1404 PART 5 Infectious Diseases

resistance conferred by a hydrolyzing class A β-lactamase, BlaC. Carbapenems are poor substrates of BlaC, and clavulanic acid leads to irreversible inhibition. While the use of either amoxicillin-clavulanic acid

or carbapenems alone for highly resistant forms of TB has been anecdotally reported with unclear results, the combination of meropenem

and clavulanic acid turned out to be highly active in vitro. Recently, the

combination was found to have effective early bactericidal activity, and

in a large individual patient data meta-analysis, the combination was

associated with positive outcomes. Nevertheless, the need to administer these carbapenems intravenously and the lack of information on the

drugs’ long-term side effects have restricted their use to certain severe

cases only. Recommended daily doses are either imipenem-cilastatin 1

g (each component) IV twice daily or meropenem 1 g IV three times

daily, each in combination with clavulanic acid 125 mg oral twice daily,

which is only available in combination with amoxicillin.

AMINOGLYCOSIDES Aminoglycosides have played a time-honed role

in the treatment of mycobacterial infections. Amikacin and streptomycin are aminoglycosides that exert mycobactericidal activity by binding

to the 16S ribosomal subunit. The spectrum of antibiotic activity for

amikacin and streptomycin includes M. tuberculosis, several NTM

species, and aerobic gram-negative and gram-positive bacteria. Due to

the need of intravenous or painful intramuscular injections and their

serious side effect profile, the WHO recommends limiting their use

with the increased availability of novel oral agents. Kanamycin and

capreomycin, a cyclic polypeptide similar to aminoglycosides, are no

longer recommended due to worse treatment outcomes and increased

mortality. This recommendation is based on a large individual patientlevel meta-analysis of observational cohort studies and is likely due to

increased toxicity seen with these agents. Streptomycin was the first

antimycobacterial agent used for the treatment of TB. Derived from

Streptomyces griseus, streptomycin is bactericidal against dividing M.

tuberculosis organisms but has only low-level early bactericidal activity.

In developing countries, it continues to be widely used due to its low

cost. The usual daily dose of streptomycin (given IM either daily or

5 days per week) is 15 mg/kg for adults and 20–40 mg/kg for children,

with a maximum of 1 g/d for both with dose reduction recommended

for patients ≥60 years of age or with renal impairment. Central nervous

system penetration is poor.

Amikacin resistance is less widespread, and streptomycin-resistant strains may still be susceptible. The usual daily adult dosage is

15–30 mg/kg given IM or IV (maximal daily dose, 1 g). It is frequently

used to treat severe nontuberculous mycobacterial infections.

Mycobacterial resistance to aminoglycosides is due to mutations in

the genes encoding the 16S ribosomal RNA gene (rrs). Adverse effects

of both amikacin and streptomycin include ototoxicity (in up to 10% of

recipients, with auditory dysfunction occurring more commonly than

vestibulotoxicity), nephrotoxicity, and neurotoxicity.

ETHIONAMIDE Ethionamide is a derivative of isonicotinic acid. Its

mechanism of action is through inhibition of the inhA gene product

enoyl–acyl carrier protein (acp) reductase, which is involved in mycolic

acid synthesis. Ethionamide is bacteriostatic against metabolically

active M. tuberculosis and some NTM. It is used in the treatment

of drug-resistant TB, but its use is limited by severe gastrointestinal

reactions (including abdominal pain, nausea, and vomiting) as well

as significant central and peripheral neurologic side effects, reversible hepatitis (in ~5% of recipients), hypersensitivity reactions, and

hypothyroidism. Ethionamide should be taken with food to reduce

gastrointestinal effects and with pyridoxine (50–100 mg/d) to limit

neuropathic side effects.

PARA-AMINOSALICYLIC ACID Para-aminosalicylic acid (PAS; 4-aminosalicylic acid) is an oral agent used in the treatment of drug-resistant

TB. Its bacteriostatic activity is due to inhibition of folate synthesis and

of iron uptake. PAS has relatively little activity as an anti-TB agent.

Adverse effects may include high-level nausea, vomiting, and diarrhea. PAS may cause hemolysis in patients with glucose-6-phosphate

dehydrogenase deficiency. The drug should be taken with acidic foods

to improve absorption. Enteric-coated PAS granules (4 g orally every

8 h) appear to be better tolerated than other formulations and produce

higher therapeutic blood levels. PAS has a short half-life (1 h), and 80%

of the dose is excreted in the urine.

■ DRUGS IN DEVELOPMENT

The pipeline of novel TB drugs is rapidly changing. We direct the

reader to the Working Group on New TB Drugs for the most up-todate information (https://www.newtbdrugs.org/pipeline/clinical).

NONTUBERCULOUS MYCOBACTERIA

More than 150 species of NTM have been identified. Only a minority

of these environmental organisms, which are extensively found in soil

and water, are important human pathogens. NTM cause extensive

disease primarily in persons with preexisting pulmonary disease or

immunocompromise but can also cause nodular/bronchiectatic disease in otherwise seemingly healthy hosts. Disseminated infections

with NTM are common in immunocompromised individuals. NTM

are also important causes of skin and soft tissue infections in surgical

settings. The two major classes of NTM are the slow-growing and rapidly growing species; subcultures of the latter grow within 1 week. The

growth characteristics of NTM have diagnostic, therapeutic, and prognostic implications. The rate of growth can provide useful preliminary

information within a specific clinical context, in that growth within

2–3 weeks is much more likely to indicate an NTM than M. tuberculosis. When NTM do grow from cultures, colonization should be distinguished from active disease in order to optimize the risk and benefit

of prolonged treatment with multiple medications. According to the

recommendations of the American Thoracic Society and the Infectious

Diseases Society of America, significant clinical manifestations and/

or radiographic evidence of progressive disease consistent with NTM

infection as well as either reproducible sputum culture results or a single positive culture from bronchoscopy are required for the diagnosis

of NTM pulmonary disease. Isolation of NTM from blood or from

an infected extrapulmonary site, such as soft tissue or bone, is usually

indicative of disseminated or local NTM infection (Chap. 180). Treatment of NTM disease is prolonged and requires multiple medications.

Side effects of the regimens employed are common, and intermittent

therapy is often used to mitigate these adverse events. Treatment

regimens depend on the NTM species, the extent or type of disease,

and—to some degree—drug susceptibility test results.

