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135-1
Here Today … Gone Tomorrow?. . . . . . . . . . . . . . . . . . Level I
John S. Esterly, PharmD, BCPS, AQ-ID
CASE SUMMARY
A man presenting with a rash and contributing risk factors is
diagnosed with syphilis. The patient has tested positive with serum
nontreponemal and treponemal syphilis testing. Signs and symptoms are consistent with secondary syphilis, and the patient has an
HIV coinfection. Workup for hepatitis B indicates immunity due to
a past infection and hepatitis C is negative. The patient should be
given first-line therapy for early stages of syphilis.
QUESTIONS
Problem Identification
1.a. Which populations are most at risk for syphilis?
• After very favorable decreases in syphilis rates during the
1990s, the incidence has remained elevated during the past
several years, particularly in men (Fig. 135-1).
• Clinicians should be very careful not to exclude the diagnosis
of syphilis in “low-risk” patients.
• Incidence among women has been stable, while most demographic categories of men appear to be increasing with disease,
even occurring in those more than 65 years of age (Figs. 135-2
and 135-3).1
• All races have been displaying increased rates of syphilis in
recent years.
• Among early stage syphilis, secondary syphilis is the most
common diagnosis for all demographics, particularly MSM
(Fig. 135-4).
1.b. What information (signs, symptoms, and laboratory values)
indicates the presence or stage of syphilis?
• The patient presents with several signs and symptoms that are
consistent with secondary syphilis. Most notably, he has a rash
Rate (per 100,000 population)
25
16:1
Male rate
Female rate
Total rate
Male-to-female rate ratio
20
8:1
15
4:1
10
2:1
5
1:1
0
1990
1992
1994
1996
1998
2000
2002
2004
2006
2008
2010
Year
FIGURE 135-1. Change in syphilis rates in the United States by gender over time.
Source: http://www.cdc.gov/std/stats13/figures/32.htm.
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Syphilis
Marc H. Scheetz, PharmD, MSc, BCPS, AQ-ID
Rate ratio (log scale)
SYPHILIS
CHAPTER 135
135
on his abdomen, arms, legs, and scalp. It is a nonpruritic rash,
as is common with the presentation of secondary syphilis.
• The patient also has a pelvic CT exam documenting proctitis
with lymphadenopathy and evidence of a recently healed ulcer
on his rectum. Lymphadenopathy is common in secondary
syphilis. The rectal ulcer was likely the result of primary syphilis transmission and fits with a temporal diagnosis of secondary
syphilis (usually 2–8 weeks after healing of an initial chancre).
• Positive serology tests indicating syphilis include the positive
rapid plasma reagin (RPR) titer (1:256) and the positive fluorescent treponemal antibody absorption (FTA-ABS) test.
1.c. What laboratory tests are used in the diagnosis of syphilis,
and how should they be interpreted?
• The causative organism, Treponema pallidum, is rarely isolated
and grown directly from a patient specimen to signify disease.
Indirect methods of testing are considered the gold standard
diagnostic approach. Diagnosis should be confirmed with
nontreponemal and treponemal testing.2,3
• The RPR test is a nontreponemal test used to screen patients for
diagnosis and to measure disease activity and efficacy of treatment. In general, patients with a true-positive nontreponemal
test have a titer >1:8. Tests are read as 1:16 > 1:8 since this
represents a greater dilution.
• Other nontreponemal tests used during screening are the
Venereal Disease Research Laboratory (VDRL) and toluidine
red unheated serum test (TRUST).
• False-negatives can occur in early syphilis due to a prozone
phenomenon, and false-positives can occur as a result of other
acute and chronic diseases.2,3 Therefore, using only one type of
serologic test is insufficient for diagnosis.
• Patients with clinical symptoms who have a negative nontreponemal test should be retested using a treponemal test.
