Farmasi Rumah Sakit - Evaluasi Penggunaan Antibiotika dengan Metode Gyssens

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Evaluasi Penggunaan Antibiotik dengan Metode Gyssens
pada Pasien Purulent Cellulitis dengan MRSA (Methicillin-
Resistant Staphylococcus aureus)
Disusun oleh:
Nama : Nesha Mutiara
NPM : 2021000056
No. Absen : 10
Kelas : Farmasi Rumah Sakit Terapan
PROGRAM STUDI PROFESI APOTEKER
UNIVERSITAS PANCASILA
JAKARTA
2021

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DAFTAR ISI
HALAMAN JUDUL.................................................................................................... 1
DAFTAR ISI................................................................................................................ 2
Kasus............................................................................................................................ 3
Pembahasan.................................................................................................................. 3
Hasil Evaluasi Penggunaan Antibiotika....................................................................... 6
Saran............................................................................................................................. 7
Daftar Pustaka.............................................................................................................. 7
Lampiran Jurnal ........................................................................................................... 8

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Kasus :
Seorang pengguna narkoba intravena (IVDU) berusia 42 tahun dirawat di rumah sakit
karena mengeluh demam dan sakit pada pangkal paha. Dia telah menyuntik selama
beberapa tahun dan mempunyai riwayat beberapa kali masuk rumah sakit untuk
tempat suntikan yang terinfeksi. Dia saat ini menyuntikkan ke pangkal paha kiri.
Pemeriksaan:
Pasien kurus dengan kebersihan pribadi yang buruk, demam (39.2O
C), nadinya 130
kali/menit, dan tekanan darah 100/70 mmHg. Pernafasan dan kardiovaskular tidak
menonjol dan perutnya lunak dan tidak kaku. Lengan bekas luka dari suntikan
sebelumnya, dan kulit menunjukkan bukti eksoriasi dari goresan kronis.
Pembengkakan inguinal kiri, menjadi panas, merah, dan menyakitkan saat disentuh.
Terdapat selulitis di sekitar area yang bengkak. Darah rutin dan kultur darah diambil
dan mulai dengan IV benzyl penicillin dan flukloksasilin untuk abses dan selulitisnya.
Pembedahan direncanakan untuk mengeringkan abses.
Pertanyaan:
Bagaimana analisis kualitatif penggunaan antimikroba pada pasien tersebut?
Pembahasan:
Metode analisis kualitatif yang digunakan adalah metode Gyssens. Alasan dipilih
metode Gyssens yaitu karena spesifik untuk mengevaluasi seluruh aspek peresepan
antibiotika yang meliputi penilaian alternatif yang lebih efektif, lebih tidak toksik,
lebih murah, spektrum lebih sempit, serta dosis obat, lama pengobatan, interval, dan
rute pemberian obat (1). Sedangkan metode kualitatif lainnya tidak dipilih karena:

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1. Metode Beers untuk mengevaluasi peresepan yang berisiko terjadi DRPs
(Drug Related Problems) pada pasien
2. Metode STOPP/START (Screening Tools of Older Person’s
Prescription/Screening Tool to Alert doctor to Right Treatment) untuk
mengetahui jumlah kejadian PIM (Potentially Inappropriate Medications) dan
PPO (Potentially Prescription Omissions) pada pasien geriatri (usia 65 tahun
ke atas) sehingga menghindari peresepan yang berpotensi tidak tepat dan
mencegah kejadian efek samping obat pada pasien geriatri
3. Metode Naranjo untuk identifikasi efek samping obat
4. ICD-10 (clinical pathway) merupakan suatu konsep pra perawatan yang
disusun berdasarkan standar prosedur dari setiap profesi dari pelayanan medis,
pelayanan keperawatan, pelayanan farmasi, dan pelayanan kesehatan lainnya
yang mengacu pada standar pelayanan dari profesi masing-masing di
pelayanan rumah sakit (2).
Metode Gyssens dilakukan dengan menggunakan alur terstruktur yang terdiri dari 13
poin kategori penilaian sebagai berikut (3):
Kategori Penilaian Keterangan
Kategori 0 Penggunaan antibiotika tepat/rasional
Kategori I Penggunaan antibiotika tidak tepat waktu
Kategori II A Penggunaan antibiotika tidak tepat dosis
Kategori II B Penggunaan antibiotika tidak tepat interval pemberian
Kategori II C Penggunaan antibiotika tidak tepat rute/cara pemberian
Kategori III A Penggunaan antibiotika terlalu lama
Kategori III B Penggunaan antibiotika terlalu singkat
Kategori IV A Ada antibiotika lain yang lebih efektif
Kategori IV B Ada antibiotika lain yang kurang toksik / lebih aman
Kategori IV C Ada antibiotika lain yang lebih murah
Kategori IV D Ada antibiotika lain yang spektrumnya lebih sempit
Kategori V Tidak ada indikasi penggunaan antibiotika
Kategori VI Data rekam medis tidak lengkap dan tidak dapat dievaluasi

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Berikut adalah diagram alur metode Gyssens (4) :
Gambar Diagram Alur Metode Gyssens (4)

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Hasil evaluasi penggunaan antibiotika termasuk kategori IVA dengan alur deskripsi
sebagai berikut :
Kategori YA / TIDAK Alasan
VI YA Data rekam medis pasien lengkap sesuai dengan Peraturan
Menteri Kesehatan Republik Indonesia No. 269 Tahun
2008 yaitu meliputi identitas pasien, hasil anamnesis,
minimal keluhan, riwayat penyakit, hasil pemeriksaan
fisik, hasil pemeriksaan penunjang medis, diagnosis,
rencana penatalaksanaan, serta pengobatan atau tindakan
medis
V YA Ada indikasi penggunaan antibiotika yaitu berdasarkan :
-Demam 39.2O
C → respon sistem imun tubuh melawan
infeksi
-White cell count di atas nilai rujukan → infeksi mikroba
-C-reactive protein di atas nilai rujukan → inflamasi serius
dalam tubuh akibat infeksi berat
-Adanya Streptococcus pyogenes → selulitis
-Adanya MRSA dari pus abses
IV A YA Meskipun flukloksasilin dan benzyl penicillin dapat
digunakan sebagai first line untuk mengobati selulitis, tapi
tidak efektif untuk mengobati selulitis yang disertai MRSA
sehingga dibutuhkan alternatif antibiotika.
MRSA (Methicilin-Resistant Staphylococcus aureus) adalah infeksi bakteri
Staphylococcus aureus yang resisten terhadap antibiotik flukloksasilin dan benzyl-
penicillin yang dapat disebabkan oleh faktor community acquired seperti tidak
menjaga kebersihan tubuh. Oleh sebab itu, dibutuhkan alternatif antibiotika untuk
mengobati purulent cellulitis yang disertai MRSA dengan pilihan antibiotika
trimetroprim-sulfametoksazol (TMP-SMX), doksisiklin, dan klindamisin (5).
PERDOSKI (Perhimpunan Dokter Spesialis Kulit dan Kelamin Indonesia) telah
menetapkan pedoman tatalaksananya yang juga telah diadaptasi oleh RSUD Dr.
Soetomo Surabaya sebagai berikut (6, 7) :
1. TMP-SMX 160/180 mg, 2x sehari
2. Doksisiklin 2x100 mg
3. Klindamisin 15 mg/kgBB/hari terbagi 3 dosis sehari

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Berdasarkan hasil evaluasi penggunaan antibiotika tersebut, penulis merumuskan tiga
saran untuk mempermudah apoteker mengevaluasi penggunaan antibiotika:
1. Dilakukan pemeriksaan laboratorium untuk mengetahui sensitivitas dan
kemungkinan alergi pasien terhadap TMP-SMX, doksisiklin maupun
klindamisin
2. Pilihan alternatif antibiotika diberikan melalui rute per oral untuk
minimalisasi risiko infeksi nosokomial dan minimalisasi biaya
3. Disertai data lengkap dosis obat, interval pemberian dan lama pemberian
untuk mempermudah evaluasi penggunaan antibiotika
Daftar Pustaka
1. Gyssens. Audits for Monitoring the Quality of Antimicrobial Prescriptions. In
Antibiotic Policies. Springer US.
2. UR, Hesty, NG Adiwisastra, dan W Arozal. Efektivitas Implementasi Clinical
Pathway pada pasien Anak Gastroenteritis Akut (GEA) dengan Dehidrasi
yang Dirawat Inap di Rumah Sakit Permata Bekasi. Jurnal Medical Profession
(MedPro) Vol. 3 No. 3. 2019.
3. Yuniar, Irene, MR Karyanti, T Tambunan, dan NA Rizkyani. Evaluasi
Penggunaan Antiobiotik dengan Kartu Monitoring Antibiotik Gyssens. Sari
Pediatri Vol. 14 No. 6. 2013.
4. Anggraini, Rika. Rasionalitas Penggunaan Antibiotika untuk Pengobatan
Infeksi pada Pasien Anak Rawat Inap di RSUP H. Adam Malik Medan.
Skripsi. Fakultas Farmasi Universitas Sumatera Utara. 2017.
5. Lambert, Mara. IDSA Guideline on the Treatment of MRSA Infections in
Adults and Children. American Academy of Family Physicians. 2011.
6. Widaty, Sandra dkk. Panduan Praktik Klinis bagi Dokter Spesialis Kulit dan
Kelamin Indonesia. PERDOSKI. 2017.
7. Listiawan, Yualinto dkk. Panduan Praktik Klinis SMF Ilmu Kesehatan Kulit
dan Kelamin RSUD Dr. Soetomo Surabaya. 2020.