■ THERAPEUTIC CONSIDERATIONS FOR

SPECIFIC NTM

Slowly Growing Mycobacteria Slowly growing mycobacteria can

be divided into three categories based on their pigment-producing capabilities and—if they do produce pigment—their requirement for light

to do so. Photochromogens, including M. marinum and M. kansasii, can

produce yellowish-orange pigment only when exposed to light. Scotochromogens, including Mycobacterium gordonae and Mycobacterium

scrofulaceum, can make pigment regardless of light exposure. MAC

organisms and Mycobacterium ulcerans are nonchromogens—i.e., are

incapable of making pigment irrespective of light exposure.

MYCOBACTERIUM AVIUM COMPLEX Among the NTM, MAC organisms

most commonly cause human disease. In immunocompetent hosts,

MAC species are most often found in conjunction with underlying

significant lung disease, such as chronic obstructive pulmonary disease or bronchiectasis. For patients with nodular or bronchiectatic

MAC lung disease, an initial regimen consisting of clarithromycin or

azithromycin, rifampin or rifabutin (the latter is preferred for HIV

patients receiving ART), and ethambutol is given three times per week

for at least 12 months after culture conversion. A daily regimen of these

three drugs, with consideration of amikacin or streptomycin in the

initial treatment phase, is recommended for patients with fibrocavitary

MAC lung disease or severe nodular/bronchiectatic disease. Routine

initial testing for macrolide resistance is recommended, as is testing

at 6 months with a failing regimen (i.e., with cultures persistently

positive for NTM). Interpretation of susceptibility tests to drugs other

than macrolides and aminoglycosides is hampered by poor correlation

with clinical outcomes. Amikacin has been reformulated as a liposomal suspension with increased penetration into airway biofilms. The

1405CHAPTER 181 Antimycobacterial Agents

CONVERT trial showed that addition of inhaled liposomal amikacin

to standard three-drug regimen of azithromycin or clarithromycin,

rifampin, and ethambutol in treatment-refractory (persistent sputum

positivity after at least 6 months) MAC lung disease significantly

increases culture conversion rates from 9 to 26% at 6 months. Respiratory adverse events (primarily dysphonia, cough, and dyspnea) were

reported in 87.4% of patients receiving inhaled liposomal amikacin

compared to 50% in the standard therapy group; however, rates of serious adverse events were not different between the regimens. Inhaled

liposomal amikacin is now approved for use in refractory pulmonary

MAC infections (persistent positive cultures after at least 6 months of

treatment). It is currently being evaluated as a first-line agent and as a

replacement for rifampin in the treatment of MAC lung disease.

Surgical resection should be considered for individuals whose

infection is localized to one lung, who have adequate lung function

to tolerate lung resection, who have had a poor response to medical

therapy, and/or who have developed macrolide-resistant MAC disease.

Treatment of MAC in persons living with HIV should be initiated

in consultation with an infectious diseases specialist. For HIV-infected

patients with well-controlled HIV disease and CD4 T-cell counts in

the normal range, MAC treatment is identical to patients without HIV

disease except that drug-drug interactions between antimycobacterial

agents and ART should be carefully considered. HIV-infected patients

with low CD4 count (CD4+ T-cell count >100/μL) are at risk for disseminated MAC infection. MAC disease in these patients is generally

treated with clarithromycin, ethambutol, and rifabutin. Azithromycin

may be preferred to clarithromycin depending on adverse effects and

patient tolerance. Amikacin and fluoroquinolones are often used in

salvage regimens. Treatment for disseminated MAC infection in AIDS

patients may be lifelong in the absence of immune reconstitution.

Therapy is recommended for at least 12 months after culture conversion and at least 6 months of effective immune reconstitution with ART

(CD4+ T-cell count >100/μL).

MYCOBACTERIUM KANSASII M. kansasii is the second most common

NTM causing human disease in the United States. It is also the second

most common cause of NTM pulmonary disease in the United States,

where it is most commonly reported in the southeastern region. M.

kansasii infection can be treated with rifampin, ethambutol, and either

isoniazid or macrolide; therapy continues for at least 18 months or for

12 months after culture conversion. The American Thoracic Society

and the Infectious Diseases Society of America recommend routine

susceptibility testing to rifampin only. Resistance to isoniazid and

ethambutol can be acquired during therapy but is usually associated

with rifampin resistance as well. Rifampin-resistant M. kansasii is

treated with a three-drug regimen including agents such as ciprofloxacin, azithromycin, ethambutol, rifabutin, amikacin, trimethoprimsulfamethoxazole, and streptomycin after drug susceptibility testing.

MYCOBACTERIUM MARINUM M. marinum is an NTM found in salt

water and freshwater, including swimming pools and fish tanks. It is

a cause of localized soft tissue infections, which may require surgical

management. Combination regimens include clarithromycin and

either ethambutol or rifampin. Other agents with activity against

M. marinum include doxycycline, minocycline, and trimethoprimsulfamethoxazole. Drug susceptibility testing is recommended only

if the swab remains culture positive after 3 months of appropriate

therapy.

Rapidly Growing Mycobacteria Rapidly growing mycobacteria

causing human disease include Mycobacterium abscessus, Mycobacterium fortuitum, and Mycobacterium chelonae. Treatment of these

mycobacteria is complex and should be undertaken with input from

experienced clinicians. It is important to note that testing rapidly

growing mycobacteria for macrolide resistance is tricky, as an inducible

erm gene may confer in vivo macrolide resistance to isolates that are

susceptible in vitro.

M. abscessus is the third most common NTM pathogen in the

United States. It is endemic in the southeastern states between Texas

and Florida. Skin, soft tissue, and bone infections occur, usually after

accidental trauma or surgery. This organism appears to have a predilection to cause lung infections in white nonsmoking women aged

>60 who have no preexisting lung disease. M. abscessus isolates are

usually resistant to standard anti-TB regimens. Skin and soft tissue

infections are usually treated for a minimum of 4 months with a macrolide (clarithromycin or azithromycin) and a parenteral agent such

as amikacin, cefoxitin, or imipenem. Bone infections are treated for

at least 6 months. This regimen can be used for the treatment of lung

infections but is often unsuccessful because of drug adverse effects

and toxicities. A regimen comprising a combination of at least three

active drugs (amikacin, linezolid, tigecycline, imipenem, azithromycin,

provided the organism is macrolide susceptible) is recommended on

the basis of in vitro drug susceptibility testing. A recent meta-analysis

has shown that overall therapeutic efficiency rates in M. abscessus

lung infection are low at ~35%; however, incorporation of amikacin,

imipenem, linezolid, and/or tigecycline was associated with improved

outcomes. Conversely, macrolide resistance has been associated with

worse outcomes. Surgical resection should be considered in all patients

with good lung reserve and a localized infection.