• Patients who have reactive RPR, VDRL, or TRUST serology
should be tested with a treponemal test to confirm an infection
using the T. pallidum particle agglutination (TPPA) test or the
FTA-ABS test. Treponemal tests do not correlate with disease
severity, however.2,3
• Although no data suggest that different testing methodologies
be done for syphilis diagnosis in HIV-infected persons, falsepositive nontreponemal serologic tests may occur more frequently, and treponemal serologic conformation is essential in
individuals where coinfection is suspected.4
• Seroreactivity with clinical evidence of disease places the
patient in a category of secondary, tertiary, or neurosyphilis
because the disease has continued for an unknown duration.
SECTION 16
Rate (per 100,000 population)
135-2
20
American Indians/Alaska Natives
Asians/Pacific Islanders
Blacks
Hispanics
Whites
16
12
8
4
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
Year
FIGURE 135-2. Change in syphilis rates in the United States by race over time.
Source: Centers for Disease Control and Prevention. 2013 Sexually Transmitted Diseases Surveillance. http://www.cdc.gov/std/stats13/figures/39.htm.
Men
25
Rate (per 100,000 population)
20
15
10
5
0
0.1
5.4
Age
0
10–14
30–34
12.6
35–39
13.5
40–44
9.0
45–54
2.9
0.8
8.2
20
25
3.8
2.6
1.9
1.1
0.9
0.5
55–64
0.2
>65
0.0
Total
15
2.4
25–29
16.6
10
0.1
20–24
21.4
Women
5
15–19
23.4
1.0
FIGURE 135-3. Syphilis rates in the United States according to age and gender.
Source: Centers for Disease Control and Prevention. 2013 Sexually Transmitted Diseases Surveillance. http://www.cdc.gov/std/stats13/figures/36.htm.
6,000
4,500
Cases
Infectious Diseases
0
Primary
Secondary
3,000
1,500
0
MSWa
Women
MSMa
aMSW, men who have sex with women only; MSM, men who have sex with men.
FIGURE 135-4. Primary and secondary syphilis rates in the United States according to stage, gender, and sexual orientation.
Source: Centers for Disease Control and Prevention. 2013 Sexually Transmitted Diseases Surveillance. http://www.cdc.gov/std/stats13/figures/40.htm.
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
135-3
• The diagnosis of neurosyphilis does not necessarily require
proof of T. pallidum in the CSF. Abnormal CSF findings of
pleocytosis, elevated protein levels, and decreased glucose
concentrations can be highly suggestive when correlated with
positive serum tests (as discussed above).
• The patient should be counseled on the importance of identifying any past sexual partners who may be infected and require
testing and treatment.
• It is possible to assess for the presence of T. pallidum in the CSF,
and this can be done with the aforementioned nontreponemal
tests (eg, RPR or VDRL), treponemal tests (eg, FTA-ABS), or
polymerase chain reaction (PCR).
• However, CSF tests are often insensitive and nonspecific, so
clinical assessment, serology, and CSF abnormalities must be
concomitantly considered.
• Low levels of mononuclear CSF pleocytosis (5–15 cells/μL)
may be a result of HIV infection; however, neurosyphilis
should be considered in coinfected patients if it cannot be
excluded by other testing methodologies.
Desired Outcome
2.What are the goals of pharmacotherapy in this case?
• The ultimate goal is to eliminate the infectivity of the patient.
• This includes eradicating the organism, halting disease progression, preventing late complications of the disease, and
ending transmissibility.
Therapeutic Alternatives
3.a.What pharmacotherapeutic alternatives are available for
this patient?
• Parenteral penicillin G is preferred for all stages of syphilis.2
• The preparation(s) used (ie, benzathine, aqueous procaine, or
aqueous crystalline), the dosage, and the duration of treatment
depend on the stage and clinical manifestations of the disease.2
• Multiple parenteral formulations exist and the pharmacist
should be intimately familiar with the types of penicillin products and the brand names.