August 15, 2011 ◆
Volume 84, Number 4 www.aafp.org/afp American Family Physician 455
The prevalence of methicillin-resistant Staph-
ylococcus aureus (MRSA) in the United States
continues to increase, with more than 94,000
cases of invasive disease reported in 2005.
Illnesses caused by MRSA include skin and
soft-tissue infections, bacteremia and endo-
carditis, pneumonia, bone and joint infec-
tions, central nervous system disease, and
toxic shock and sepsis syndromes. The Infec-
tious Diseases Society of America (IDSA) has
released its first evidence-based guidelines
on the treatment of MRSA infections. In
addition to common clinical syndromes, the
guidelines address treatment with vancomy-
cin, limitations of susceptibility testing, and
alternative therapies.
Skin and Soft-Tissue Infections in
Community-Associated MRSA
Simple abscesses or boils may be managed
with incision and drainage alone; more data
are needed on the use of antibiotics in this
setting. Antibiotics are recommended for
patients who have abscesses associated with
severe or extensive disease (e.g., multiple
sites of infection) or rapid progression in
the presence of associated cellulitis; signs
and symptoms of systemic illness; associated
comorbidities or immunosuppression; very
young or very old age; abscesses in areas diffi-
cult to drain (e.g., face, hand, genitalia); asso-
ciated septic phlebitis; or lack of response to
incision and drainage alone. Empiric therapy
for five to 10 days is recommended pending
culture results for outpatients with purulent
cellulitis. Infection from β-hemolytic strep-
tococci does not usually require empiric
therapy. For those with nonpurulent cel-
lulitis, five to 10 days of empiric therapy
for β-hemolytic streptococcal infection is
recommended, based on the patient’s clinical
response. Empiric coverage for community-
associated MRSA is recommended in patients
who do not respond to beta-lactam antibiot-
ics, and also may be considered in those with
systemic toxicity.
Oral antibiotic options for treating skin
and soft-tissue infections in patients with
community-associated MRSA include
clindamycin, trimethoprim/sulfamethoxa-
zole (TMP/SMX; Bactrim, Septra), a tet-
racycline (doxycycline or minocycline
[Minocin]), and linezolid (Zyvox). Options
for treating both β-hemolytic streptococci
and community-associated MRSA include
clindamycin alone, TMP/SMX or a tetra-
cycline in combination with a beta-lactam
antibiotic (e.g., amoxicillin), or linezolid
alone. Rifampin is not recommended for use
as a single agent or adjunctive therapy.
For hospitalized patients with complicated
skin and soft-tissue infections (i.e., deeper
soft-tissue infections, surgical or traumatic
wound infection, major abscesses, cellulitis,
or infected ulcers and burns), empiric ther-
apy for MRSA should be considered pend-
ing culture results, in addition to surgical
debridement and broad-spectrum antibiotics.
Empiric therapy options include intravenous
vancomycin, linezolid (600 mg orally or intra-
venously twice per day), daptomycin (Cubi-
cin; 4 mg per kg intravenously once per day),
telavancin (Vibativ; 10 mg per kg intrave-
nously once per day), or clindamycin (600 mg
IDSA Guidelines on the Treatment of MRSA Infections
in Adults and Children
MARA LAMBERT
Coverage of guidelines
from other organizations
does not imply endorse-
ment by AFP or the AAFP.
A collection of Practice
Guidelines published in
AFP is available at http://
www.aafp.org/afp/
practguide.
Guideline source: Infectious Diseases Society of America
Evidence rating system used? Yes
Literature search described? Yes
Published source: Clinical Infectious Diseases, February 1, 2011
Available at: http://cid.oxfordjournals.org/content/early/2011/01/04/cid.
ciq146.full
Practice Guidelines
Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright © 2011 American Academy of Family Physicians. For the private, noncommercial use of
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Practice Guidelines
456 American Family Physician www.aafp.org/afp Volume 84, Number 4 ◆
August 15, 2011
intravenously or orally three times per day). A beta-lactam
antibiotic (e.g., cefazolin) may be considered in hospital-
ized patients with nonpurulent cellulitis. MRSA-active
therapy may be modified if there is no clinical response.
Treatment for seven to 14 days is recommended, but
should be individualized to the patient’s clinical response.
Cultures from abscesses and other purulent infections
are recommended in patients who have received anti-
biotic therapy, those with severe local infection or signs
of systemic illness, and those who have not responded
adequately to initial treatment. Cultures are also recom-
mended if there is concern of a cluster or outbreak.
CHILDREN
In children with minor skin infections (e.g., impetigo)
or secondarily infected lesions (e.g., eczema, ulcers, lac-
erations), treatment with mupirocin 2% topical cream
(Bactroban) is recommended. Tetracyclines are not rec-
ommended for children younger than eight years. Van-
comycin is recommended in hospitalized children. If the
child is stable without ongoing bacteremia or intravas-
cular infection, empiric therapy with clindamycin (10 to
13 mg per kg intravenously every six to eight hours for a
total of 40 mg per kg per day) is an option if the resistance
rate is less than 10 percent. If the strain is susceptible,
transition to oral therapy is advised. Linezolid may be
considered as an alternative (600 mg orally or intrave-
nously twice per day for children 12 years and older;
10 mg per kg orally or intravenously every eight hours for
children younger than 12 years).
Recurrent MRSA Skin and Soft-Tissue Infections
Physicians should provide instructions on personal
hygiene and wound care for patients with skin and soft-
tissue infections. Patients should cover draining wounds
with clean, dry bandages. Regular bathing is advised, as
well as hand washing with soap and water or an alcohol-
based hand gel, especially after touching infected skin or
an item that has been in contact with a draining wound.
Patients should also avoid reusing or sharing items that
that have touched infected skin (e.g., disposable razors,
linens, towels). Commercially available cleaners or deter-
gents should be used to clean high-touch surfaces (e.g.,
doorknobs, counters, bathtubs, toilet seats) that may
come in contact with bare skin or uncovered infections.
Decolonization may be considered if a patient devel-
ops a recurrent infection despite good personal hygiene
and wound care, or if other household members develop
infections. Strategies for decolonization include nasal
decolonization with mupirocin twice per day for five to
10 days, or nasal decolonization with mupirocin twice
per day for five to 10 days plus topical body decoloniza-
tion with a skin antiseptic solution (e.g., chlorhexidine
[Peridex]) for five to 14 days or dilute bleach baths.
Dilute bleach baths can be made with 1 teaspoon of
bleach per 1 gallon of water (or one-fourth cup per
one-fourth bathtub or 13 gallons of water) and are given
for 15 minutes twice per week for three months. Oral
antimicrobial therapy is recommended only for treat-
ing active infection and is not routinely recommended
for decolonization. An oral agent in combination with
rifampin, if the strain is susceptible, may be considered
if infections recur despite these measures.
If household or interpersonal transmission is sus-
pected, patients and contacts should be instructed to
practice personal and environmental hygiene measures.
In symptomatic contacts, nasal and topical body decolo-
nization strategies may be considered after treating the
active infection. Decolonization strategies also may be
considered in asymptomatic household contacts. The
role of cultures in managing recurrent skin and soft-
tissue infections is limited. Screening cultures before
decolonization are not routinely recommended if at least
one of the previous infections was caused by MRSA. Sur-
veillance cultures after a decolonization regimen are not
routinely recommended if there is no active infection.
MRSA Bacteremia and Infective Endocarditis
BACTEREMIA AND INFECTIVE ENDOCARDITIS,
NATIVE VALVE
Uncomplicated bacteremia is defined as positive blood
culture results and the following: exclusion of endocar-
ditis; no implanted prostheses; follow-up blood cultures
performed on specimens obtained two to four days after
the initial set that do not grow MRSA; defervescence
within 72 hours of initiating effective therapy; and no
evidence of metastatic sites of infection. Recommended
treatment for adults with uncomplicated bacteremia
includes vancomycin or daptomycin at a dosage of 6 mg
per kg intravenously once per day for at least two weeks.
For adults with complicated bacteremia (positive blood
culture results without meeting criteria for uncompli-
cated bacteremia), four to six weeks of therapy is recom-
mended, depending on the extent of infection. Some
experts recommend higher dosages of daptomycin (8 to
10 mg per kg intravenously once per day).
For adults with infective endocarditis, intravenous
vancomycin or daptomycin (6 mg per kg intravenously
once per day for six weeks) is recommended. Some
experts recommend higher dosages of daptomycin (8 to
10 mg per kg intravenously once per day). Adding
gentamicin or rifampin to vancomycin is not recom-
mended in patients with bacteremia or native valve
infective endocarditis. A clinical assessment to identify
the source and extent of the infection with elimina-
tion and/or debridement of other sites of infection is
▲