■ DRUGS FOR THE TREATMENT OF NTM

Clarithromycin Clarithromycin is a macrolide antibiotic with

broad activity against many gram-positive and gram-negative bacteria

as well as NTM. This drug is active against MAC organisms and many

other NTM species, inhibiting protein synthesis by binding to the 50S

mycobacterial ribosomal subunit. NTM resistance to macrolides is

probably caused by overexpression of the gene ermB, with consequent

methylation of the binding site. Strains of M. abscessus subsp. abscessus

harbor an inducible macrolide resistance mechanism coded by erm41,

which leads to ribosomal methylation and becomes apparent after

macrolide incubation of 3−5 days, significantly hampering treatment

success. Twenty percent of strains have a nonfunctional erm41 gene.

Clarithromycin is well absorbed orally and distributes well to tissues. It

is cleared both hepatically and renally; the dosage should be reduced in

renal insufficiency. Clarithromycin is a substrate for and inhibits cytochrome 3A4 and should not be administered with cisapride, pimozide,

or terfenadine because cardiac arrhythmias may occur. Numerous

drugs interact with clarithromycin through the CYP3A4 metabolic

pathway. Rifampin lowers clarithromycin levels; conversely, rifampin

levels are increased by clarithromycin. However, the clinical relevance

of this interaction does not appear to be great.

For patients with nodular/bronchiectatic MAC infection, the dosage

of clarithromycin is 500 mg, given morning and evening three times a

week. For the treatment of fibrocavitary or severe nodular/bronchiectatic

MAC infection, a dose of 500–1000 mg is given daily. Disseminated

MAC infection is treated with 1000 mg daily. Clarithromycin is used in

combination regimens that typically include ethambutol and a rifamycin in order to avoid the development of macrolide resistance. Adverse

effects include frequent gastrointestinal intolerance, hepatotoxicity,

headache, rash, and rare instances of hypoglycemia. Clarithromycin

is contraindicated during pregnancy because of its teratogenicity in

animal models.

Azithromycin Azithromycin is a derivative of erythromycin.

Although technically an azalide and not a macrolide, it works similarly

to macrolides, inhibiting protein synthesis through binding to the 50S

ribosomal subunit. Azithromycin is preferred over clarithromycin due

to once-daily dosing, better tolerability, fewer drug interactions, and

equal efficacy. Resistance to azithromycin is almost always associated

with complete cross-resistance to clarithromycin. Azithromycin is well

absorbed orally, with good tissue penetration and a prolonged half-life

(~48 h). The usual dosage for treatment of MAC infection is 250 mg

daily or 500 mg three times per week. Azithromycin is used in combination with other agents to avoid the development of resistance. For

prophylaxis against disseminated MAC infection in immunocompromised individuals, a dose of 1200 mg once per week is given. Because

azithromycin is not metabolized by cytochrome P450, it interacts with

few drugs. Adjustment of the dosage on the basis of renal function is

not necessary.

1406 PART 5 Infectious Diseases

Section 9 Spirochetal Diseases

182

DEFINITION

Syphilis, a chronic systemic infection caused by Treponema pallidum

subspecies pallidum, is usually sexually transmitted and is characterized by episodes of active disease interrupted by asymptomatic periods

(latency). After an incubation period averaging 2–6 weeks, a primary

lesion appears—often associated with regional lymphadenopathy—and

then resolves without treatment. The secondary stage, with generalized

mucosal and cutaneous lesions and generalized lymphadenopathy, also

resolves spontaneously and is followed by a latent period of subclinical infection lasting years or decades. Central nervous system (CNS)

invasion may occur early in infection, and CNS involvement may

be symptomatic or asymptomatic. In the preantibiotic era, one-third

of untreated patients developed tertiary syphilis, characterized by

destructive mucocutaneous, skeletal, or parenchymal lesions; aortitis;

or late CNS manifestations.

ETIOLOGY

The Spirochaetales include five genera that are pathogenic for humans

and for a variety of other animals: Leptospira species (leptospirosis,

Chap. 184); Borrelia and Borreliella species (relapsing fever and Lyme

disease, respectively; Chaps. 185 and 186); Brachyspira species (gastrointestinal infections); and Treponema species (syphilis and the endemic

treponematoses; see also Chap. 183). The Treponema subspecies

include T. pallidum subsp. pallidum (venereal syphilis); T. pallidum

subsp. pertenue (yaws); T. pallidum subsp. endemicum (endemic syphilis or bejel); and T. carateum (pinta). Historically, the subspecies were

distinguished by the clinical syndromes they produce, but phylogenetic

analyses of whole genome sequences from a relatively small number

of strains (excluding T. carateum) yield the three named subspecies

groupings. Whether these groupings represent geographical variation

or true biological differences is unclear. The crossing of subspecies

boundaries by some “molecular signatures” and the recent recognition of treponemes of the endemicum genotype in sexually acquired

genital ulcers (chancres) and secondary rashes (Chap. 183) support

the concept of a genetic and clinical “continuum” among strains and

subspecies of the pathogenic treponemes.

T. pallidum subspecies are thin spiral organisms, with a cell body

surrounded by a trilaminar cytoplasmic membrane, a delicate peptidoglycan layer, and a lipid-rich outer membrane. Endoflagella wind

around the cell body in the periplasmic space and are responsible for

motility.

Historically, T. pallidum could not be cultured in vitro, but longterm propagation of the Nichols strain of T. pallidum in complex

medium with eukaryotic cells was recently reported. To date, the

pertenue and endemicum subspecies have not been cultured. All T.

pallidum subspecies have severely limited metabolic capabilities and

are highly dependent on host-derived amino acids, carbohydrates, and

lipids. Genetic analyses have revealed the existence of a 12-member

Syphilis

Sheila A. Lukehart

Amikacin Liposome Inhalation Suspension (ALIS) ALIS

is a new formulation of the aminoglycoside amikacin, which allows

for improved penetration in the lung with reduced toxicity. It is now

approved for treatment of refractory MAC lung infection with persistent sputum positivity at 6 months while on appropriate background

regimen. Typical dose is 590 mg (one vial once a day) for 6 months

along with the standard three-drug regimen of macrolide, rifampin,

and ethambutol. Dosage adjustments in patients with hepatic and renal

dysfunction are not required. Half-life elimination typically occurs

in ~5.9–9.5 h. Respiratory side effects such as bronchospasm, cough,

dysphonia, and dyspnea are common. Monitoring for systemic aminoglycoside toxicity should be considered.

