Research Article :
This paper aims to provide a concise review of
doxycycline, including a case report that provides an exemplar of a short-term
application of this drug to a patient who developed skin and soft tissue
infection of the lower extremity after elective surgery. Doxycycline appears to
be benign but research suggests that it does have notable side effects and
contraindications. A short duration of treatment is recommended after the risks
and benefits of Doxycycline are carefully considered, and after the therapeutic
guidelines provided by CDC, IDSA and WHO are reviewed. Studies have shown that
Doxycycline is effective; however, it is not appropriate for every patient and
increased reports of overuse have become a serious problem. Doxycycline should
be used on organisms that are sensitive or suspected to be sensitive to it.
Synthesis of the literature also suggests that dose and duration needs to be
careful examined. When used in outpatient therapy, use of Doxycycline prevents
extended hospital stays, thus potentially reducing hospital-acquired infections
and reduced costs for the hospital and the patient. Although it does have a
broad antimicrobial coverage, patients should be transitioned to a narrow
therapy following the discovery of sensitivity results. Doxycycline is a
broad-spectrum antibiotic that remains one of the most inexpensive antibiotic
regimens for treating soft tissue and bone infection in the human body. It
belongs to a class of drugs called tetracyclines,
discovered in 1948 [1]. Five tetracycline drugs are widely used today-oxytetracycline,
tetracycline, demeclocycline, minocycline, and doxycycline-but only the last
four are commercially available for patient use in the United States. Of these,
doxycycline and minocycline are the most frequently prescribed in hospital and
clinical settings [1]. We have used doxycycline in our clinical practice for
patients who develop post-surgical skin infection and have found that judicious
use of this drug for short courses in select patients can be beneficial. Applications Due
to doxycyclines broad spectrum of action, it is useful against many aerobic gram-positive and
gram-negative bacteria. In addition, it has superb activity against
atypical organisms including Rickettsia spp,
Borrelia spp, Coxiella burnetii, Treponema spp,
Chlamydia spp, Mycoplasma pneumoniae, Plasmodium
spp, Vibrio cholerae, Vibrio vulnificus, Brucella spp, Calymmatobacterium
granulomatis, Leptospira, Burkholderia pseudomallei, Mycobacterium marinum, and Entamoeba histolytica [3]. Although
it does not have any effect on fungal and viral agents, it does provide
excellent prophylaxis against protozoa that cause malaria. In addition,
doxycycline provides anthelmintic activity; an eight-week course was found to
reduce the growth of Wolbachia
bacteria in the reproductive tracts of parasitic filarial nematodes, which
reduces transmission of diseases such as elephantiasis [4]. Absorption
of doxycycline occurs in the small intestine and stomach. Its bioavailability is ~ 95%
regardless of dosing with or without with food, and peak concentration occurs
three hours after an oral dose. Its bioavailability decreases if the drug is
taken with any agents (e.g. antacids) containing divalent and trivalent cations
such as aluminum, calcium, iron, and magnesium. These cations chelate with
tetracycline agents and reduce their concentrations in plasma [5]. The maximum
serum concentration after an intravenous dose of doxycycline in an average
patient occurs within 30 minutes. Peak concentrations range from 1.5 to 2.5
mcg/mL after a dose of 200 mg when taken by mouth, and from 4 to 10 mcg/mL for
the same dose administered intravenously [5]. Doxycycline penetrates plasma
fluid fairly well due to its excellent lipid solubility. It is known to
penetrate soft tissue and bone, which makes it an excellent antibiotic for
organisms, e.g. Staphylococcus aureus
and Streptococcus spp that cause
infection of these tissues. The drug has been found at therapeutic levels in
vitreous humors, tears sinuses,
lungs, digestive and biliary tracts, and kidneys. Its excretion takes place
primarily in the intestine, while about 20% is excreted by the kidneys via
glomerular filtration [6-10]. Doxycycline
is a bacteriostatic agent that passively diffuses into cells and is also known
to use energy-dependent active transport systems. When inside the cell, it
reversibly binds the 30s ribosomal subunits a position and blocks the binding
of the aminoacyl-tRNA
to the acceptor site on the mRNA-ribosome complex. As a result protein
synthesis is inhibited and leading to a bacteriostatic effect [11]. Resistance
to doxycycline unlike some other antibiotics does not result from a chemical
change in the drug but rather from decreased influx or increased efflux from
the microbial cell [11]. The genes conferring resistance are carried in transferrable elements,
e.g. plasmids and transposons; organisms carrying these elements can provide
cytoplasmic protection that allows the microbial ribosome to carry out normal
protein synthesis despite an increase in intracellular drug concentrations [11,12]. Doxycycline
is generally well-tolerated by patients; however, it has notable potential
adverse effects. The most common are esophageal erosion and photosensitivity