Practice Guidelines
August 15, 2011 ◆
recommended. Additional blood cultures two to four
days after initial positive cultures and as needed there-
after are recommended to document clearance of bacte-
remia. Echocardiography is recommended for all adults
with bacteremia. Transesophageal echocardiography is
preferred over transthoracic echocardiography. Evalu-
ation for valve replacement surgery is recommended if
any of the following are present: large vegetation (greater
than 10 mm in diameter), occurrence of one or more
embolic events during the first two weeks of therapy,
severe valvular insufficiency, valvular perforation or
dehiscence, decompensated heart failure, perivalvular
or myocardial abscess, new heart block, or persistent
fevers or bacteremia.
INFECTIVE ENDOCARDITIS, PROSTHETIC VALVE
Patients with infective endocarditis and a prosthetic
valve should be treated with intravenous vancomycin
and rifampin (300 mg orally or intravenously every
eight hours for at least six weeks), plus gentamicin
(1 mg per kg intravenously every eight hours for two
weeks). Early evaluation for valve replacement surgery is
recommended.
CHILDREN
In children, intravenous vancomycin (15 mg per kg
every six hours) is recommended for treating bactere-
mia and infective endocarditis. The duration of therapy
may range from two to six weeks depending on the
source, the presence of endovascular infection, and
metastatic foci of infection. Data regarding the safety
and effectiveness of alternative agents in children are
limited, although daptomycin (6 to 10 mg per kg intra-
venously once per day) may be an option. Clindamycin
and linezolid should not be used if there is concern
of infective endocarditis or an endovascular source of
infection, although they may be considered in children
with bacteremia that rapidly clears and is not related to
an endovascular focus. Data are insufficient to support
the routine use of combination therapy with rifampin
or gentamicin in children with bacteremia or infective
endocarditis. The decision to use combination therapy
should be individualized. Echocardiography is recom-
mended in children with congenital heart disease, bac-
teremia lasting more than two to three days, or other
clinical findings suggestive of endocarditis.
MRSA Pneumonia
PNEUMONIA
Empiric therapy for MRSA is recommended, pending
sputum and/or blood culture results, for hospitalized
patients with severe community-acquired pneumonia
defined by one of the following: a requirement for
admission to the intensive care unit, necrotizing or
cavitary infiltrates, or empyema. Treatment options for
health care–associated MRSA or community-associated
MRSA pneumonia include seven to 21 days of intrave-
nous vancomycin or linezolid, or clindamycin (600 mg
orally or intravenously three times per day) if the strain is
susceptible. In patients with MRSA pneumonia compli-
cated by empyema, antimicrobial therapy should be used
with drainage procedures.
CHILDREN
In children, intravenous vancomycin is recommended
for treating MRSA pneumonia. If the patient is stable
without ongoing bacteremia or intravascular infection,
clindamycin (10 to 13 mg per kg intravenously every six
to eight hours for a total of 40 mg per kg per day) can
be used as empiric therapy if the clindamycin resistance
rate is low (e.g., less than 10 percent). Patients can be
transitioned to oral therapy if the strain is susceptible.
Linezolid is an alternative option.
MRSA Bone and Joint Infections
OSTEOMYELITIS
The mainstay of therapy for osteomyelitis is surgical
debridement with drainage of associated soft-tissue
abscesses. The optimal route of administration of anti-
biotic therapy has not been established; parenteral, oral,
or initial parenteral therapy followed by oral therapy may
be used, depending on patient circumstances. Antibiotic
options for parenteral administration include intravenous
vancomycin and daptomycin (6 mg per kg intravenously
once per day). Antibiotic options with parenteral and oral
routes of administration include the following: TMP/
SMX (4 mg per kg [TMP component] twice per day) in
combination with rifampin (600 mg once per day), line-
zolid, and clindamycin (600 mg every eight hours). Some
experts recommend adding oral rifampin (600 mg per
day, or 300 to 450 mg twice per day) to the chosen anti-
biotic. For patients with concurrent bacteremia, rifampin
should be added after bacteremia has cleared.
The optimal duration of therapy for MRSA osteomy-
elitis is unknown, although a minimum of eight weeks
is recommended. Some experts suggest an additional
one to three months (and possibly longer for chronic
infection or if debridement is not performed) of oral
rifampin-based combination therapy with TMP/SMX,
doxycycline, minocycline, clindamycin, or a fluoro-
quinolone, chosen based on susceptibilities. Magnetic
resonance imaging with gadolinium is the imaging
modality of choice for detecting early osteomyelitis and
associated soft-tissue disease. Measuring erythrocyte
sedimentation rate, C-reactive protein level, or both may
help guide the response to therapy.

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462 American Family Physician www.aafp.org/afp Volume 84, Number 4 ◆
August 15, 2011
SEPTIC ARTHRITIS
Drainage or debridement of the joint space should be
performed. For patients with septic arthritis, the antibi-
otic choices for osteomyelitis are recommended; a three-
to four-week course of therapy is suggested.
DEVICE-RELATED OSTEOARTICULAR INFECTIONS
For patients with early-onset (less than two months after
surgery) or acute hematogenous prosthetic joint infec-
tions involving a stable implant with short duration of
symptoms (three weeks or less) and debridement (but
device retention), parenteral therapy should be initiated
(see antibiotic recommendations for osteomyelitis) plus
rifampin (600 mg per day, or 300 to 450 mg orally twice
per day for two weeks), followed by rifampin plus a fluo-
roquinolone, TMP/SMX, a tetracycline, or clindamycin
for three months for hips and six months for knees.
Prompt debridement with device removal is recom-
mended for unstable implants or late-onset infections,
or in patients with more than three weeks of symptoms.
For early-onset spinal implant infections (30 days or
less after surgery) or implants in an actively infected site,
initial parenteral therapy plus rifampin followed by pro-
longed oral therapy is recommended. The optimal dura-
tion of parenteral and oral therapy is unclear; oral therapy
should be continued until spinal fusion has occurred.
For late-onset infections (more than 30 days after sur-
gery), device removal is recommended. Long-term oral
suppressive antibiotics (e.g., TMP/SMX, a tetracycline, a
fluoroquinolone in conjunction with rifampin, clinda-
mycin) with or without rifampin may be considered,
particularly if device removal is not possible.
CHILDREN
Vancomycin is recommended in children with acute
hematogenous MRSA osteomyelitis and septic arthritis. If
the patient is stable without ongoing bacteremia or intra-
vascular infection, clindamycin (10 to 13 mg per kg intra-
venously every six to eight hours for a total of 40 mg per
kg per day) can be used as empiric therapy if the resistance
rate is low (e.g., less than 10 percent), with transition to
oral therapy if the strain is susceptible. The duration of
therapy should be individualized, but a minimum of three
to four weeks is recommended for patients with septic
arthritis, and four to six weeks for patients with osteomy-
elitis. Daptomycin (6 mg per kg intravenously once per
day) and linezolid are alternative therapies.
MRSA Infections of the Central Nervous System
MENINGITIS
The recommended treatment for patients with menin-
gitis is intravenous vancomycin for two weeks. Some
experts recommend adding rifampin (600 mg per day,
or 300 to 450 mg twice per day). Alternatives include
linezolid or TMP/SMX (5 mg per kg intravenously every
eight to 12 hours). Shunt removal is recommended in
cases of central nervous system shunt infection, and the
shunt should not be replaced until cerebrospinal fluid
cultures are repeatedly negative.
BRAIN ABSCESS, SUBDURAL EMPYEMA, AND SPINAL
EPIDURAL ABSCESS
Neurosurgical evaluation for incision and drainage is
recommended for patients with brain abscess, subdural
empyema, or spinal epidural abscess. Recommended
treatment is intravenous vancomycin for four to six
weeks. Some experts recommend adding rifampin. Alter-
natives include linezolid and TMP/SMX.
SEPTIC THROMBOSIS OF CAVERNOUS OR DURAL
VENOUS SINUS
Surgical evaluation for incision and drainage of contigu-
ous sites of infection or abscess is recommended. The role
of anticoagulation is controversial. Recommended treat-
ment is intravenous vancomycin for four to six weeks.
Some experts recommend adding rifampin. Alternatives
include linezolid and TMP/SMX.
CHILDREN
Children with MRSA infections of the central nervous
system should be treated with intravenous vancomycin.
Adjunctive Therapies for the Treatment
of MRSA Infections
Protein synthesis inhibitors (e.g., clindamycin, linezolid)
and intravenous immune globulin are not routinely rec-
ommended as adjunctive therapy for the management of
invasive MRSA disease, although they may be considered
in certain scenarios (e.g., necrotizing pneumonia, severe
sepsis).
Vancomycin Dosing and Monitoring
Recommendations for vancomycin dosing are based on a
consensus statement of the American Society of Health-
System Pharmacists, the IDSA, and the Society of Infec-
tious Diseases Pharmacists.
ADULTS
In patients with normal renal function, intravenous van-
comycin (15 to 20 mg per kg every eight to 12 hours) is
recommended, but should not exceed 2 g per dose. In
seriously ill patients (e.g., those with sepsis, meningitis,
pneumonia, or infective endocarditis) with suspected
MRSA infection, a loading dose of 25 to 30 mg per kg may
be considered. Because of the risk of red man syndrome
and possible anaphylaxis associated with large doses of

Practice Guidelines
August 15, 2011 ◆
vancomycin, physicians should consider prolonging the
infusion time to two hours and giving an antihistamine
before administering the loading dose.
Use of trough vancomycin concentrations is the most
accurate and practical method to guide vancomycin dos-
ing. Serum trough concentrations should be obtained at
steady state conditions, before the fourth or fifth dose.
Monitoring peak vancomycin concentrations is not
recommended. Vancomycin trough concentrations of
15 to 20 mcg per mL are recommended in patients with
serious infections, such as bacteremia, infective endo-
carditis, osteomyelitis, meningitis, pneumonia, or severe
skin and soft-tissue infections (e.g., necrotizing fasciitis)
caused by MRSA. For most patients with skin and soft-
tissue infections who have normal renal function and
are not obese, traditional dosages of 1 g every 12 hours
are adequate, and trough monitoring is not required.
Trough vancomycin monitoring is recommended for
patients with serious infections or who are morbidly
obese, have renal dysfunction (including those receiving
dialysis), or have fluctuating volumes of distribution. A
regimen of continuous infusion is not recommended.
CHILDREN
Data on vancomycin dosing in children are limited. The
recommended treatment is vancomycin (15 mg per kg
intravenously every six hours) in children with serious or
invasive disease. The effectiveness and safety of targeting
trough concentrations of 15 to 20 mcg per mL in children
require additional study, but should be considered in
those with serious infections, such as bacteremia, infec-
tive endocarditis, osteomyelitis, meningitis, pneumonia,
or severe skin and soft-tissue infections.
Vancomycin Susceptibility Testing for Guiding
Therapy
For isolates with a vancomycin minimal inhibitory con-
centration of 2 mcg per mL or less (e.g., susceptible
according to Clinical and Laboratory Standards Institute
breakpoints), the patient’s clinical response should dic-
tate the continued use of vancomycin, independent of
the minimal inhibitory concentration. If the patient has
had a previous clinical and microbiologic response to
vancomycin, it may be continued with close follow-up.
If the patient has not responded to vancomycin therapy
despite adequate debridement and removal of other foci
of infection, an alternative agent is recommended. For
isolates with a vancomycin minimal inhibitory concen-
tration greater than 2 mcg per mL (e.g., vancomycin-
intermediate S. aureus, vancomycin-resistant S. aureus),
an alternative agent should be prescribed.
Persistent MRSA Bacteremia and Vancomycin
Treatment Failures in Adults
A search for and removal of other foci of infection,
drainage, or surgical debridement is recommended.
High-dose daptomycin (10 mg per kg per day), if the
isolate is susceptible, in combination with another agent
(e.g., gentamicin, rifampin, linezolid, TMP/SMX, a beta-
lactam antibiotic) should be considered. If reduced
susceptibility to vancomycin and daptomycin is pres-
ent, alternative treatment options include dalfopristin/
quinupristin (Synercid; 7.5 mg per kg intravenously every
eight hours), TMP/SMX, linezolid, or telavancin. These
may be given as a single agent or in combination with
other antibiotics.
MRSA Infections in Neonates
NEONATAL PUSTULOSIS
For mild cases of pustulosis with localized disease, topi-
cal treatment with mupirocin may be adequate in full-
term neonates and young infants. For localized disease
in a premature or very low-birth-weight infant or more
extensive disease involving multiple sites in full-term
infants, intravenous vancomycin or clindamycin is rec-
ommended until bacteremia is excluded.
NEONATAL MRSA SEPSIS
Recommended treatment of neonatal MRSA sepsis is
intravenous vancomycin, with dosing as outlined in Red
Book. Clindamycin and linezolid are alternative treat-
ments for nonendovascular infections. ■
Answers to This Issue’s CME Quiz
Q1. D
Q2. B
Q3. A, B
Q4. A
Q5. A, B, C, D
Q6. D
Q7. B
Q8. A, B, C, D
Q9. A
Q10. D