Imipenem Imipenem primarily inhibits cell-wall biosynthesis by

binding to the penicillin-binding proteins. It is rapidly gaining importance for the treatment of M. abscessus with a meta-analysis showing

improved outcomes with its inclusion in a multidrug regimen. It is

dosed at 500 mg to 1 g twice to three times a day as part of a combination regimen for the treatment of M. abscessus. Half-life of imipenem is

~1 h, and because it is metabolized in the kidneys, dosing adjustment is

needed with renal dysfunction. Adverse effects include anemia, thrombocythemia, and liver dysfunction.

Cefoxitin Cefoxitin is a second-generation parenteral cephalosporin

with activity against rapidly growing NTM, particularly M. abscessus

and M. chelonae. Its mechanism of action against NTM is unknown but

may involve inactivation of cell-wall synthesis enzymes. High doses are

used for treatment of NTM: 200 mg/kg IV three or four times per day,

with a maximal daily dose of 12 g. The half-life of cefoxitin is ~1 h, with

primary renal clearance that requires adjustment in renal insufficiency.

Adverse effects are uncommon but include gastrointestinal manifestations, rash, eosinophilia, fever, and neutropenia.

Newer Drugs Three newer classes of drugs—the oxazolidinones,

the glycylcyclines, and the ketolides—are currently being evaluated

for possible use in the treatment of NTM infections, especially those

caused by M. abscessus. Approximately 50% of M. abscessus isolates

have shown some degree of susceptibility in vitro to linezolid, an

oxazolidinone. Tigecycline, which is a glycylcycline and a tetracycline

derivative, and telithromycin, a ketolide, also appear to have in vitro

activity against M. abscessus. These drugs, however, have not yet been

clinically tested in patients.

In addition, some anti-TB drugs, including clofazimine and

bedaquiline, are being evaluated as alternative agents for the treatment

of refractory NTM infections. In particular, clofazimine appears to act

synergistically in combination with amikacin, bedaquiline, or tigecycline. The exact role of these agents in the treatment of refractory NTM

infections remains unclear. Suppressive therapy with periodic parenteral/oral drugs to limit disease progression and control symptoms may

be an appropriate alternative to curative treatment.

CONCLUSION

Treatment of mycobacterial infections requires multiple-drug regimens that often exert significant side effects with the potential to limit

tolerability. The prolonged duration of treatment has vastly improved

results over those obtained in past decades, but drugs and regimens

that will shorten treatment duration and limit adverse drug effects and

interactions are needed.

■ FURTHER READING

Collaborative Group for the Meta-Analysis of Individual

Patient Data in Mdr-Tb Treatment–2017: Treatment correlates

of successful outcomes in pulmonary multidrug-resistant tuberculosis: An individual patient data meta-analysis. Lancet 392:821, 2018.

Daley CL et al: Treatment of nontuberculous mycobacterial pulmonary disease: An official ATS/ERS/ESCMID/IDSA clinical practice

guideline. Clin Infect Dis 71:e1, 2020.

Nahid P et al: Official American Thoracic Society/Centers for Disease

Control and Prevention/Infectious Diseases Society of America clinical practice guidelines: Treatment of drug-susceptible tuberculosis.

Clin Infect Dis 63:e147, 2016.

Sterling TR et al: Guidelines for the treatment of latent tuberculosis infection: Recommendations from the National Tuberculosis

Controllers Association and CDC, 2020. MMWR Recomm Rep 69

(No. RR-1):1, 2020.

World Health Organization: Consolidated guidelines on drugresistant tuberculosis treatment. Geneva: World Health Organization,

2019. License: cc by-nc-sa 3.0 igo.

1407CHAPTER 182 Syphilis

in such high-risk populations. Cases of P&S syphilis among African

Americans increased 2.7-fold between 2000 and 2018, and the rate

(28.1 per 100,000 population) remains higher than rates for other

racial/ethnic groups.

Of individuals named as sexual contacts of persons with infectious

syphilis, many will have developed manifestations of syphilis when

they are first seen, and ~30% of asymptomatic contacts examined

within 30 days of exposure actually have incubating infection and will

later develop infectious syphilis if not treated. Thus, identification and

treatment of all recently exposed sexual contacts continue to be important aspects of syphilis control.

■ GLOBAL SYPHILIS

Syphilis remains a significant health problem globally; the number

of new infections is estimated at 6−8 million per year. The regions

most affected include sub-Saharan Africa, South America, China, and

Southeast Asia. The incidence rate for total syphilis in China continues

to rise, and rates of P&S syphilis have increased dramatically among

MSM in many European, Asian, and South American countries. Globally, through efforts by World Health Organization (WHO), progress

has been made in the prevention of congenital syphilis, although there

are still ~988,000 pregnant women with syphilis per year, with 661,000

cases of congenital syphilis including 200,000 stillbirths and infant

deaths.

NATURAL COURSE AND PATHOGENESIS OF

UNTREATED SYPHILIS

T. pallidum rapidly penetrates intact mucous membranes or microscopic abrasions in skin and, within a few hours, enters the lymphatics

and blood to produce systemic infection and metastatic foci long

before the appearance of a primary lesion. Blood from a patient with

incubating or early syphilis is infectious. The generation time of T. pallidum during early disease is estimated to be ~30 h, and the incubation

period of syphilis is inversely proportional to the number of organisms

transmitted. The 50% infectious dose for intradermal inoculation in

humans has been calculated to be 57 organisms, and the treponeme

concentration generally reaches 107

/g of tissue before a clinical lesion

appears. The median incubation period in humans (~21 days) suggests

an average inoculum of 500–1000 infectious organisms for naturally

acquired disease; the incubation period rarely exceeds 6 weeks.

