Add-On Testing for Sexually Transmitted Infections (STIs)

Emery Haley, PhD, Scientific Writing Specialist

Add-On Testing for Sexually Transmitted Infections (STIs)

Clinical Relevance in UTI

Chlamydia trachomatis, Mycobacterium tuberculosis, Neisseria gonorrhoeae, and Trichomonas vaginalis are the organisms responsible for common sexually transmitted infections (STIs; chlamydia, genital tuberculosis, gonorrhea, and trichomoniasis, respectively). Urogenital infections with these organisms can cause clinical signs and lower urinary tract symptoms that overlap significantly with common signs and symptoms of urinary tract infections (UTIs), such as dysuria, urinary frequency/urgency, pyuria, and hematuria.[1]  STIs can also co-occur with classical UTIs.

None of these organisms can grow in the standard urine culture conditions commonly used for UTI diagnosis. Instead, they are diagnosed by specialized cultures or advanced molecular tests, such as PCR. To ensure correct diagnosis and appropriate treatment, molecular testing for these STI pathogens alongside uropathogens is recommended in individuals with lower urinary tract and/or urogenital symptoms who are sexually active or have other risk factors for contracting STIs.[2,3] Due to risks of pregnancy complications and neonatal infection, testing for these STIs is also recommended in symptomatic pregnant individuals.

Bacterial Species

Chlamydia trachomatis

Clinical Summary

• C. trachomatis is recognized as a biofilm-forming, nitrite-negative, gram-negative, sexually transmitted urogenital pathogen.
• C. trachomatis is associated with both genital infection and complicated or recurrent UTI.
• Detection of C. trachomatis in a urine specimen is nationally notifiable to the CDC.
• Reported serious complications of C. trachomatis urogenital infections include both male and female infertility and pelvic inflammatory disease in females. Pregnancy complications such as ectopic pregnancy, chorioamnionitis, low birth weights, and neonatal infections are also a significant concern.

Bacterial Characteristics

Gram-stain

Gram-negative

Morphology

Spherical obligate intracellular parasitic bacterium

Growth Requirements

Fastidious
Obligate anaerobe

Nitrate Reduction

No

Urease

Negative

Biofilm Formation

Yes

Pathogenicity

Pathogen

Clinical Relevance in UTI

C. trachomatis is most commonly recognized as the microorganism causative of the sexually transmitted infection (STI), chlamydia. According to the United States Centers for Disease Control and Prevention (CDC), almost 60% of chlamydia cases are diagnosed in adolescents and young adults between the ages of 15 and 24 years, with a higher prevalence in females than in males.[4,5] Since many chlamydia infections are asymptomatic, these numbers primarily reflect access to and utilization of STI screening services. Detection of C. trachomatis in a urine specimen is nationally notifiable to the CDC.[6]

C. trachomatis infection can also cause clinical signs and lower urinary tract symptoms that overlap with common signs and symptoms of UTI, such as dysuria and pyuria.[7,8] While UTI is commonly diagnosed by urine culture, C. trachomatis does not grow in standard culture conditions, and chlamydia diagnosis is instead performed via nucleic acid amplification testing, such as PCR.[9] Additionally, C. trachomatis lacks nitrate reductase activity, so screening strategies involving urinalysis for nitrite positivity will be false-negative.[10,11]

Further complicating diagnosis, UTI and chlamydia STI can co-occur,[12]  and C. trachomatis itself has been identified as the cause of some culture-negative recurrent UTIs.[13]  Importantly, despite similarities in the initial clinical presentation, UTI and chlamydia have different long-term complication risks and frequently require different treatment strategies. Therefore, molecular-based diagnostics, such as PCR, covering both UTI pathogens and STI pathogens are recommended, particularly in sexually active adolescents and young adults, or adults with high STI exposure risk.[12,14]  Due to risks of pregnancy complications and neonatal infection, testing for these STIs is also recommended in symptomatic pregnant individuals.

In males, past C. trachomatis infection has been associated with infertility.[15]  Reported complications of C. trachomatis infection in females include pelvic inflammatory disease, chorioamnionitis in pregnancy, ectopic pregnancy, and tubal factor infertility.[16]  Complications in neonates who are infected via vertical transmission of C. trachomatis during birth include low birth weight, afebrile pneumonia, and conjunctivitis, potentially resulting in blindness.[9,17]

Treatment

According to the CDC,[9] recommended treatments for C. trachomatis infection include:

1. The first-line choice in non-pregnant individuals is Doxycycline 100mg orally (PO) twice daily for seven days
   • Alternatively, a single 1g oral (PO) dose of Azithromycin
   • Alternatively, Levofloxacin 500mg orally (PO) once daily for seven days
2. The first-line choice in pregnant individuals is a single 1g oral (PO) dose of Azithromycin
   • Alternatively, Amoxicillin 500mg orally (PO) three times daily for seven days

Mycobacterium tuberculosis

Clinical Summary

• M. tuberculosis is recognized as a biofilm-forming, urease-positive, gram-variable, sexually transmitted urogenital pathogen.
• Urogenital M. tuberculosis is associated with complicated, persistent, and/or recurrent UTI.
• Reported serious complications of M. tuberculosis urogenital infections include both male and female infertility, reduced bladder capacity/constricted bladder, urinary obstruction, ureteric strictures, stenosis, pyelonephritis, hydronephrosis, renal scarring, and renal failure.