Clindamycin versus Trimethoprim–Sulfamethoxazole for
Uncomplicated Skin Infections
Loren G. Miller, M.D., M.P.H., Robert S. Daum, M.D., C.M., C. Buddy Creech, M.D., M.P.H.,
David Young, M.D., Michele D. Downing, R.N., M.S.N., Samantha J. Eells, M.P.H., Stephanie
Pettibone, B.S., Rebecca J. Hoagland, M.S., Henry F. Chambers, M.D., and for the DMID
07-0051 Team*
Los Angeles Biomedical Research Institute (L.G.M., S.J.E.) and Division of Infectious Diseases,
Harbor–UCLA (University of California, Los Angeles) Medical Center (L.G.M., S.J.E.), Torrance,
David Geffen School of Medicine at UCLA, Los Angeles (L.G.M., S.J.E.), Division of Plastic and
Reconstructive Surgery, University of California, San Francisco (UCSF) (D.Y.), and Division of
Infectious Diseases, San Francisco General Hospital and UCSF (M.D.D., H.F.C.), San Francisco
— all in California; Division of Pediatric Infectious Diseases, University of Chicago, Chicago
(R.S.D.); Division of Pediatric Infectious Diseases, Vanderbilt University, Nashville (C.B.C.); the
EMMES Corporation, Rockville, MD (S.P.); and Cota Enterprises, Meriden, KS (R.J.H.). Address
reprint requests to Dr. Miller at the Division of Infectious Diseases, Harbor–UCLA Medical Center,
1000 W. Carson St., Box 466, Torrance, CA 90509
Loren G. Miller: lgmiller@ucla.edu
Abstract
Background—Skin and skin-structure infections are common in ambulatory settings. However,
the efficacy of various antibiotic regimens in the era of community-acquired methicillin-resistant
Staphylococcus aureus (MRSA) is unclear.
Methods—We enrolled outpatients with uncomplicated skin infections who had cellulitis,
abscesses larger than 5 cm in diameter (smaller for younger children), or both. Patients were
enrolled at four study sites. All abscesses underwent incision and drainage. Patients were
randomly assigned in a 1:1 ratio to receive either clindamycin or trimethoprim–sulfamethoxazole
(TMP-SMX) for 10 days. Patients and investigators were unaware of the treatment assignments
and microbiologic test results. The primary outcome was clinical cure 7 to 10 days after the end of
treatment.
*A list of additional members of the Division of Microbiology and Infectious Diseases (DMID) 07-0051 Team is provided in the
Supplementary Appendix, available at NEJM.org.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of
Health.
No other potential conflict of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
My Nejm in the Journal Online: Individual subscribers can store articles and searches using a feature on the Journal's website
(NEJM.org) called “My NEJM.” Each article and search result links to this feature. Users can create personal folders and move
articles into them for convenient retrieval later.
HHS Public Access
Author manuscript
N Engl J Med. Author manuscript; available in PMC 2015 September 19.
Published in final edited form as:
N Engl J Med. 2015 March 19; 372(12): 1093–1103. doi:10.1056/NEJMoa1403789.
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Results—A total of 524 patients were enrolled (264 in the clindamycin group and 260 in the
TMP-SMX group), including 155 children (29.6%). One hundred sixty patients (30.5%) had an
abscess, 280 (53.4%) had cellulitis, and 82 (15.6%) had mixed infection, defined as at least one
abscess lesion and one cellulitis lesion. S. aureus was isolated from the lesions of 217 patients
(41.4%); the isolates in 167 (77.0%) of these patients were MRSA. The proportion of patients
cured was similar in the two treatment groups in the intention-to-treat population (80.3% in the
clindamycin group and 77.7% in the TMP-SMX group; difference, −2.6 percentage points; 95%
confidence interval [CI], −10.2 to 4.9; P = 0.52) and in the populations of patients who could be
evaluated (466 patients; 89.5% in the clindamycin group and 88.2% in the TMP-SMX group;
difference, −1.2 percentage points; 95% CI, −7.6 to 5.1; P = 0.77). Cure rates did not differ
significantly between the two treatments in the subgroups of children, adults, and patients with
abscess versus cellulitis. The proportion of patients with adverse events was similar in the two
groups.
Conclusions—We found no significant difference between clindamycin and TMP-SMX, with
respect to either efficacy or side-effect profile, for the treatment of uncomplicated skin infections,
including both cellulitis and abscesses. (Funded by the National Institute of Allergy and Infectious
Diseases and the National Center for Advancing Translational Sciences, National Institutes of
Health; ClinicalTrials.gov number, NCT00730028.)
Skin and Skin-Structure Infections (hereafter referred to as skin infections) are common
conditions among patients seeking medical care in the United States,1,2 accounting for
approximately 14.2 million outpatient visits in 20051 and more than 850,000 hospital
admissions.3 Skin infections are associated with considerable complications, including
bacteremia, the need for hospitalization and surgical procedures, and death.4,5
Results of cultures of skin-infection lesions in the United States have shown that most of the
infections are caused by methicillin-resistant Staphylococcus aureus (MRSA),6,7 but the
efficacy of various antibiotic regimens in areas where community-associated MRSA is
endemic has not been defined.8,9 Either clindamycin or trimethoprim–sulfamethoxazole
(TMP-SMX) is recommended because of the low cost and activity against community-
associated MRSA and methicillin-susceptible S. aureus (MSSA) strains of each of these
drugs,2,10-12 yet there are few comparative data on the safety and efficacy of these antibiotic
agents for the treatment of skin infections. To address this limitation, we performed a
randomized clinical trial comparing clindamycin and TMP-SMX for the treatment of
uncomplicated skin infections at four U.S. centers located in areas of community-associated
MRSA endemicity.
Methods
Study Design and Population
We performed a multicenter, prospective, randomized, double-blind clinical trial of
clindamycin versus TMP-SMX for the treatment of uncomplicated skin infections. Patients
were eligible if they had two or more of the following signs or symptoms for 24 or more
hours: erythema, swelling or induration, local warmth, purulent drainage, and tenderness to
pain or palpation. Patients were categorized as having cellulitis (defined as inflammation of
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the skin and associated skin structures without signs of a drainable fluid collection), abscess
(defined as a circumscribed, drainable collection of pus), or both (if lesions of both cellulitis
and abscess were present). Exclusion criteria were superficial skin infections (e.g.,
impetigo), skin infection at a body site that requires specialized management (e.g.,
perirectal, genital, or hand infection), a human or animal bite at the infection site, high fever
(oral temperature, 38.5°C [38.0°C in children 6 to 11 months of age]), receipt of
immunosuppressive medications or the presence of an immunocompromising condition such
as diabetes or chronic renal failure, morbid obesity (body-mass index [the weight in
kilograms divided by the square of the height in meters], 40), surgical-site or prosthetic-
device infection, and receipt of antibacterial therapy with antistaphylococcal activity in the
previous 14 days. Patients were ineligible if they lived in a long-term care facility, had
cancer or an inflammatory disorder that required treatment in the previous 12 months, or had
major surgery in the previous 12 months. All the inclusion and exclusion criteria are listed in
Table S1 in the Supplementary Appendix, available with the full text of this article at
NEJM.org. The full protocol and statistical-analysis plan are also available at NEJM.org.
Study Population, Stratification, and Randomization
From May 2009 through August 2011, patients were recruited at four locations (University
of Chicago Medical Center, Chicago; San Francisco General Hospital, San Francisco;
Harbor–UCLA [University of California, Los Angeles] Medical Center, Torrance, CA; and
Vanderbilt University Medical Center, Nashville) from urgent care clinics, emergency
departments, and affiliated clinics. All the patients or their parents or guardians provided
written informed consent, and assent was obtained when age-appropriate. The protocol was
approved by the institutional review board at each institution.
Patients were stratified into one of two groups on the basis of the characteristics of their
infection before randomization: a group that included patients with a larger abscess or
cellulitis (larger-abscess–cellulitis group) or a group that included patients with a smaller
abscess (limited-abscess group). The protocol and data-analysis plan prespecified that the
limited-abscess group and the larger-abscess–cellulitis group be analyzed separately because
their treatment assignments differed, in that the limited-abscess stratum included a placebo
group. Patients who had a single abscess with a greatest diameter up to 5.0 cm (≤3.0 cm in
patients 6 to 11 months of age and ≤4.0 cm in patients 1 to 8 years of age) were stratified
into the limited-abscess group. All other patients, including those with an abscess greater
than 5.0 cm in diameter (and proportionally smaller in young children), patients with two or
more sites of skin infection, and patients with cellulitis without abscess (including
erysipelas), were stratified into the larger-abscess–cellulitis group. The size of the abscess
cavity was measured manually in three dimensions (width, length, and depth) and recorded
on a standardized form. All abscesses were treated by means of incision and drainage. In this
article, we describe the results for the larger-abscess–cellulitis group only.
Study Medication
After abscesses were drained (if present) and the size of the abscesses was determined,
patients were randomly assigned in a 1:1 ratio to receive clindamycin or TMP-SMX.
Variable-block randomization, with assignments made independently at each site, was
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performed by an independent contract research organization (EMMES) that developed the
randomization code.
Clindamycin was given as two 150-mg tablets three times daily. TMP-SMX was given at
doses of 160 mg of trimethoprim and 800 mg of sulfamethoxazole administered as two
single-strength tablets twice daily. Patients randomly assigned to receive TMP-SMX were
given two placebo pills for the midday dose. Pediatric doses were adjusted according to the
body weight of the patient (Table S2 in the Supplementary Appendix); liquid suspensions
were available for pediatric dosing. Pills were overencapsulated to prevent identification by
study staff and patients, and the taste of the clindamycin liquid preparations was masked
with the use of flavoring both to prevent identification and to improve adherence. Patients
were unaware of the treatment assignments, as were the study staff members, with the
exception of the research pharmacists, who determined the correct dosing. The study
medications were purchased by the study sponsor, the National Institute of Allergy and
Infectious Diseases of the National Institutes of Health.
Microbiologic Studies and Demographic Data
To prevent investigator bias if treatment failures occurred, investigators were unaware of the
microbiologic results, although the results could be obtained by an independent safety
monitor on request. Swab cultures were obtained if there was a skin break, exudate, blister
fluid, or other material that could be cultured. Nonsuppurative lesions were not cultured.
Cultures, species identification of isolates, and susceptibility tests were performed by the
clinical microbiology laboratory at each participating institution in accordance with methods
approved by the Clinical and Laboratory Standards Institute.13 External oversight for study
activities was provided by two contract research organizations, Pharmaceutical Product
Development (PPD) and the Division of Microbiology and Infectious Diseases Clinical
Research Operations and Management Support (DMID-CROMS).
Patients were surveyed about demographic characteristics and coexisting conditions.
Patients were seen at the end of treatment (day 12), at the test of cure (7 to 10 days after
completion of the prescribed 10-day course of therapy), and at the 1-month follow-up (day
40). Information about clinical response and possible medication side effects was obtained
with the use of standardized forms.
Statistical Analysis
The primary study outcome was clinical cure at the test-of-cure visit. Two primary efficacy
analyses were performed: one in the intention-to-treat population and the other in the
population of patients who could be evaluated (Fig. 1). A lack of clinical cure was defined
as a lack of resolution of signs or symptoms of infection, the occurrence of side effects that
necessitated discontinuation of treatment with the study medication within the first 48 hours,
or any one of the following before the test-of-cure visit: occurrence of a skin infection at a
new body site, unplanned surgical treatment of the skin infection, or hospitalization related
to the infection. The primary null hypothesis was that clindamycin and TMP-SMX would
have equal rates of cure. The study was designed as a superiority trial with 80% power to
detect an absolute difference between the two treatment groups of 10 percentage points in
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cure rates (85% vs. 95%) in the population that could be evaluated, at an alpha level of 0.05.
Assuming a 20% attrition rate, we calculated that 524 patients (262 in each group) needed to
be enrolled. The prespecified secondary outcomes were cure rates at the end of treatment
and at the 1-month follow up visit; cure rates in the adult and pediatric populations; cure
rates among patients with cellulitis, abscess, or mixed abscess and cellulitis (defined as
separate lesions of abscess and cellulitis) at the test-of-cure visit; and adverse-event rates.
Comparisons between groups were performed with the use of Pearson's chi-square test,
Fisher's exact test, or an analysis-of-variance test, as appropriate; all tests were two-sided.
Interim analyses for safety were performed by an independent data and safety monitoring
committee. Findings from the trial are described in accordance with Consolidated Standards
of Reporting Trials (CONSORT) guide-lines.14
Results
Demographic and Clinical Characteristics of the Patients
A total of 524 patients were enrolled; 264 received clindamycin treatment, and 260 received
TMP-SMX treatment (Fig. 1). A total of 52.3% of the patients were male, 53.2% were
black, 40.3% were white, and 28.6% were Hispanic. The mean age was 27.1 years. A total
of 29.6% of the patients were children (Table 1, and Table S3 in the Supplementary
Appendix). There were no significant demographic differences between the groups.
Abscess was present in 160 patients (30.5%), cellulitis in 280 (53.4%), and mixed abscess
and cellulitis in 82 (15.6%); the lesions in 2 patients (0.4%) were not characterized. There
were no significant differences between the groups with regard to clinical presentation,
signs, or symptoms. Incision and drainage were performed in 44.5% of the patients. Detailed
clinical information on the patients is provided in Table 1.
Cultures were obtained for 296 patients (56.5%). The most common baseline isolate found
in culture was S. aureus (217 of 524 patients, 41.4%) (Table 2); 27 of the 217 isolates
(12.4%) were clindamy-cin-resistant, and 1 of 217 isolates (0.5%) was TMP-SMX–resistant.
Stratification of culture results according to skin infection type is shown in Table S4 in the
Supplementary Appendix.
Clinical Cure at the Test-of-Cure Visit
The rate of cure in the intention-to-treat population (524 patients) at the test-of-cure visit
was 80.3% (95% confidence interval [CI], 75.2 to 85.4) in the clindamycin group and 77.7%
(95% CI, 72.3 to 83.1) in the TMP-SMX group (difference, −2.6 percentage points; 95% CI,
-10.2 to 4.9; P = 0.52) (Table 3). In the population that could be evaluated (466 patients), the
rate of cure was 89.5% (95% CI, 85.2 to 93.7) in the clindamycin group and 88.2% (95% CI,
83.7 to 92.7) in the TMP-SMX group (difference, −1.2 percentage points; 95% CI, −7.6 to
5.1; P = 0.77) (Fig. 2).
There were no significant differences between treatment groups, in either the intention-to-
treat population or the population that could be evaluated, in subgroups consisting of
children, adults, or patients with cellulitis, abscesses, or mixed abscess and cellulitis lesions
(Table 3). In addition, there were no significant between-group differences in subgroups of
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patients infected with S. aureus, MRSA, or MSSA in either the intention-to-treat population
or the population that could be evaluated. In the population that could be evaluated, 11 of 15
clindamycin-treated patients with clindamycin-resistant S. aureus isolates were cured, as
compared with 77 of 84 patients with susceptible isolates (73.3% [95% CI, 47.0 to 99.7] vs.
91.7% [95% CI, 85.0 to 98.3], P = 0.06).
Efficacy at 1 Month
Cure rates at the 1-month follow-up visit were similar for the clindamycin and TMP-SMX
groups in the intention-to-treat population (193 of 264 patients [73.1%; 95% CI, −67.6 to
78.6] and 176 of 260 patients [67.7%; 95% CI, 61.8 to 73.6], respectively; difference, −5.4
percentage points [95% CI, −13.6 to 2.8]; P = 0.18) and in the population that could be
evaluated (193 of 230 patients [83.9%; 95% CI, 78.9 to 88.9] and 176 of 225 patients
[78.2%; 95% CI, 72.6 to 83.8]; difference, −5.7 percentage points [95% CI, −13.3 to 1.9]; P
= 0.15), respectively.
Adverse Events
Overall rates of adverse events were similar in the clindamycin and TMP-SMX groups
(18.9% and 18.6%, respectively). The most common adverse events in the clindamycin and
TMP-SMX groups were diarrhea (9.7% and 10.1%), nausea (2.3% and 2.7%), vomiting
(2.3% and 1.6%), pruritus (1.5% and 1.2%), and rash (1.2% and 0.8%) (Table S5 in the
Supplementary Appendix). There were no cases of Clostridium difficile–associated diarrhea.
Most adverse events were mild or moderate and resolved without sequelae. There were no
treatment-associated serious adverse events (Table S6). The rates of treatment
discontinuation due to adverse events were similar in the two groups (8.3% and 8.8%)
(Table S7 in the Supplementary Appendix).
Discussion
We performed a double-blind, multicenter, randomized clinical trial to compare TMP-SMX
and clindamycin, each of which is commonly recommended as empirical therapy for
uncomplicated skin infections in the outpatient population with only minor or no coexisting
conditions.6,7,15,16 The cure rates with TMP-SMX and clindamycin did not differ
significantly. The cure rate with TMP-SMX ranged from 5 percentage points higher to 7 to
10 percentage points lower than the cure rate with clindamycin, on the basis of the 95%
confidence intervals for rate differences in the intention-to-treat population and the
population that could be evaluated. This well-powered superiority trial did not show the
superiority of either intervention. Although it is not appropriate to claim that there are no
differences on the basis of the negative result of the superiority test, important differences
can reasonably be ruled out with the use of confidence intervals. Adverse-event rates with
the two therapies were similar.
Among all the patients, 46% had one or more abscesses larger than 5 cm in diameter
(proportionally smaller in young children), all of which underwent incision and drainage.
The 5-cm cutoff was based on data from a single-center observational study involving
children, in which abscesses larger than 5 cm were associated with treatment failure.17
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Although incision and drainage alone may be sufficient for treatment in many cases, there
are likely to be subgroups in which antibiotic therapy is needed. Outcomes in antibiotic-
treated patients with abscesses in our relatively low-risk population could reflect either
similar true efficacies or the adequacy of incision and drainage alone. Large placebo-
controlled trials are needed to further understand the role of active pharmacologic therapy in
the treatment of patients with abscesses.
The cure rates for TMP-SMX and clindamycin were similar among patients who had
cellulitis as the sole lesion type. In the prespecified analysis of patients with cellulitis only,
the point estimates of the TMP-SMX mean cure rates were 86.6% and 76.4% for the
population that could be evaluated and the intention-to-treat population, respectively —
rates that are 4.3 percentage points (95% CI, −13.1 to 4.6) to 4.5 percentage points (95% CI,
−15.1 to 6.1) lower than the rates with clindamycin. In a post hoc analysis of patients with
cellulitis with or without an abscess at another site, the cure rates were 87.9% (138 of 157
patients) with TMP-SMX and 90.9% (149 of 164) with clindamycin in the population that
could be evaluated (difference, −3.0 percentage points [95% CI, −10.5 to 4.6]) and 77.1%
(138 of 179) and 81.4% (149 of 183), respectively, in the intention-to-treat population
(difference, −4.3 percentage points [95% CI, −13.5 to 4.8]). Our study was not powered to
determine the superiority of one agent over the other in the subgroup of patients with
cellulitis, but the data suggest that if there is a difference in outcome it is probably small.
Moreover, in further support of the efficacy of TMP-SMX, the lower boundaries of the
confidence intervals are above the 18 to 30% range for the inferiority of placebo to active
agents cited for the outcome of cellulitis in the 2013 Food and Drug Administration
guidance for acute bacterial skin and skin structure infections.18,19
The cause of cellulitis is incompletely understood, because a causative pathogen is not
identified in most cases20; this is consistent with our study, in which 80% of cellulitis
lesions could not be cultured because skin was intact. Expert opinion8 and empirical
data21,22 suggest that cellulitis is most commonly caused by Streptococcus pyogenes. Our
findings are provocative, because TMP-SMX has been considered a poor empirical choice
for the treatment of cellulitis. Recent data show that S. pyogenes strains may be TMP-SMX–
susceptible if low-concentration thymidine agar is used for testing.23 Our results showing
that TMP-SMX and clindamycin have similar efficacy in patients with cellulitis are
consistent with these in vitro data.
With respect to adverse events, the rates were similar in the two groups. In particular, the
rates of diarrhea were similar. The absence of C. difficile–associated diarrhea may stem from
its relatively low incidence in patients with low disease severity and younger age,24-26
characteristics that were typical of the patients in this trial. Rash has been a concern with
TMP-SMX therapy27; however, dermatologic side-effect rates were similar in the two
groups. Overall adverse-event rates were similar in the pediatric and adult subgroups.
Our study has limitations. First, we excluded patients with serious coexisting conditions, and
the outcomes of skin infections treated with clindamycin and TMP-SMX in populations with
such conditions may differ. However, our investigation involved outpatients, the population
in which approximately 95% of skin infections are treated,28 and thus is generalizable to a
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large population. Second, we examined only two antibiotics, and the comparative efficacy
and side-effect profile of other oral medications are unclear. However, the two antibiotics
we studied are those typically recommended by experts in areas of MRSA endemicity.2,10-12
Third, patients were followed for 1 month after therapy was completed, which is a strength
in comparison with studies lacking a documented follow-up visit but is also a limitation. S.
aureus infections are often recurrent,29,30 and 1 month of follow-up may be inadequate for
assessing the efficacy of a drug in preventing recurrent disease.
Fourth, the dosages of clindamycin and TMP-SMX for skin infections are not well defined.
Some have suggested using twice the dose we used (see, e.g., clinicaltrials.gov number
NCT00729937), whereas others have recommended the same dose.8 Our data show that the
efficacy of TMP-SMX doses of 160 mg and 800 mg does not differ significantly from that
of a commonly recommended dose of clindamycin — specifically, 300 mg three times
daily.8 Finally, the proportions of patients who had an S. aureus isolate that was resistant to
clindamycin or TMP-SMX (5.2% and 0.2%, respectively) were relatively low. Given the
low prevalence of resistance, its contribution to treatment failure is unclear, although there
was a trend toward a lower clindamycin cure rate for infections caused by clindamycin-
resistant S. aureus versus clindamycin-susceptible isolates (73.3% vs. 91.7%, P = 0.06),
which also raises important questions about the spontaneous response rate. The number of
patients with inducible clindamycin-resistant isolates was even smaller (three patients in the
population that could be evaluated), which precluded making conclusions about its role in
treatment failure.
Our study has important strengths. It was a double-blind, randomized clinical trial
accompanied by detailed drug accountability (i.e., storage, handling, and dispensing of study
drugs, as well as documentation of their administration), detailed systematic reviews of
adverse drug effects, and relatively low rates of attrition (10.5%). We included both adults
and children, which is of critical importance given that skin infections are highly prevalent
among persons of all ages.7,28 Finally, the populations studied were ethnically and
geographically diverse. In summary, we found no significant differences between the
efficacy of clindamycin and that of TMP-SMX for the treatment of uncomplicated skin
infections in children and adults with few or no major coexisting conditions.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
Supported by grants from the National Institutes of Allergy and Infectious Diseases (1U01 HHSN272200700031C,
to Dr. Chambers) and the National Center for Research Resources (UL1RR033176, now at the National Center for
Advancing Translational Sciences, UL1TR000124).
Dr. Miller reports receiving consulting fees from Cubist, Durata, and Pfizer; Dr. Daum, fees for serving on an
advisory board from Pfizer; Dr. Creech, grant support from Pfizer and Cubist; Dr. Hoagland, fees for providing
statistical analysis and programming services from EMMES; and Dr. Chambers, fees for serving on advisory
boards from Theravance and AstraZeneca, consulting fees from Cubist, Pfizer, Trius, and AstraZeneca, and grant
support from Cubist; Dr. Chambers also reports that he holds stock in Trius and Merck and that his institution holds
a contract for a clinical trial from Cerexa.
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We thank Christine Chiou, M.D., Maureen Mehigan, R.N., B.S.N., and Hyung Koo, R.N., B.S.N., at the Division of
Microbiology and Infectious Diseases; and Thad Zajdowicz, Nancy Browning, and the staff at EMMES for their
support with the conduct of this clinical trial.
References
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17. Lee MC, Rios AM, Aten MF, et al. Management and outcome of children with skin and soft tissue
abscesses caused by community-acquired methicillin-resistant Staphylococcus aureus. Pediatr
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Evaluation and Research (CDER). Guidance for industry: acute bacterial skin and skin structure
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Guidances/ucm071185.pdf
19. Itani KM, Shorr AF. FDA guidance for ABSSSI trials: implications for conducting and interpreting
clinical trials. Clin Infect Dis. 2014; 58(Suppl 1):S4–S9. [PubMed: 24343831]
20. Chira S, Miller LG. Staphylococcus aureus is the most common identified cause of cellulitis: a
systematic review. Epidemiol Infect. 2010; 138:313–7. [PubMed: 19646308]
21. Jeng A, Beheshti M, Li J, Nathan R. The role of beta-hemolytic streptococci in causing diffuse,
nonculturable cellulitis: a prospective investigation. Medicine (Baltimore). 2010; 89:217–26.
[PubMed: 20616661]
22. Eells SJ, Chira S, David CG, Craft N, Miller LG. Non-suppurative cellulitis: risk factors and its
association with Staphylococcus aureus colonization in an area of endemic community-associated
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23. Bowen AC, Lilliebridge RA, Tong SY, et al. Is Streptococcus pyogenes resistant or susceptible to
trimethoprim-sulfa-methoxazole? J Clin Microbiol. 2012; 50:4067–72. [PubMed: 23052313]
24. Loo VG, Bourgault AM, Poirier L, et al. Host and pathogen factors for Clostridium difficile
infection and colonization. N Engl J Med. 2011; 365:1693–703. [PubMed: 22047560]
25. Kyne L, Sougioultzis S, McFarland LV, Kelly CP. Underlying disease severity as a major risk
factor for nosocomial Clostridium difficile diarrhea. Infect Control Hosp Epidemiol. 2002;
23:653–9. [PubMed: 12452292]
26. Pallin DJ, Binder WD, Allen MB, et al. Clinical trial: comparative effectiveness of cephalexin plus
trimethoprim-sulfa-methoxazole versus cephalexin alone for treatment of uncomplicated cellulitis:
a randomized controlled trial. Clin Infect Dis. 2013; 56:1754–62. [PubMed: 23457080]
27. Ho JM, Juurlink DN. Considerations when prescribing trimethoprim-sulfa-methoxazole. CMAJ.
2011; 183:1851–8. [PubMed: 21989472]
28. Miller, LG.; Eisenberg, DF.; Chang, CL., et al. The burden of skin and soft tissue infections:
incidence and costs from a large U.S. population of commercially insured persons aged 0-64 years
from 2005 to 2008. Presented at the 51st Annual International Conference on Antimicrobial
Agents and Chemotherapy; Chicago. September 17-20 2011; abstract
29. Fritz SA, Hogan PG, Hayek G, et al. Household versus individual approaches to eradication of
community-associated Staphylococcus aureus in children: a randomized trial. Clin Infect Dis.
2012; 54:743–51. [PubMed: 22198793]
30. Miller LG, Tan J, Eells SJ, Benitez E, Radner AB. Prospective investigation of nasal mupirocin,
hexachlorophene body wash, and systemic antibiotics for prevention of recurrent community-
associated methicillin-resistant Staphylococcus aureus infections. Antimicrob Agents Chemother.
2012; 56:1084–6. [PubMed: 22083485]
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Figure 1. Enrollment, Randomization, and Follow-up
TMP-SMX denotes trimethoprim–sulfamethoxazole.
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Figure 2. Comparison of the Efficacy of Clindamycin and TMP-SMX in Patients with
Uncomplicated Skin Infection
The graph shows the proportion of patients cured by the time of the test-of-cure visit in the
intention-to-treat population and the population that could be evaluated. The actual
confidence level was 95.60% after adjustment for interim analyses.
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Table 1
Baseline Characteristics of the Patients, According to Treatment Group*
Characteristic Clindamycin Group (N = 264) TMP-SMX Group (N = 260) All Patients (N = 524)
Female sex — no. (%) 129 (48.9) 121 (46.5) 250 (47.7)
Hispanic ethnic background — no. (%)†
Non-Hispanic or Non-Latino 188 (71.2) 186 (71.5) 374 (71.4)
Hispanic or Latino 76 (28.8) 74 (28.5) 150 (28.6)
Race or ethnic group — no. (%)†
American Indian or Alaskan Native 1 (0.4) 2 (0.8) 3 (0.6)
Asian 5 (1.9) 4 (1.5) 9 (1.7)
Hawaiian or Pacific Islander 4 (1.5) 2 (0.8) 6 (1.1)
Black 141 (53.4) 138 (53.1) 279 (53.2)
White 102 (38.6) 109 (41.9) 211 (40.3)
Multiracial 10 (3.8) 4 (1.5) 14 (2.7)
Other or unknown 1 (0.4) 1 (0.4) 2 (0.4)
Age group — no. (%)
1 yr 6 (2.3) 5 (1.9) 11 (2.1)
1–8 yr 45 (17.0) 42 (16.2) 87 (16.6)
9–17 yr 30 (11.4) 27 (10.4) 57 (10.9)
≥18 yr 183 (69.3) 186 (71.5) 369 (70.4)
Temperature — °C 36.61±0.50 36.59±0.52 36.60±0.51
Area of wound — cm2,‡,§ 43.84±140.03 35.35±71.13 39.62±111.28
Purulent drainage present — no. (%) 124 (47.0) 113 (43.5) 237 (45.2)
Incision and drainage performed — no. (%) 122 (46.2) 111 (42.7) 233 (44.5)
Type of lesion — no. (%)¶
Abscess only 80 (30.3) 80 (30.8) 160 (30.5)
Cellulitis only 136 (51.5) 144 (55.4) 280 (53.4)
Mixed abscess and cellulitis‖ 47 (17.8) 35 (13.5) 82 (15.6)
*
Complete data on demographics and age, stratified according to treatment group, are provided in Table S3 in the Supplementary Appendix. P
values for all comparisons were nonsignificant (P0.05 for all comparisons). The denominator for calculation of percentages is the number of
patients in the intention-to-treat population for each treatment group. Plus–minus values are means ±SD. TMP-SMX denotes trimethoprim–
sulfamethoxazole.
†
Race and ethnic group and information on Hispanic ethnic background were self-reported.
‡
Data were available for 263 patients in the clindamycin group and 259 in the TMP-SMX group.
§
Areas were calculated with the use of the formula for an ellipse ([length × width × π]/4).
¶
The type of lesion was not known for 2 patients.
‖
Patients categorized as having mixed abscess and cellulitis lesions were those who had more than one lesion, with at least one abscess lesion that
underwent incision and drainage and at least one cellulitis lesion that did not require incision and drainage.