The primary lesion appears at the site of inoculation, usually persists

for 4–6 weeks, and then heals spontaneously. Histopathologic examination shows perivascular infiltration, chiefly by CD4+ and CD8+ T

lymphocytes, plasma cells, and macrophages, with capillary endothelial

proliferation and subsequent obliteration of small blood vessels. The

cellular infiltration produces a TH1-type cytokine profile, consistent

with the activation of macrophages. Phagocytosis of opsonized organisms by activated macrophages ultimately causes their destruction,

resulting in spontaneous resolution of the chancre.

The generalized parenchymal, constitutional, mucosal, and cutaneous manifestations of secondary syphilis usually appear ~6–12 weeks

after infection, although primary and secondary manifestations may

occasionally overlap. In contrast, some patients may enter the latent

stage without ever recognizing secondary lesions. The histopathologic

features of secondary maculopapular skin lesions include hyperkeratosis of the epidermis, capillary proliferation with endothelial swelling in

the superficial dermis, and—in the deeper dermis—perivascular infiltration by CD8+ T lymphocytes, CD4+ T lymphocytes, macrophages,

and variable numbers of plasma cells. T. pallidum disseminates during

the first days to weeks of infection, invading many tissues, including

the CNS; cerebrospinal fluid (CSF) abnormalities can be detected in

as many as 40% of patients during the secondary stage. Clinical hepatitis and immune complex–induced glomerulonephritis are rare, but

recognized, manifestations of secondary syphilis. Generalized nontender lymphadenopathy is noted in 85% of patients with secondary

syphilis. The paradoxical appearance of secondary manifestations,

even after the development of an immune response that clears primary

lesions, likely results from immune evasion due to antigenic variation

of TprK surface antigens. Secondary lesions generally subside within

40000

30000

20000

Number of cases

10000

1990

0

1995 2000 2005 2010 2015

Men Women

FIGURE 182-1 Primary and secondary syphilis in the United States, 1990–2018, by

sex. (Data from the Centers for Disease Control and Prevention.)

gene family (tpr) encoding outer-membrane antigens. One member,

TprK, has discrete variable regions that undergo antigenic variation

during infection, providing a mechanism for immune evasion.

The only known natural host for T. pallidum subsp. pallidum

(referred to hereafter as T. pallidum) is the human. T. pallidum can

infect many mammals, but only humans, higher apes, and a few laboratory animals develop syphilitic lesions. Rabbits are used to propagate

T. pallidum and serve as the animal model that best reflects human

disease and immunopathology.

TRANSMISSION AND EPIDEMIOLOGY

Nearly all cases of syphilis are acquired by sexual contact with infectious lesions (i.e., the chancre, mucous patch, skin rash, or condylomata lata; see Fig. A1-20). Less common modes of transmission

include nonsexual skin contact, infection in utero, blood transfusion,

and organ transplantation.

■ SYPHILIS IN THE UNITED STATES

Following the introduction of penicillin therapy in the 1940s, the

number of cases of syphilis of all stages reported in the United States

declined 95% to a low of 31,575 cases in 2000, with 5979 reported cases

of primary and secondary (P&S) syphilis. (P&S cases are infectious and

are a better indicator of disease activity than total syphilis cases.) Since

2000, total cases have increased 3.6-fold to 115,045, and the number of

P&S cases has increased nearly sixfold, with 35,063 cases reported in

2018 (Fig. 182-1). Nationally, ~54% of these cases were in men who

have sex with men (MSM), ~41.6% of whom are co-infected with HIV.

From 2017 to 2018, P&S cases rose 11.7% among all men and 34.2%

among women, with increases in all racial and ethnic groups and in

all geographic regions of the United States. Because the incidence of

congenital syphilis parallels that of infectious syphilis in women, the

striking increase in early syphilis in women has resulted in a dramatic

increase in congenital syphilis. In 2018, 1306 cases of congenital

syphilis were reported, resulting in 78 stillbirths and 16 infant deaths.

Since 2014, the number of reported cases in infants <1 year of age has

increased nearly threefold. Data from 2018 show that nearly 12% of

women with syphilis reported injecting drugs in the past 12 months

and nearly 8% reported heroin use.

The populations at highest risk for acquiring syphilis have changed

over time, with outbreaks among MSM in the pre-HIV era of the

late 1970s and early 1980s, as well as at present. The dramatic recent

increases in syphilis and other sexually transmitted infections in

MSM may be due to unprotected sex between persons who are HIV

concordant and to disinhibition facilitated by highly effective antiretroviral therapy (ART). Many MSM diagnosed with syphilis have had

syphilis previously, and more frequent (every 3 months) screening

for syphilis and other sexually transmitted infections is warranted

1408 PART 5 Infectious Diseases

2–6 weeks, and the infection enters the latent stage, which is detectable only by serologic testing. In the preantibiotic era, up to 25% of

untreated patients experienced at least one cutaneous relapse of secondary lesions, usually during the first year. Therefore, identification

and examination of sexual contacts are most important for patients

with syphilis of <1 year’s duration.

In the preantibiotic era, about one-third of patients with untreated

latent syphilis developed clinically apparent tertiary disease, the most

common types being the gumma (a usually benign granulomatous

lesion); cardiovascular syphilis (usually involving the vasa vasorum of

the ascending aorta and resulting in aneurysm); and late symptomatic

neurosyphilis (tabes dorsalis and paresis). In Western countries today,

specific treatment for early and latent syphilis and coincidental therapy

(i.e., therapy with antibiotics active against treponemes, but given for

other conditions) have nearly eliminated tertiary syphilis. Asymptomatic CNS involvement, however, is still demonstrable in up to 40% of

persons with early syphilis and 25% of patients with late latent syphilis, and modern cases of general paresis and tabes dorsalis are being

reported from China. The factors that contribute to the development

and progression of tertiary disease are unknown.

CLINICAL MANIFESTATIONS

■ PRIMARY SYPHILIS

The typical primary chancre usually begins as a single painless papule that rapidly erodes and becomes indurated, with a characteristic

cartilaginous consistency on palpation of the edge and base of the

ulcer. Multiple primary lesions are seen in a minority of patients. In

heterosexual men, the chancre is usually located on the penis, where

it is readily seen (Fig. 182-2; see also Fig. A1-17), but in MSM, it may

also be found in the anal canal, rectum, or mouth. Oral sex has been

identified as the source of infection in some MSM. In women, common primary sites are the cervix, vaginal wall, and labia, as well as anal

canal and mouth. Consequently, primary syphilis goes unrecognized in

women and MSM more often than in heterosexual men.