Bacterial Characteristics

Gram-stain

Gram-variable (a waxy outer coating of mycolic acid prevents it from reliably staining gram-positive)

Morphology

Bacillus; obligate intracellular parasitic bacterium

Growth Requirements

Fastidious (extremely slow growing, requires a specialty culture medium such as Lowenstein-Jensen or Middlebrook 7H9/7H11)
Obligate aerobe

Nitrate Reduction

Yes

Urease

Positive

Biofilm Formation

Yes

Pathogenicity

Pathogen

Clinical Relevance in UTI

M. tuberculosis is most commonly recognized as the microorganism causative of tuberculosis (TB). Although not considered one of the six highest priority “ESKAPE” pathogens, The World Health Organization (WHO) has included this organism in the 2024 Bacterial Priority Pathogens List (BPPL).[18] According to the United States Centers for Disease Control and Prevention (CDC), up to 13 million people in the United States have latent (inactive, untransmissible, and asymptomatic) tuberculosis infections.[19] Both initial active tuberculosis disease and reactivation of latent tuberculosis infection can manifest with symptoms in either the lungs (pulmonary TB) or in other organs (extra-pulmonary). A common extra-pulmonary manifestation of TB is urogenital TB.

Urogenital M. tuberculosis infection is often difficult to diagnose, with diagnostic delays attributed to the nonspecific nature of the symptoms.[20] Persistent and/or recurrent lower urinary tract symptoms, such as dysuria and voiding irregularities, are common, but may be mistaken clinically for UTI, resulting in ineffective treatment.[21]  Culture-negative or so-called “sterile” pyuria and hematuria can also be a sign of urogenital TB.[22,23] M. tuberculosis does not grow in standard urine culture conditions, so urogenital TB is instead diagnosed via specialized culture or nucleic acid amplification testing, such as PCR.[24]

M. tuberculosis may cause menstrual irregularities and both male and female infertility.[25,26] Severe complications of uncontrolled urogenital M. tuberculosis infection include reduced bladder capacity/constricted bladder, urinary obstruction, ureteric strictures, stenosis, pyelonephritis, hydronephrosis, renal scarring, and renal failure.[27,28]Testing for urogenital M. tuberculosis infection is recommended in symptomatic individuals with previously diagnosed latent TB or recent travel/risk of exposure to TB.

Treatment

In the United States, both active tuberculosis disease and latent M. tuberculosis infection are treated with individualized treatment regimens, based on susceptibility testing of clinical isolates, and typically involving multidrug cocktails taken for several months.[29]

Neisseria gonorrhoeae

Clinical Summary

• N. gonorrhoeae is recognized as a biofilm-forming, nitrite-negative, gram-negative, sexually transmitted urogenital pathogen.
• N. gonorrhoeae is associated with urethritis and may present with signs and symptoms clinically indistinguishable from complicated, persistent, and/or recurrent UTI.
• Detection of N. gonorrhoeae in a urine specimen is nationally notifiable to the CDC.
• Reported serious complications of N. gonorrhoeae urogenital infections include both male and female infertility and pelvic inflammatory disease in females. Pregnancy complications such as ectopic pregnancy, preterm birth, low birth weights, and neonatal infections are also a significant concern. Rarely, disseminated infection (bacteremia) can occur, with potentially lethal complications including infective/reactive arthritis, endocarditis, and meningitis.

Bacterial Characteristics

Gram-stain

Gram-negative

Morphology

Coccus

Growth Requirements

Fastidious (slow growing, requires supplemental nutrients, including glucose and glutamine)
Facultative anaerobe

Nitrate Reduction

No

Urease

Negative

Biofilm Formation

Yes

Pathogenicity

Pathogen

Clinical Relevance in UTI

N. gonorrhoeae is most commonly recognized as the microorganism causative of the sexually transmitted infection (STI), gonorrhea. According to the United States Centers for Disease Control and Prevention (CDC), most gonorrhea cases are diagnosed in adolescents and young adults between the ages of 15 and 35 years, with a higher prevalence in males than in females.[30] Since many chlamydia infections are asymptomatic, these numbers primarily reflect access to and utilization of STI screening services.

Although not considered one of the six highest priority “ESKAPE” pathogens, The World Health Organization (WHO) has included this organism in the 2024 Bacterial Priority Pathogens List (BPPL).[18] Detection of N. gonorrhoeae in a urine specimen is nationally notifiable to the CDC.[31]

N. gonorrhoeae infection can also cause clinical signs and lower urinary tract symptoms that overlap with common signs and symptoms of UTI, such as dysuria, urinary frequency/urgency, and pyuria.[32,33] Further complicating diagnosis, UTI and gonorrhea STI can co-occur. Importantly, despite similarities in the initial clinical presentation, UTI and gonorrhea have different long-term complication risks and frequently require different treatment strategies.

