 1399-1408.
5. Marie TJ. Community-Acquired Pneumonia:
Epidemiology, Etiology, Treatment. Infect Dis
Clin North Am. 1998; 12:723-740.
6. Barlett, JG et al. "Practice Guidelines for the
Management of Community-Acquired Pneumo-
nia in Adults." Guidelines from the Infectious
Disease Society of America. Clin Inf Dis
2000;31:347-82.
7. Kaplan SL, et al. Management of Infections due
to Antibiotic-Resistant Strep. Pneumoniae. Clin
Microbiol Rev 1998; 11: 628.
8. J Garau. "The Clinical Impact of Macrolide Re-
sistance in Pneumococcal Respiratory Infec-
tions. International Journal of Antimicrobial
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9. Shales, DM et al. Society for Healthcare Epi-
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10. Guidelines for the Management of Adults with
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11. Harwell, JI. "The Drug-Resistant Pneumococ-
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12. Mandell, LA. "Antibiotic Therapy for Commu-
nity-Acquired Pneumonia" Clinics in Chest
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13. File et al. "A Multicenter, Randomized Study
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Pneumococcal Pneumonia in Adults." Chest
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- kim


The PharmaNote is Published by:
The Department of Pharmacy Services,
UF Family Practice Medical Group,
Departments of Community Health and
Family Medicine and Pharmacy Practice
University of Florida

John G. Gums Editor
Pharm.D.

R. Whit Curry, M.D. Associate Editor

John M. Tovar Assistant Editor
Pharm.D.
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PharmaNote


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