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Table 2
Wound Culture Results at Baseline*
Culture Result Clindamycin Group (N = 264)
TMP-SMX Group (N =
260) All Patients (N = 524)
no. of patients (%)
No culture obtained 110 (41.7) 118 (45.4) 228 (43.5)
Culture obtained but no growth 6 (2.3) 6 (2.3) 12 (2.3)
Culture obtained but no results 4 (1.5) 3 (1.2) 7 (1.3)
Positive culture 144 (54.5) 133 (51.2) 277 (52.9)
Staphylococcus aureus 108 (40.9) 109 (41.9) 217 (41.4)
MRSA 84 (31.8) 83 (31.9) 167 (31.9)
Clindamycin-resistant 12 (4.5) 9 (3.5) 21 (4.0)
TMP-SMX–resistant 1 (0.4) 0 1 (0.2)
MSSA 25 (9.5) 27 (10.4) 52 (9.9)
Clindamycin-resistant 3 (1.1) 3 (1.2) 6 (1.1)
TMP-SMX–resistant 0 0 0
Streptococcus pyogenes 3 (1.1) 5 (1.9) 8 (1.5)
Group B streptococcus 1 (0.4) 1 (0.4) 2 (0.4)
Beta-hemolytic group C streptococcus 2 (0.8) 0 2 (0.4)
Beta-hemolytic group F streptococcus 0 1 (0.4) 1 (0.2)
Non–group A and B beta-hemolytic streptococcus 1 (0.4) 0 1 (0.2)
Viridans group streptococcus 9 (3.4) 9 (3.5) 18 (3.4)
Enterobacter species 1 (0.4) 0 1 (0.2)
Enterococcus species 1 (0.4) 1 (0.4) 2 (0.4)
Escherichia coli 2 (0.8) 2 (0.8) 4 (0.8)
Hemophilus species 2 (0.8) 2 (0.8) 4 (0.8)
Klebsiella species 1 (0.4) 2 (0.8) 3 (0.6)
Lactobacillus species 2 (0.8) 0 2 (0.4)
Proteus mirabilis 9 (3.4) 1 (0.4) 10 (1.9)
Bacterial growth not otherwise specified 2 (0.8) 0 2 (0.4)
Coagulase-negative staphylococcus 19 (7.2) 19 (7.3) 38 (7.3)
Diphtheroid bacilli 8 (3.0) 7 (2.7) 15 (2.9)
Other 11 (4.2) 7 (2.7) 18 (3.4)
*
The denominator for the calculation of percentages is the number of patients in the intention-to-treat population for each group. Patients are
counted once for each species identified. MRSA denotes methicillin-resistant S. aureus, and MSSA methicillin-susceptible S. aureus.