• Patients reporting a penicillin allergy should be assessed for a
history of immunoglobulin E (IgE)-mediated reactions (which
include urticaria, angioedema, or anaphylaxis).
• For the treatment of early stages of syphilis in penicillinallergic patients, the following alternative regimens may be
recommended:
✓Doxycycline 100 mg orally twice daily for 14 days or tetracycline 500 mg orally for 14 days.
✓Ceftriaxone 1–2 g daily IV or IM for 10–14 days may be an
option as well, although optimal duration of treatment has
not been well defined. Additionally, ceftriaxone should not
be given if the patient had a history of IgE-mediated reactions unless allergy testing has been performed.
✓Azithromycin 2 g orally as a single dose was recently evaluated in a meta-analysis of three clinical trials.5 Azithromycin
showed equivalence to a single dose of benzathine penicillin for the treatment of early syphilis; however, it should be
noted that HIV-infected patients were only included in one
of the trials analyzed and treatment guidelines suggest more
data are needed in this population.
• The patient should be educated about the transmission of
STDs, with suggestions to avoid sexual contact or to use latex
or polyurethane condoms during intercourse with intimate
contacts.
• Transmission of infection occurs when mucocutaneous lesions
are present (ie, most frequently occurring during primary and
secondary stages).
• In addition, the compromised defense barrier caused by genital
lesions increases the potential for HIV transmission.
• Although not applicable in this case because the patient is
known to be HIV infected, CDC guidelines recommend that
all patients with a diagnosis of syphilis also be tested for HIV.
Optimal Plan
4.What is the recommended treatment (drug, dose, and duration) for this patient?
• Treatment of early stage (primary or secondary) syphilis
should be completed with a single intramuscular injection of
2.4 million units of benzathine penicillin G.2
• Classification of latency can be dismissed in this patient
because latent by definition is the positive laboratory diagnosis
of syphilis in the absence of clinical symptoms.
• Most HIV-infected patients show sufficient response to the
standard treatment recommendation6; however, HIV-infected
patients might be at increased risk of treatment failure and
progression to neurosyphilis.2 Many clinicians advocate a
treatment course of three weekly benzathine penicillin injections.4 Minimally, close follow-up for evaluation after therapy
is recommended.
• Other nonpenicillin treatment agents for early stage syphilis,
such as oral doxycycline, azithromycin, or ceftriaxone, have
not been appropriately evaluated in HIV-infected patients and
therefore should be considered with caution.2,4
• For all patients with a true type I-mediated reaction to penicillin (IgE-mediated anaphylactic allergy), allergy testing for the
usage of a third-generation cephalosporin is recommended.
There is a non-negligible chance of cross-reactivity.
• In situations where nonpenicillin agents must be used for
therapy (eg, doxycycline), management should include close
serologic monitoring and clinical follow-up.2
Outcome Evaluation
5.What clinical and laboratory parameters are necessary to
evaluate the therapy for achievement of the desired therapeutic
outcome and to detect or prevent adverse effects?
• Repeat serial clinical and laboratory evaluation at a minimum
of 6 and 12 months after treatment. Additional evaluation in
HIV-infected patients is recommended at 3, 9, and 24 months.2
• Nontreponemal tests are quantitated, and if the infection is
treated adequately, the titer generally decreases. Conversely, the
treponemal tests remain positive for life and are therefore of no
benefit in monitoring therapy.2
• Nontreponemal antibody titers (eg, RPR and VDRL) usually
correlate with disease activity.
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Syphilis
3.b.What nondrug measures should be implemented in this
case?
CHAPTER 135
• It is unknown if the risk for developing neurosyphilis is greater
in HIV-infected patients; however, some clinicians recommend a cerebral spinal fluid (CSF) analysis for all HIV-infected
patients, regardless of stage. A CD4 cell count of <350 cells/μL
or a serum RPR of 1:32 is a clinical marker that may merit
particular consideration.4
135-4
SECTION 16
• A fourfold change in titer (equivalent to a change of two dilutions, eg, 1:16 to 1:4) suggests a clinically significant response.