(reported as a 10% risk), but only 130 such cases were described between 1966
and 2003 [13]. It is safe to assume that hundreds of millions of doxycycline
prescriptions were written in this time frame, and the rate of these adverse
reactions is thus vanishingly small. Other side effects can be prevented with
the use of simple precautions. Some unusual side effects include photo-onycholysis,
various skin eruptions, Stevens-Johnson syndrome, a Jarisch-Herxheimer reaction
and benign intracranial hypertension [13]. Liver
disease and hepatotoxicity do occur with other tetracyclines, but have not been
observed for doxycycline [14]. Compared to other drugs in its class,
doxycycline causes nausea and vomiting at a lower frequency [15]. Dose-related
gastrointestinal effects may include diarrhea that subsides once the regimen is
stopped. Prolonged use may result in fungal or bacterial superinfection,
including Clostridium difficile-Associated Diarrhea (CDAD) and
pseudomembranous colitis; CDAD has been observed >2 months post-treatment [14]. Doxycycline
should not be given to patients who have experienced severe allergic reaction
or hypersensitivity to tetracyclines. The World Health Organization states that
maternal use of doxycycline should be avoided if possible, but that a single
dose or short-term use is probably safe; there is a possibility of dental
staining and inhibition of bone growth in fetuses and breastfeeding infants, as
well as among children given doxycycline before the age of 8 (WHO 2002). Many
patients with impaired kidney function can take doxycycline without dose
adjustment, but in cases of severe hepatic impairment, such an adjustment may
be necessary [15]. There
have been reports of increased resistance to doxycycline in various parts of
the world. Resistance has been most commonly reported in Staphylococcus aureus, Streptococcus
pneumoniae, Bacteroides spp and Gonococcus spp. The drug continues to be
effective against atypical organisms [16]. The
use of doxycycline should be avoided in patients taking warfarin, as
concomitant use increases the anticoagulant effect of warfarin in the body,
which increases patient bleeding risk [17]. Doxycycline is also thought to
reduce the metabolism of warfarin by reducing cytochrome p450 action in
hepatocytes, increasing the amount of free warfarin in the blood [18].
Doxycycline can be used by women in combination with oral contraceptives; a
metanalysis by Archer, et al. concluded that available scientific and
pharmacokinetic data do not support the hypothesis that antibiotics-with the
exception of rifampin-lower the efficacy of oral contraceptives [2,15]. Accepted
guidelines recommend the empiric use of antibiotic therapy to target likely
pathogens while cultures are in progress [5]. In cases of non-purulent skin
infection and cellulitis, a diagnosis should be made based on clinical
observation; culture is not required in these cases, as most cellulitis and
erysipelas is caused by group A, B, C, and G beta-hemolytic streptococci and Methicillin-Susceptible
Staphylococcus Aureus (MSSA) [5].
However, in cases of purulent, draining abscesses, the recommendation is to
drain the abscess in the hope that symptoms will resolve and obtain gram stain
and culture of the purulent material to identify the microorganisms involved [19].
Doxycycline, 200 mg PO followed by 100 mg PO every 12 hours for 7-14 days is
the recommended outpatient treatment [5]. A
63-year-old patient with a 10-year history of type 2 diabetes, chronic kidney disease,
Charcot arthropathy of the left foot, prior osteomyelitis
of the left heel bone, and an extensive ulceration that led to the exposure of
tibial bone distally. We performed multiple irrigation and debridement on the
wound and applied bioengineered skin substitute to allow epithelialization of
the ulcer base. We also obtained bone and soft tissue specimen for pathology
and microbiological analysis. The patient was transferred to a long-term acute
care hospital the same day. A week after surgery, she presented to the
emergency room with a temperature of 101°C, a respiratory rate of
19, a heart rate of 68, a WBC count of 12,000/mm3, and 5% band
cells. Her blood pressure was 124/80, her lactic acid was 1 mmol/L, her BUN was
30 mg/dL, and her serum creatinine was 4 mg/dL. She complained of pain and
seropurulent drainage around the medial aspect of the soleus pin site. On
clinical examination, the area appeared to contain scant purulent drainage and
moderate erythema to the surrounding skin extending 5 cm2 around the
pin site, and it exhibited increased warmth. An x-ray of the tibia/fibula of
her left leg showed the implant was intact in the original position without any
loosening, but with no acute findings related to the soft tissue and bony
structures. The patient was discharged the same day with a script for
doxycycline 100 mg, by mouth, twice a day for seven days and a period
sufficient to allow culture results and finalize a recommendation for
narrow-spectrum antibiotic therapy. She presented to the clinic one week later
for a post-operative visit. The erythema surrounding the pin tract site had
resolved, with no drainage noted. She reported no pain, and her labs and vitals
were found to be normal. A