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Table
3
Cure
Rate
at
Test-of-Cure
Visit
in
the
Overall
Population
and
Relevant
Subgroups
*
Group
with
Clinical
Cure
Clindamycin
Group
TMP-SMX
Group
Difference
P
Value
no./total
no.
%
(95%,
CI)
no./total
no.
%
(95%,
CI)
percentage
points
All
patients
Intention-to-treat
population
212/264
80.3
(75.2
to
85.4)
202/260
77.7
(72.3
to
83.1)
−2.6
(-10.2
to
4.9)
0.52
Population
that
could
be
evaluated
212/237
89.5
(85.2
to
93.7)
202/229
88.2
(83.7
to
92.7)
−1.2
(−7.6
to
5.1)
0.77
Children
Intention-to-treat
population
70/81
86.4
(78.1
to
94.7)
60/74
81.1
(71.2
to
90.9)
−5.3
(−18.6
to
7.9)
0.39
Population
that
could
be
evaluated
70/76
92.1
(85.2
to
99.0)
60/67
89.6
(81.3
to
97.8)
−2.6
(−13.7
to
8.6)
0.77
Adults
Intention-to-treat
population
142/183
77.6
(71.1
to
84.1)
142/186
76.3
(69.8
to
82.9)
−1.3
(−10.6
to
8.1)
0.81
Population
that
could
be
evaluated
142/161
88.2
(82.8
to
93.6)
142/162
87.7
(82.1
to
93.2)
−0.5
(−8.5
to
7.4)
1.00
Patients
with
cellulitis
without
abscess
Intention-to-treat
population
110/136
80.9
(73.7
to
88.0)
110/144
76.4
(68.9
to
83.9)
−4.5
(−15.1
to
6.1)
0.38
Population
that
could
be
evaluated
110/121
90.9
(85.2
to
96.6)
110/127
86.6
(80.1
to
93.1)
−4.3
(−13.1
to
4.6)
0.32
Patients
with
abscess
Intention-to-treat
population
63/80
78.8
(68.9
to
88.6)
64/80
80.0
(70.4
to
89.6)
1.3
(−12.9
to
15.4)
1.00
Population
that
could
be
evaluated
63/73
86.3
(77.5
to
95.1)
64/72
88.9
(80.7
to
97.0)
2.6
(−9.8
to
15.0)
0.80
Patients
with
mixed
abscess
and
cellulitis
Intention-to-treat
population
39/47
83.0
(70.9
to
95.1)
28/35
80.0
(65.0
to
95.0)
−3.0
(−23.0
to
17.0)
0.78
Population
that
could
be
evaluated
39/43
90.7
(80.6
to
100)
28/30
93.3
(82.5
to
100)
2.6
(−13.0
to
18.3)
1.00
Patients
with
a
single
lesion
in
the
intention-to-treat
population
136/170
80.0
(73.5
to
86.5)
141/174
81.0
(74.8
to
87.3)
1.0
(−8.1
to
10.2)
0.89
Patients
with
1
lesion
in
the
intention-to-treat
population
76/93
81.7
(73.1
to
90.3)
61/85
71.8
(61.3
to
82.2)
−10.0
(−23.8
to
3.9)
0.15
*
The
actual
confidence
level
was
95.60%
after
adjustment
for
interim
analyses.
P
values
for
comparisons
were
determined
with
the
use
of
Fisher's
exact
test.