Atypical primary lesions are common, and may be multiple, small,

or partially resolved. Therefore, syphilis should be considered in the

evaluation of trivial or atypical dark-field-negative genital lesions. The

lesions that most commonly must be differentiated from those of primary syphilis include those caused by herpes simplex virus infection

(Chap. 192), chancroid (Chap. 157), traumatic injury, and donovanosis (Chap. 173). Regional (usually inguinal) lymphadenopathy accompanies the primary syphilitic lesion, appearing within 1 week of lesion

onset. The nodes are firm, nonsuppurative, and painless. Inguinal

lymphadenopathy is bilateral and may occur with anal as well as with

genital chancres. The chancre generally heals within 4–6 weeks (range,

2–12 weeks), but lymphadenopathy may persist for months.

■ SECONDARY SYPHILIS

The classical manifestations of the secondary stage include mucocutaneous or cutaneous lesions and generalized nontender lymphadenopathy. The healing primary chancre may still be present in ~15%

of cases—more frequently in persons with concurrent HIV infection.

The skin rash consists of macular, papular, papulosquamous, and

occasionally pustular syphilides; often more than one form is present

simultaneously. The eruption may be very subtle, and 25% of patients

with a discernible rash may be unaware that they have dermatologic

manifestations. Initial lesions are pale red or pink, nonpruritic, discrete

macules distributed on the trunk and extremities; these macules progress

to papular lesions that are distributed widely and that frequently involve

the palms and soles (Fig. 182-3; see also Figs. A1-18 and A1-19). Rarely,

severe necrotic lesions (lues maligna) may appear and are more commonly reported in HIV-infected individuals. Involvement of the hair

follicles may result in patchy alopecia of the scalp hair, eyebrows, or

beard in up to 5% of cases.

In warm, moist, intertriginous areas (commonly the perianal region,

vulva, and scrotum), papules can enlarge to produce broad, moist,

pink or gray-white, highly infectious lesions (condylomata lata; see

Fig. A1-20) in 10% of patients with secondary syphilis. Superficial

mucosal erosions (mucous patches) occur in 10–15% of patients and

commonly involve the oral or genital mucosa (see Fig. A1-21). The

typical mucous patch is a painless silver-gray erosion surrounded by

a red periphery. T. pallidum DNA has been detected in oral mucosal

swabs from persons with early syphilis, but who have no visible oral

lesions. The implications of this finding for transmission are unclear

but warrant further research.

Constitutional signs and symptoms that may accompany or precede

secondary syphilis include sore throat (15–30%), fever (5–8%), weight

loss (2–20%), malaise (25%), anorexia (2–10%), headache (10%), and

meningismus (5%). Acute meningitis occurs in only 1–2% of cases, but

CSF cell and protein concentrations are increased in up to 40% of early

syphilis cases, and viable T. pallidum organisms have been recovered

from CSF during primary and secondary syphilis in 30% of cases,

sometimes without other CSF abnormalities. Persons with current or

recent secondary syphilis may present with ocular or otic manifestations. Ocular findings include pupillary abnormalities and optic neuritis as well as the classic iritis or uveitis. The diagnosis of ocular syphilis

is often considered in affected patients only after they fail to respond

to topical steroid therapy. Anterior uveitis has been reported in 5–10%

of patients with secondary syphilis, and T. pallidum has been demonstrated in aqueous humor from such patients. Permanent blindness

may result without prompt diagnosis and treatment. Otic syphilis may

present as sensorineural hearing loss, vertigo, or tinnitus. The recent

publication of several reports of ocular and otic syphilis reminds clinicians to inquire about neurologic manifestations in all stages of syphilis

infection. In a recent study, 7.9% of patients with syphilis, when asked,

reported recent vision or hearing changes, and more than half of those

had abnormal CSF or ophthalmologic findings consistent with syphilis.

Less often recognized complications of secondary syphilis include

hepatitis, nephropathy, gastrointestinal involvement (hypertrophic

gastritis, patchy proctitis, or a rectosigmoid mass—sometimes mistakenly assumed to be malignant), arthritis, and periostitis. Hepatic

involvement is common in syphilis; although it is usually asymptomatic, up to 25% of patients may have abnormal liver function tests.

Frank syphilitic hepatitis is rare. Renal involvement usually results

from immune complex deposition and produces proteinuria associated

FIGURE 182-2 Primary syphilis with a firm, nontender chancre. with an acute nephrotic syndrome. Like those of primary syphilis, most

1409CHAPTER 182 Syphilis

FIGURE 182-3 Secondary syphilis. Left: Maculopapular truncal eruption. Middle: Papules on the palms. Right: Papules

on the soles. (Photos courtesy of Jill McKenzie and Christina Marra.)

manifestations of the secondary stage resolve spontaneously, usually

within 1–6 months.

■ LATENT SYPHILIS

Positive serologic tests for syphilis, together with a normal CSF examination and the absence of clinical manifestations of syphilis, indicate a

diagnosis of latent syphilis in an untreated person. The diagnosis may

be made following routine serologic screening or may be suspected due

to a history of primary or secondary lesions, a history of exposure to

syphilis, or the delivery of an infant with congenital syphilis. A previous

nonreactive serologic test or clear history of lesions or exposure may

help to establish the duration of infection, which is an important factor

in the selection of appropriate therapy. Early latent syphilis is limited

to the first year after infection, whereas late latent syphilis is defined

as that of ≥1 year’s (or unknown) duration. The classical definition of

early latent syphilis would include a person whose secondary rash has

resolved, as well as a person whose chancre has healed but who has not

yet developed secondary manifestations. The Centers for Disease Control and Prevention (CDC) have recently revised the case definitions

for surveillance and reporting purposes to better reflect the recognition

that some clinical manifestations may appear at several stages of infection. These definitions include the traditional primary and secondary

stages, as well as “syphilis, early nonprimary nonsecondary,” describing

infections of <12 months’ duration, and “syphilis, unknown duration

or late,” encompassing the previous late latent and late (tertiary) classifications. In this new scheme, neurologic, ocular, otic, and late clinical

manifestations are reported separately in the context of their separate

primary, secondary, early nonprimary nonsecondary, and unknown

duration or late categories.