short course (seven days) of doxycycline was appropriate in this case based on
the guidelines of the Infectious Diseases Society of America, which recommends
a brief course of systemic
antimicrobial therapy for patients with soft tissue and skin infections
following clean operations on the trunk, head and neck or extremities who also
have systemic signs of infection [19]. Our patients prior history of
osteomyelitis culture-positive for Staph
aureus rendered a broad-spectrum antibiotic most appropriate. Our selection
was based on the patients existing medical conditions; doxycycline is generally
safe for patients with impaired renal function, and no dose adjustment was
necessary. In addition, doxycycline can be administered on an outpatient basis,
reducing healthcare costs and preventing other bacterial infections associated
with inpatient treatments (e.g. MRSA or VRE). The excellent bioavailability and
bone penetration of doxycycline helped the patient recuperate while waiting for
culture and sensitivity results to arrive [19]. We were unable to find
information on the safety of long-term (longer than three months) doxycycline
use in the foot and ankle literature. However, we found that some providers use
lower doses of doxycycline for an extended period to treat acne. It was not
clear what Schlagenhauf consider an extended period and lower dose as the
information was not provided in the book [20]. Besides, no documented cases of
hepatotoxicity were found associated with prolonged use of doxycycline in a
single reported case-control study. However, Schlagenhauf indicated that
doxycycline does interact with other drugs. For example, antacids may reduce
the serum level. Older literature indicates that the concurrent use of
doxycycline with estrogen-containing birth control pills causes decreased
contraceptive efficacy. However, there have been few reports of contraceptive
failure when doxycycline is used concurrently [21]. Further, the current
literature does show that doxycycline can be used concurrently without leading
to an increased rate of contraceptive failure [21]. As
far as the soft tissue infection in the foot and ankle is concerned, timely
administration of antibiotics can be an effective therapy in cases like this,
and can save lives in cases of sepsis. However, physicians tend to
overprescribe the antibiotics, whether it is at a dentists office, an emergency
medicine setting, or a family physician. This increased antibiotic use is a
troubling phenomenon. It has been reported that ~20-50% of antibiotic
prescriptions for inpatient care, and 25% of those for outpatient care, are
clinically unnecessary [22]. Overuse poses clear threats, including increased
resistance, increased healthcare costs, and above all, an increased risk of
serious adverse events with no clinical benefit to patients [22]. In
our case, we used our clinical judgment first and foremost to decide if the
antibiotic was needed in the patients case, or if the patient could benefit
from its use. Then we decided to find what current literature shows about
safety and efficacy and proceeded to prescribe a dose that we felt was
therapeutic for the patient. Additionally, we followed facility-specific
treatment recommendations. This is a program that exists in most hospitals as
part of an antibiotic stewardship program that has the goal of appropriate
pharmacy-driven infection- and syndrome-specific antibiotic prescription [22].
One of its goals, in our view, is to curtail the rampant prescription of
antibiotic regimens. We spoke with a pharmacist who educated us about safety
profile, indications, and interactions so that we could improve patient
outcomes, reduce microbial resistance, and decrease the spread of infections
caused by multidrug-resistant
organisms. Doxycycline
is well-suited for certain applications, especially soft-tissue and bone
infections. However, antibiotic overuse carries the risk of adverse reactions
and antibiotic resistance. Therefore, the risks/rewards and contraindications
must be weighed in each specific case. In cases such as the one presented here,
the benefits of avoiding hospital-acquired infections, lower cost, and
compatibility with existing health conditions outweigh the risks. Healthcare
providers must follow evidence-based guidelines in deciding whether to
prescribe antibiotics, and if appropriate, which antibiotic to prescribe. I
would like to express my gratitude to Dr. Lawrence A. DiDomenico for teaching
me about the use of doxycycline in the foot and ankle clinical setting. I would
also like to extend my gratitude to Andrew Hillebrand for scientific editing of
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Appropriate use of doxycycline for skin and soft tissue infection after foot
and ankle surgery: a brief review and case presentation (2019) Edelweiss Pharma
Analy Acta 1: 9-11. Doxycycline, Bone infection,
Osteomyelitis, MRSA, Antibiotic stewardship program.Appropriate Use of Doxycycline for Skin and Soft Tissue Infection after Foot and Ankle Surgery: A Brief Review and Case Presentation
Abstract
Full-Text
Introduction
Absorption,
Serum Concentration and Distribution
Mechanism
of Action and Resistance
Safety
Contraindications
Efficacy
Drug
interaction
Dosing
Case
Presentation
Discussion
Conclusion
Acknowledgements
References
Keywords