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QUESTIONS • CHALLENGES • CONTROVERSIES
Introduction
Community-acquired methicillin-
resistant Staphylococcus aureus
(CA-MRSA), first recognized in the
early 1980s, was noted to occur in
patients with MRSA infections who
had no identifiable, predisposing risk
factors.1–5
Over time, the prevalence
of CA-MRSA infection has increased
across the United States in both the
pediatric and adult populations with
CA-MRSA infections commonly
encountered in ambulatory
dermatology practices. Some have
theorized that CA-MRSA was at first
a hospital-acquired pathogen with
strains traceable to specific
healthcare facilities, while others
developed de novo within the
community.6–10
With the passing of
time, CA-MRSA has become more
distinct, both genetically and
epidemiologically, from nosocomial
MRSA, leading many to believe that
CA-MRSA isolates did not emerge
from local nosocomial MRSA
strains.1
Molecular, genetic, and
microbiologic studies have revealed
that CA-MRSA is associated with a
unique genetic profile and
phenotype.11
It has been observed
that many CA-MRSA strains have
become endemic in a given
geographic region, progressively
replacing other strains due to
selective genetic advantages.12–15
According to a 15-year study
performed in San Diego, there has
been a dramatic increase in CA-
MRSA infections since 2002, with an
increasing proportion of cases
related to intrafamilial spread.1
An
estimated 85 percent of CA-MRSA
infections present in the skin as
abscesses or as folliculitis.16
Outbreaks are usually in the
younger populations and in small
clusters in localized geographic
regions in both rural and urban
areas. In its most severe form, CA-
MRSA has also been shown to cause
septic arthritis, osteomyelitis,
pyomyositis, necrotizing fasciitis,
and necrotizing pneumonia,
especially in young children.11
The
incidence of infection increases with
close physical contact, loss of skin
integrity, and sharing of
contaminated personal use articles
or equipment.1
Other factors, such
as hygiene and physical crowding,
also play a large role in spreading
CA-MRSA infections. With regard to
carriage, the estimated prevalence
of S. aureus and MRSA nasal
colonization in the United States
was reported to be 32.4 percent and
0.8 percent, respectively, based on a
large population-based evaluation.17
A high rate of S. aureus
colonization also involves the
perineum, which like the anterior
nares, demonstrates high organism
density and a greater propensity for
consistent carriage over time.18–21
What is the role of oral antibiotic
therapy in the treatment of
cutaneous CA-MRSA infections
seen in outpatient dermatology
practices?
Oral antibiotic therapy is an
important component of therapy for
uncomplicated cutaneous CA-MRSA
infections.11,18
In office-based
dermatology practices, most CA-
MRSA infections present as
folliculitis or furunculosis, with
many patients presenting with at
least a few abscess-like lesions.11,16
Incision and drainage represents the
primary therapy for treatment of
lesions presenting as abscesses.11,18,20
Because many patients present with
multiple lesions, oral antibiotic
therapy is indicated to assist in
eradicating the infection.11,16,18
In
cases confounded by multiple
recurrences over time, it is often
necessary to address decolonization
Section Editor: James Q. Del Rosso, DO, FAOCD
Use of Oral Doxycycline
for Community-acquired
Methicillin-resistant
Staphylococcus aureus
(CA-MRSA) Infections
James Q. Del Rosso, DO, FAOCD;
Sanjay Bhambri, DO;
Grace Kim, DO