While UTI is commonly diagnosed by urine culture, N. gonorrhoeae does not grow in standard culture conditions, and gonorrhea diagnosis is instead performed via nucleic acid amplification testing, such as PCR.[31] Additionally, N. gonorrhoeae lacks nitrate reductase activity, so screening strategies involving urinalysis for nitrite positivity will be false-negative.[10,11]  Molecular-based diagnostics, such as PCR, covering both UTI pathogens and STI pathogens are recommended, particularly in sexually active adolescents and young adults, or adults with high STI exposure risk. Due to risks of pregnancy complications and neonatal infection, testing for these STIs is also recommended in symptomatic pregnant individuals.

In males, N. gonorrhoeae infection has been associated with infertility.[33,34]  Reported complications of N. gonorrhoeae infection in females include pelvic inflammatory disease, ectopic pregnancy, and tubal factor infertility.[33,34]   Complications such as preterm birth, low birth weight, and conjunctivitis, potentially resulting in blindness, can occur in neonates who are infected via vertical transmission of N. gonorrhoeae during birth.[35]  Untreated N. gonorrhoeae can progress to disseminated infection (bacteremia) with potentially lethal complications including infective/reactive arthritis, endocarditis, and meningitis[36–38]

Treatment

According to the CDC,[39]  recommended treatments for N. gonorrhoeae infection include:

• The first-line choice is a single 500mg intramuscular injection (IM) dose of Ceftriaxone
  • Alternatively, a single 800mg oral (PO) dose of Cefixime

Protozoan Parasite
Trichomonas vaginalis

Clinical Summary

• T. vaginalis is recognized as a sexually transmitted single-celled protozoan parasitic urogenital pathogen.
• T. vaginalis is associated with urethritis and recurrent UTI.
• T. vaginalis urogenital infection increased risks for contracting HSV-2 or HIV and for developing cervical cancer. Complications of trichomoniasis during pregnancy include low birth weight, preterm rupture of membranes, preterm birth, and transmission of infection to the newborn.

Microorganism Characteristics

Morphology

A single-celled extracellular protozoan parasite

Biofilm Formation

Yes

Pathogenicity

Pathogen

Clinical Relevance in UTI

T. vaginalis is most commonly recognized as the microorganism causative of the sexually transmitted infection (STI), trichomoniasis, also called “trich”. According to the United States Centers for Disease Control and Prevention (CDC), trichomoniasis is the most prevalent non-viral STI globally and affects an estimated 2.6 million people in the US.[40] Epidemiologic studies indicated a higher prevalence in females than in males, but unlike with other STIs, there was not a significant difference in prevalence by age.[40] Since many trichomoniasis infections are asymptomatic, these findings primarily reflect access to and utilization of STI screening services.

T. vaginalis infection can also cause clinical signs and lower urinary tract symptoms that overlap with common signs and symptoms of UTI, such as dysuria and pyuria.[41,42] Further complicating diagnosis, T. vaginalis infection has been associated with recurrent UTI and trichomoniasis STI can co-occur with UTI.[43] Importantly, despite similarities in the initial clinical presentation, UTI and trichomoniasis have different long-term complication risks and frequently require different treatment strategies.

While UTI is commonly diagnosed by urine culture, T. vaginalis does not grow in standard culture conditions, and trichomoniasis diagnosis is instead performed via point-of-care tests or nucleic acid amplification testing, such as PCR.[41]  Additionally, unlike common bacterial uropathogens, parasites including T. vaginalis do not display nitrate reductase activity, so screening strategies involving urinalysis for nitrite positivity will be false-negative.[10,11]  Molecular-based diagnostics, such as PCR, covering both UTI pathogens and STI pathogens are recommended, particularly in sexually active adolescents and young adults, or adults with high STI exposure risk. Due to risks of pregnancy complications and neonatal infection, testing for these STIs is also recommended in symptomatic pregnant individuals.

Complications of T. vaginalis urogenital infection include increased risks of contracting human immunodeficiency virus (HIV) infection, contracting herpes simplex virus type 2 (HSV-2) infection, or developing cervical cancer.[40,41] Complications of trichomoniasis during pregnancy include low birth weight, preterm rupture of membranes, preterm birth, and transmission of infection to the newborn.[40,41]

Treatment

According to the CDC,[40]  recommended treatments for T. vaginalis infection include:

• The first-line choice is Metronidazole, with dosage depending on sex
  • For males, a single 2g oral (PO) dose is recommended
  • For females, a regimen of 500mg oral (PO) doses twice a day for seven days is recommended
• Alternatively, a single 2g oral (PO) dose of Tinidazole may be used in both males and females