6.b. What information should be provided to the patient to prevent a future sexually transmitted disease?
• Monitor patients with the same quantitative testing methodology, because titers are not comparable among methodologies.
• It is important for you to know about prevention measures to
prevent sexual transmission of syphilis, HIV, and other sexually transmitted diseases.
• Offer re-treatment to patients with titers that increase fourfold
(eg, 1:16 to 1:64), to patients who have initially high titers that
do not decrease (≥1:32) at least fourfold, and to those who
progress clinically.2
Infectious Diseases
• Monitor patients clinically for evidence of neurosyphilis and
advanced (tertiary) disease, including manifestations such as
aortitis, gumma, or ocular involvement.
• Refer patients to an ophthalmologist for ocular slit lamp
examination for assessment of uveitis, iritis, neuroretinitis, or
optic neuritis.
• These strategies include using a new latex or polyurethane
condom for each act of intercourse.2
• It is recommended that you receive regular testing. Individuals
who have a sexually transmitted disease are at risk for acquiring other infections.
• In addition, it is recommended that previous sexual partners
be notified and evaluated for syphilis. Treatment of infected
persons will have significant health implications.
REFERENCES
Patient Education
6.a.What information should be provided to the patient to
enhance adherence, ensure successful therapy, and minimize adverse effects?
• Notify your physician or report to an emergency room immediately if any of the following occur after medication administration: irregular breathing; light-headedness or sudden
fainting; pain, redness, or swelling at the injection site; swelling
of the face; shortness of breath; skin rash, hives, or itching; or
a sore mouth or tongue.
• Many patients experience a Jarisch–Herxheimer reaction
(a fever that may be accompanied by headache, muscle pain,
and other symptoms) within 24 hours after receiving therapy
for syphilis due to breakdown products and endotoxin release
from killed spirochetes.7 These symptoms are generally selflimiting. Contact your physician if you experience severe or
nonresolving symptoms.
✓Treatment for syphilis should not be postponed or delayed
because of this possible reaction. It is not an allergy.
✓Premedication with nonprescription analgesics and antipyretics such as nonsteroidal anti-inflammatory drugs
(eg, ibuprofen and naproxen) may be helpful.
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
1. Centers for Disease Control and Prevention. Sexually Transmitted
Disease Surveillance, 2013. Atlanta, U.S. Department of Health and
Human Services, December 2014. Available at: http://www.cdc.gov/std
/stats13/syphilis.htm. Accessed November 11, 2015.
2.Centers for Disease Control and Prevention. Sexually transmitted
diseases treatment guidelines, 2015. MMWR Morb Mortal Wkly Rep
2015;64(RR-3):34–50. Available at: www.cdc.gov. Accessed November
12, 2015.
3. Tramont EC. Treponema pallidum (syphilis). In: Mandell GL, Bennett
JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 7th ed.
Philadelphia, Churchill Livingstone, 2010. p. 3035–3053.
4. Panel on Opportunistic Infections in HIV-infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic
infections in HIV-infected adults and adolescents: recommendations
from CDC, the National Institutes of Health, and the HIV Medicine
Association of the Infectious Diseases Society of America. Available at:
http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed
November 12, 2015.
5. Bai ZG, Wang B, Yang K, et al. Azithromycin versus penicillin G benzathine for early syphilis. Cochrane Database Syst Rev 2012;6:CD007270.
6. Warwick Z, Dean G, Fisher M. Should syphilis be treated differently in
HIV-positive and HIV-negative individuals? Treatment outcomes at a
university hospital, Brighton, UK. Int J STD AIDS 2009;20(4):229–230.
7. See S, Scott EK, Levin MW. Penicillin-induced Jarisch-Herxheimer
Reaction. Ann Pharmacother 2005;39(12):2128–2130.