# 72 - SECTION 9 Spirochetal Diseases

## SECTION 9 Spirochetal Diseases

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. In the 
CONVERT study, treatment with amikacin liposome inhalation sus­
pension in addition to standard background regimen was associated 
with significantly increased culture conversion (29 vs 8.9%; p < .0001) 
by month 6 in patients with treatment-refractory MAC lung disease 
compared to standard background regimen alone. It is now approved 
for treatment of refractory MAC lung infection with persistent sputum 
positivity at 6 months while on appropriate background regimen. The 
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 impor­
tance 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 combina­
tion 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, throm­
bocythemia, 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 manifesta­
tions, rash, eosinophilia, fever, and neutropenia.
PART 5
Infectious Diseases
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 
prospectively tested for NTM in patients.
In addition, some anti-TB drugs, including clofazimine and beda­
quiline, 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 tigecy­
cline. 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 regi­
mens 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 tuberculo­
sis: An individual patient data meta-analysis. Lancet 392:821, 2018.

Daley CL et al: Treatment of nontuberculous mycobacterial pulmo­
nary 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 clini­
cal 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 Con­
trollers Association and CDC, 2020. MMWR Recomm Rep 69:1, 2020.
World Health Organization: WHO consolidated guidelines on 
tuberculosis Module 4: Treatment, Drug-resistant tuberculosis treat­
ment Geneva: World Health Organization, 2022.
Section 9	 Spirochetal Diseases
Sheila A. Lukehart

Syphilis
DEFINITION
Syphilis, a chronic systemic infection caused by Treponema pallidum 
subspecies pallidum, is usually sexually transmitted and is character­
ized 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 subclini­
cal 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. 189); Borrelia and Borreliella species (relapsing fever and Lyme 
disease, respectively; Chaps. 190 and 191); Brachyspira species (gastro­
intestinal infections); and Treponema species (syphilis and the endemic 
treponematoses; see also Chap. 188). The Treponema pallidum subspe­
cies include T. pallidum subsp. pallidum (venereal syphilis), T. pallidum 
subsp. pertenue (yaws), and T. pallidum subsp. endemicum (bejel). 

T. carateum (pinta), for which no extant strains are available for molec­
ular studies, is still classified as a separate species. Historically, the 
pathogenic Treponema were distinguished by the clinical syndromes 
they produce, but phylogenetic analyses of whole genome sequences 
from several strains (excluding T. carateum) yield the three named 
subspecies groupings. Whether these groupings represent geographi­
cal variation or actual 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. 188) 
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