[ A p r i l 2 0 0 9 • V o l u m e 2 • N u m b e r 4 ]
46
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of foci of staphylococcal carriage,
such as the anterior nares,
perineum, and hands.17–21
What antibiotic therapy options
are available for treatment of
cutaneous CA-MRSA infections?
Several antibiotic options, such as
trimethoprim-sulfamethoxazole,
fluoroquinolones, lincosamides (i.e.,
clindamycin), rifampin, daptomycin,
carbapenems, and linezolid, are
available to treat skin and soft-tissue
infections (SSTIs) caused by CA-
MRSA.11,16,18,22,23
Oral antibiotics
belonging to the tetracycline family,
including minocycline and
doxycycline, provide an effective
means of treating CA-MRSA
infections.11,16,18,22,23
As stated above,
incision and drainage remains the
single most important intervention
against CA-MRSA infections, which
present as abscess-like lesions.
However, when oral antibiotic
therapy is indicated based on the
judgement of the clinician,
tetracycline agents and
trimethoprim-sulfamethoxazole are
effective in the majority of patients
presenting with uncomplicated
SSTIs caused by CA-MRSA, and are
commonly recommended.1,2,11,16,18,22,23
Tetracyclines are effective against
many strains of CA-MRSA.1,2,24–26
What information is available on
the use of oral doxycycline for
treatment of cutaneous CA-MRSA
infections?
Multiple reports support the use
of doxycycline in patients with
suspected or confirmed cutaneous
CA-MRSA infection.24–26
A
retrospective cohort study
investigated the therapeutic
outcomes of patients with CA-MRSA
infection treated with extended-
spectrum tetracyclines.24
This study
evaluated results from 276 patients
who presented with 282 episodes of
cutaneous MRSA between 2002 and
2007. Ninety episodes (32%) were
treated with extended-spectrum
tetracyclines (doxycycline or
minocycline); whereas, 192 episodes
(68%) were treated with a β-lactam
agent. The rate of susceptibility of
MRSA strains to tetracyclines
remained stable at 95 percent
during the study. Doxycycline
monotherapy was administered in 87
of 90 episodes (97%) treated with
tetracyclines. Ninety-six percent of
patients (86/90) treated with an
extended-spectrum tetracycline
achieved success with resolution of
their CA-MRSA infection, as
compared to 88 percent (168/192)
of patients treated with β-lactam
monotherapy. Treatment failure was
higher in the β-lactam group than in
the extended-spectrum tetracycline
group (12.5% vs. 4.4%). Four
patients who were treatment failures
in the tetracycline group exhibited
improvement on continued
tetracycline therapy after a repeat
incision and drainage procedure.
In another study of adult patients
with CA-MRSA infections, 54
percent (13/24) were treated with
doxycycline and 46 percent (11/24)
were treated with minocycline.25
Doxycycline achieved a 92-percent
success rate as compared to a 73-
percent success rate with
minocycline. Based on microbiologic
testing in vitro, doxycycline has
also been shown to be a very potent
agent against CA-MRSA strains with
a minimum inhibitory concentration
(MIC50) value of 0.25µg/mL.26
When used to treat cutaneous
CA-MRSA infections, a daily
doxycycline dose of 200mg per day
is generally used. The duration of
therapy varies based on clinical
response, with an average duration
of treatment ranging from 10 to 21
days.22,23
Interestingly, when utilized
in combination with rifampin,
doxycycline may prevent the
emergence of CA-MRSA strains that
become resistant to rifampin.27
What concerns exist regarding CA-
MRSA resistance to non-β-lactam
oral antibiotics, including
agents?
Antibiotic resistance to CA-MRSA
is emerging with resistance reported
to many antibiotics including
fluoroquinolones, macrolides, and
lincosamides.22,23,28,29
Resistance of S.
aureus to tetracyclines has been
reported and is achieved by two
potential mechanisms: active reflux
and ribosomal protection.24,25,30
Active
reflux is mediated by plasmid-
located tetK and tetL genes;
whereas, chromosome-located tetM
or tetO genes mediate ribosomal
protection.18,24,25,30
Presence of the
tetM gene confers resistance to all
antibiotics within the tetracycline
family including doxycycline and
minocycline; however, presence of
tetK gene confers resistance to
tetracycline, but the isolates can still
be inhibited by minocycline.30
There
exists potential for cross-resistance
between tetracycline and the
derivatives. Therefore, tetracycline-
resistant S. aureus should also be
considered resistant to doxycycline
and minocycline unless sensitivity
testing is performed against each
individual tetracycline agent that
demonstrates otherwise.25,30
In most
reference microbiology laboratories
used by dermatologists in clinical
practice across the United States,
sensitivity to tetracycline is all that
is reported routinely.
May the formulation of oral
doxycycline be clinically

47
47
47
47
significant in the treatment of
cutaneous CA-MRSA infections?
Doxycycline is available as either
the monohydrate or hyclate salt,
with most formulations being
immediate release and nonenteric
coated. An enteric-coated
formulation of doxycycline hyclate is
also available (75mg, 100mg, and
150mg tablets). This enteric-coating
technology allows for a delay in
degradation of the enteric-coated
pellets, which are embedded within
the body of the tablet matrix. Thus,
release of doxycycline bypasses the
stomach and occurs within the
upper small intestine where the
active drug is absorbed.31
Abdominal pain, esophageal pain,
nausea, and vomiting are common
gastrointestinal (GI) side effects
associated with immediate-release,
nonenteric coated formulations of
doxycycline hyclate and
monohydrate.32,33
In one study, a
three-fold higher incidence of
nausea and vomiting was noted in
subjects receiving nonenteric-coated
doxycycline as compared to those
treated with either penicillin,
ampicillin, or tetracycline.32
Nonenteric-coated doxycycline has
also proven to be more poorly
tolerated in terms of GI side effects
as compared to roxithromycin and
ciprofloxacin.34,35
Although it has
been suggested that nonenteric-
coated doxycycline monohydrate
produces fewer GI side effects than
nonenteric-coated doxycycline
hyclate, due to the lower pH of the
former, definitive clinical evidence
supporting this theoretical
suggestion is lacking.31,36
In a randomized, prospective,
double-blind, multiple-dose,
placebo-controlled, three-way cross-
over study, healthy adult subjects
(N=98; mean age 29 years) were
treated for four consecutive days
with either enteric-coated
doxycycline hyclate 100mg,
hyclate 100mg, or placebo capsules,
after treatment on Day 1 with
100mg twice daily.37
All subjects
received all three treatments, with a
three-day washout between the
four-day courses of active treatment.
The order of drug administration
was balanced and randomized, and a
double-dummy technique was used
to preserve the study blind.
Medication was administered with
180mL of water and at least one
hour before food intake. Study
diaries were used to capture the
incidence and severity of GI
complaints, with recordings
completed at 0.5, 1, 1.5, 2, 4, 6, 12,
and 24 hours post dose. Symptom
scores were computed by summing
the individual complaints within
each treatment period. Figure 1
depicts the mean symptom scores
for all three treatment periods,
indicating that reports of GI side
effects were greatest with
hyclate capsules.
In another randomized, double-
blind, multiple-dose, prospective,
three-way cross-over, placebo-
controlled trial completed in
healthy adults (N=111; mean age 26
years), enteric-coated doxycycline
hyclate 150mg, nonenteric-coated
doxycycline monohydrate 150mg,
and placebo tablets were compared
regarding the incidence of adverse
events, especially GI side effects.31
All subjects received each
treatment over three consecutive
days with a washout period of 4 to
10 days between active study
periods. Medication was
administered in the morning after
an overnight 10-hour fast with
200mL of water, with no food intake
allowed for at least two hours post
dose. Subject diaries were used
each day to capture the timing,
frequency, severity, and cessation of
any side effects. Figure 2
demonstrates the results reported
by subjects during the study. The

48
48
48
incidence of adverse events was
highest during treatment with
monohydrate 150mg tablets. The
number of subjects experiencing GI
side effects, especially nausea and
abdominal pain, was markedly
higher during administration of
monohydrate 150mg tablets.
Effective oral antibiotic treatment
of cutaneous CA-MRSA infections
requires adherence with the
treatment regimen, which in some
cases may be 1 to 2 weeks longer
than a conventional duration of
treatment.22,23
Therefore, decreasing
the potential for subjective GI
complaints that often lead to
voluntary discontinuation of therapy
by the patient is clinically relevant.
The marked reduction in GI side
effects associated with enteric-
coated doxycycline hyclate tablets
favors greater overall adherence
with the recommended treatment
course.
What can be concluded from the
available information on the use
of oral doxycycline for the
treatment of cutaneous CA-MRSA
infections?
Based on available data,
doxycycline should be considered
among the group of first-line oral
antibiotic agents used to treat
uncomplicated cutaneous CA-MRSA
infections. Both in-vitro and clinical
studies support its use.24–26
Doxycycline exhibits a more
favorable safety profile as compared
to trimethoprim-sulfamethoxazole
and immediate-release minocycline
formulations used to treat CA-MRSA
infections.38,39
Unlike rifampin and
fluoroquinolones, there is no
evidence of rapid emergence of
bacterial resistance when
doxycycline is used as monotherapy
to treat cutaneous CA-MRSA
infections.16,23–27
Additionally, the
availability of an enteric-coated
doxycycline formulation, which is
associated with a lower incidence of
GI side effects, provides an option
that is likely to optimize
adherence.31,37
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Dr. Del Rosso is Dermatology Residency Director, Valley Hospital Medical Center, Las Vegas, Nevada, Touro
University College of Osteopathic Medicine, Henderson, Nevada; Clinical Associate Professor, Dermatology,
University of Nevada School of Medicine, Las Vegas, Nevada; Las Vegas Skin Cancer Clinics, Las Vegas and
Henderson, Nevada. Dr. Bhambri is Chief Dermatology Resident, Valley Hospital Medical Center, Las Vegas,
Nevada. Dr. Kim is a dermatologist at Valley Hospital Medical Center, Las Vegas, Nevada. The authors report
no conflicts of interest in relationship to the content of this article.

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