It was previously thought that untreated late latent syphilis had three

possible outcomes: (1) persistent lifelong infection; (2) development of

tertiary syphilis; or (3) spontaneous cure, with reversion of serologic

tests to negative. Although progression to clinically evident late syphilis

is very rare today, the occurrence of spontaneous microbiologic cure

is in doubt.

Because T. pallidum continues to be present throughout untreated

infection, it may seed the bloodstream intermittently during the latent

stage, and a pregnant woman with latent syphilis may infect her fetus

in utero. Moreover, syphilis has been transmitted through blood transfusion or organ donation from patients with latent syphilis.

■ REINFECTION SYPHILIS

A growing number of individuals, particularly MSM, are acquiring

multiple episodes of syphilis, with important implications for clinical

presentation and serologic testing. Although no national data are available, 32% of enrollees (mostly MSM) in a recent 18-year longitudinal

study of CNS involvement were known to have had multiple episodes

of syphilis. It is well recognized that, after treatment, persons with

past syphilis are less likely to revert to nonreactive in the Venereal

Disease Research Laboratory (VDRL)/rapid plasma reagin (RPR) than

persons with first episode syphilis, and treponemal tests will remain

reactive. However, several recent studies

also indicate that subsequent episodes

of syphilis are more likely to be asymptomatic than initial episodes, less likely

to have T. pallidum identified in blood

or CSF, and less likely to have laboratorydefined neurosyphilis. These cases would

be detectable only by serologic screening,

reinforcing the utility of frequent screening in high-risk populations.

■ INVOLVEMENT OF THE CNS

Traditionally, neurosyphilis has been

considered a late manifestation of syphilis, but this view is inaccurate. CNS

syphilis represents a continuum encompassing early invasion (usually within the

first weeks of infection), months to years

of asymptomatic involvement, and, in some cases, development of early

or late neurologic manifestations. Early neurosyphilis includes asymptomatic or symptomatic meningitis and meningovascular syphilis; late

neurosyphilis includes tabes dorsalis and general paresis.

Asymptomatic Neurosyphilis The diagnosis of asymptomatic

neurosyphilis is made in patients who lack neurologic symptoms

and signs but who have CSF abnormalities, including mononuclear

pleocytosis, increased protein concentration, or reactivity in the CSF

VDRL test. CSF abnormalities are demonstrated in up to 40% of cases

of untreated primary or secondary syphilis and in 25% of cases of

untreated latent syphilis. T. pallidum has been recovered by inoculation

into rabbits of CSF from up to 30% of patients with primary or secondary syphilis but less frequently from patients with syphilis of >1 year’s

duration. The presence of T. pallidum in CSF is often associated with

other CSF abnormalities, but organisms can be recovered from patients

with otherwise normal CSF. Although the prognostic implications of

these findings in early syphilis are uncertain, it may be appropriate to

conclude that even patients with early syphilis who have CSF abnormalities do indeed have asymptomatic neurosyphilis and should be

treated for neurosyphilis; such treatment is particularly important in

patients with concurrent untreated HIV infection. Before the advent of

penicillin, the risk of development of clinical neurosyphilis in untreated

asymptomatic persons was roughly proportional to the intensity of CSF

changes, with the overall cumulative probability of progression to clinical neurosyphilis ~20% in the first 10 years of infection but increasing

with time. In several large studies, neurosyphilis was associated with an

RPR titer of ≥1:32, regardless of clinical stage or HIV infection status.

While most experts agree that neurosyphilis is more common among

persons with untreated HIV infection, the immune reconstitution seen

with effective ART may have a protective effect against development of

clinical neurosyphilis in HIV-infected persons with syphilis. Nonetheless, RPR titer ≥1:32 is still associated with reactive CSF VDRL, even in

persons taking effective ART. HIV-uninfected persons with untreated

latent syphilis and normal CSF probably run a very low risk of subsequent neurosyphilis.

Symptomatic Neurosyphilis The major clinical categories of

symptomatic neurosyphilis include early meningeal and meningovascular and late parenchymatous syphilis. The last category includes

general paresis and tabes dorsalis. The onset of symptoms usually

occurs <1 year after infection for meningeal syphilis, up to 10 years

after infection for meningovascular syphilis, at ~20 years for general

paresis, and at 25–30 years for tabes dorsalis. Neurosyphilis is more

frequently symptomatic in patients co-infected with untreated HIV,

particularly those with low CD4+ T lymphocyte counts. In addition,

evidence suggests that syphilis infection worsens the cognitive impairment seen in HIV-infected persons and that this effect persists after

treatment for syphilis.

Meningeal syphilis may present as headache, nausea, vomiting, neck

stiffness, cranial nerve involvement, seizures, and changes in mental

status. This condition may be concurrent with or may follow the

1410 PART 5 Infectious Diseases

secondary stage. Patients presenting with uveitis, iritis, or hearing loss

often have meningeal syphilis, but these clinical findings can also be

seen in patients with normal CSF.

Meningovascular syphilis reflects meningitis together with inflammatory vasculitis of small, medium, or large vessels. The most common

presentation is a stroke syndrome involving the middle cerebral artery

of a relatively young adult. However, unlike the usual thrombotic or

embolic stroke syndrome of sudden onset, meningovascular syphilis

often becomes manifest after a subacute encephalitic prodrome (with

headaches, vertigo, insomnia, and psychological abnormalities), which

is followed by a gradually progressive vascular syndrome.

The manifestations of general paresis reflect widespread late parenchymal damage and include abnormalities corresponding to the mnemonic paresis: personality, affect, reflexes (hyperactive), eye (e.g., Argyll

Robertson pupils), sensorium (illusions, delusions, hallucinations),

intellect (a decrease in recent memory and in the capacity for orientation, calculations, judgment, and insight), and speech. Tabes dorsalis is

a late manifestation of syphilis that presents as symptoms and signs of

demyelination of the posterior columns, dorsal roots, and dorsal root

ganglia, including ataxia, foot drop, paresthesia, bladder disturbances,

impotence, areflexia, and loss of positional, deep-pain, and temperature sensations. The small, irregular Argyll Robertson pupil, a feature

of both tabes dorsalis and paresis, reacts to accommodation but not

to light. Optic atrophy also occurs frequently in association with tabes.

■ OTHER MANIFESTATIONS OF LATE SYPHILIS

The slowly progressive inflammatory process leading to tertiary disease begins early during infection, although these manifestations may

not become clinically apparent for years or decades. Early syphilitic

aortitis first becomes evident soon after secondary lesions subside, and

treponemes that trigger the development of gummas may have seeded

the tissue years earlier.

Cardiovascular Syphilis Cardiovascular manifestations, usually

appearing 10–40 years after infection, are attributable to endarteritis

obliterans of the vasa vasorum, which provide the blood supply to

large vessels; T. pallidum DNA has been detected by polymerase chain

reaction (PCR) in aortic tissue. Cardiovascular involvement results

in uncomplicated aortitis, aortic regurgitation, saccular aneurysm

(usually of the ascending aorta), or coronary ostial stenosis. In the preantibiotic era, symptomatic cardiovascular complications developed

in ~10% of persons with untreated late syphilis. Today, cardiovascular

syphilis is rarely seen in the developed world.

Late Benign Syphilis (Gumma) Gummas are usually solitary

lesions ranging from microscopic to several centimeters in diameter.

Histologic examination shows a granulomatous inflammation, with a

central area of necrosis due to endarteritis obliterans. T. pallidum has

been detected by PCR in these lesions, and penicillin treatment results

in rapid resolution, confirming the treponemal stimulus for the inflammation. Common sites include the skin and skeletal system; however,

any organ (including the brain) may be involved. Gummas of the skin

produce indolent, painless, indurated nodular or ulcerative lesions that

may resemble other chronic granulomatous conditions. Skeletal gummas may affect any bone or cartilage. Upper respiratory gummas can

lead to perforation of the nasal septum or palate.

■ CONGENITAL SYPHILIS

Transmission of T. pallidum across the placenta from a syphilitic

woman to her fetus may occur at any stage of pregnancy, but fetal damage generally does not occur until after the fourth month of gestation

when fetal immunologic competence begins to develop. This timing

suggests that the pathogenesis of congenital syphilis, like that of adult

syphilis, depends on the host immune response rather than on a direct

toxic effect of T. pallidum. The risk of fetal infection during untreated

early maternal syphilis is ~75–95%, decreasing to ~35% for maternal

syphilis of >2 years’ duration. Adequate treatment of the woman before

the 16th week of pregnancy should prevent fetal damage, and treatment before the third trimester should adequately treat the infected

fetus. Untreated maternal infection may result in a rate of fetal loss

of up to 40% with second-trimester spontaneous abortion, stillbirth,

prematurity, and neonatal death. Among infants born alive, only fulminant congenital syphilis is clinically apparent at birth, and these babies

have a very poor prognosis. The most common clinical problem is the

healthy-appearing baby born to a mother with a positive serologic test.

Routine serologic testing for syphilis in early pregnancy is costeffective in virtually all populations, even in areas with a low prenatal

prevalence of syphilis. Low-tech point-of-care tests have been developed

and widely implemented to facilitate antenatal testing in resource-poor

settings. Globally, the past 10 years have seen a dramatic reduction

in congenital syphilis in the face of relatively steady rates of maternal

syphilis, showing the effectiveness of increased antenatal screening and

treatment. Progress has been uneven, however, with major advances in

Thailand, Cuba, several Baltic States, and India, but continuing high

levels in Africa and China. Periodic lack of penicillin availability in

low- and middle-income countries prevents treatment of seropositive

women. Integration of programs to prevent congenital syphilis with programs to prevent maternal transmission of HIV would be highly costeffective but is hampered by the restrictions placed on HIV-focused funds.

All pregnant women should be screened at their first antenatal visit.

Where the prevalence of syphilis in women is high or when the patient

is at high risk of reinfection, serologic testing should be repeated in the

third trimester and at delivery. Neonatal congenital syphilis must be

differentiated from other generalized congenital infections, including

rubella, cytomegalovirus or herpes simplex virus infection, and toxoplasmosis, as well as from erythroblastosis fetalis.

Manifestations of congenital syphilis may appear early (within the

first 2 years of life, often at 2–10 weeks of age) or late (after 2 years).

The earliest manifestations of congenital syphilis include rhinitis, or

“snuffles” (23%); mucocutaneous lesions (35–41%); bone changes

(61%), including periostitis detectable by x-ray examination of long

bones; hepatosplenomegaly (50%); lymphadenopathy (32%); anemia

(34%); jaundice (30%); thrombocytopenia; and leukocytosis. CNS

invasion by T. pallidum is detectable in 22% of infected neonates. Neonatal death is usually due to pulmonary hemorrhage, secondary bacterial infection, or severe hepatitis. Late congenital syphilis (untreated

after 2 years of age) is subclinical in 60% of cases; the clinical spectrum

in the remainder of cases may include interstitial keratitis (which

occurs at 5–25 years of age), eighth-nerve deafness, and recurrent

arthropathy. Neurosyphilis was documented in about one-quarter of

untreated patients with late congenital syphilis in the preantibiotic

era. Gummatous periostitis occurs at 5–20 years of age and, as in

nonvenereal endemic syphilis, tends to cause destructive lesions of the

palate and nasal septum. Classic stigmata include Hutchinson’s teeth

(centrally notched, widely spaced, peg-shaped upper central incisors),

“mulberry” molars (sixth-year molars with multiple, poorly developed

cusps), saddle nose, and saber shins.

LABORATORY EXAMINATIONS

■ DEMONSTRATION OF THE ORGANISM

Historically, dark-field microscopy and immunofluorescence antibody

staining have been used to identify T. pallidum in moist lesions such

as chancres or condylomata lata, but these tests are rarely available

outside of research laboratories. Sensitive and specific PCR tests have

been developed but are not commercially available, although a number

of laboratories perform in-house validated PCR testing. The recent

advances in cultivation of T. pallidum in a tissue culture system have

not yet been implemented in clinical laboratories.

T. pallidum can be found in tissue by immunofluorescence or immunohistochemical methods using specific monoclonal or polyclonal

antibodies to T. pallidum. Silver stains should be interpreted with caution because artifacts resembling T. pallidum are often seen. T. pallidum

DNA has been detected by PCR in lesion swabs, tissue samples, blood,

CSF, ocular fluid, urine, and oropharyngeal swabs.

■ SEROLOGIC TESTS FOR SYPHILIS

Treponemal and Lipoidal Tests There are two types of serologic

tests for syphilis: lipoidal (so-called nontreponemal) and treponemal.