Mycoplasma & Ureaplasma

The smallest free-living, self-replicating prokaryotes — and the only bacteria that completely lack a cell wall. That single fact drives almost every exam point: no Gram reaction, intrinsic resistance to all cell-wall-active drugs (beta-lactams, vancomycin), pleomorphism, and dependence on sterols for membrane integrity. This note covers Mycoplasma pneumoniae (atypical/"walking" pneumonia, the Eaton agent), the genital mycoplasmas (M. hominis, Ureaplasma urealyticum), and the high-yield discriminators NEET PG loves.

Classification & defining biology

Mycoplasmas belong to the class Mollicutes ("soft skin", reflecting absence of a rigid wall). Genera tested in NEET PG:

Organism	Major disease	Key niche / clue
Mycoplasma pneumoniae	Atypical (primary) pneumonia, tracheobronchitis	"Eaton agent"; cold agglutinins; school-age/young adults
Mycoplasma hominis	Pyelonephritis, PID, post-partum/post-abortal fever, neonatal sepsis	Hydrolyses arginine; does not split urea
Mycoplasma genitalium	Non-gonococcal urethritis (NGU), cervicitis, PID	Slowest grower; macrolide-resistance emerging
Ureaplasma urealyticum	NGU, chorioamnionitis, neonatal lung/CNS disease	Splits urea (urease +); "T-strain" — tiny colonies

Distinguishing biological features:

• No cell wall → no peptidoglycan, no muramic acid → not seen on Gram stain → resistant to penicillins, cephalosporins, vancomycin.
• Sterol-containing cell membrane (cholesterol incorporated from host/medium) — unique among bacteria; this is why media must be enriched with serum, and why digitonin/saponin (sterol-binding) sensitivity is a classic identification test (mycoplasmas are inhibited; the wall-less Acholeplasma is not).
• Pleomorphic (cocci, filaments, rings) — pass through 0.45 µm filters ("filterable").
• Smallest genome of any self-replicating organism; fastidious, slow growers.

High-yield: Mycoplasma is the only bacterium with cholesterol/sterols in its cell membrane, and the only one truly lacking a cell wall — hence intrinsically resistant to ALL beta-lactams and vancomycin.

High-yield: "Fried-egg" colonies on Eaton's agar (dense raised centre, flat translucent periphery). M. pneumoniae colonies are atypically homogeneous/granular ("mulberry"), whereas the classic textbook fried-egg morphology with a buried centre is most striking for M. hominis and other species. Examiners accept "fried-egg" as the Mycoplasma hallmark.

Mycoplasma pneumoniae — atypical pneumonia

Epidemiology & pathogenesis

• Spread by respiratory droplets; long incubation (2–3 weeks); endemic with epidemics every 3–7 years.
• Classic in children (5–15 yrs) and young adults, crowded settings (boarding schools, military barracks, families).
• The organism is an extracellular surface parasite: the tip adhesin P1 protein binds sialylated glycoprotein receptors on respiratory epithelium at the base of cilia → ciliostasis, loss of ciliated cells → persistent paroxysmal cough.
• Produces CARDS toxin (Community-Acquired Respiratory Distress Syndrome toxin, an ADP-ribosylating toxin) and hydrogen peroxide / superoxide, causing local oxidative epithelial damage.
• Much of the disease is immune-mediated rather than purely cytopathic.

Clinical features

• Insidious onset: low-grade fever, headache, malaise, sore throat, then a dry, hacking, persistent non-productive cough ("walking pneumonia" — patient is ambulatory, not toxic).
• Classic clinico-radiological dissociation: chest X-ray looks worse (patchy reticulonodular/interstitial infiltrates, often unilateral lower lobe) than the unimpressive auscultatory findings.
• Bullous myringitis — haemorrhagic bullae on the tympanic membrane — a near-pathognomonic association (though uncommon).

Extrapulmonary manifestations (frequently tested)

Driven by autoimmunity and cold agglutinins:

• Haematologic: autoimmune haemolytic anaemia from cold agglutinins (anti-I IgM); Raynaud-like acrocyanosis.
• Dermatologic: erythema multiforme / Stevens–Johnson syndrome (now termed MIRM — Mycoplasma-induced rash and mucositis).
• Neurologic: encephalitis (commonest cause of admission for extrapulmonary disease in children), Guillain–Barré syndrome, transverse myelitis, aseptic meningitis, cerebellar ataxia.
• Cardiac: myocarditis, pericarditis.
• MSK/renal: arthralgia/arthritis, glomerulonephritis.

High-yield: M. pneumoniae is a classic precipitant of Stevens–Johnson syndrome in children and of cold-agglutinin autoimmune haemolytic anaemia (anti-I antibody, IgM, optimal reactivity at 4 °C).

Diagnosis & investigations

Cold agglutinins — the classic MCQ discriminator

• IgM autoantibodies against the I antigen on adult RBCs; agglutinate RBCs at 4 °C, disperse at 37 °C.
• Develop in ~50–60% of clinically significant infections by the end of week 1–2.
• Diagnostic cut-off titre: ≥ 1:32 (≥ 1:64 more specific), or a four-fold rise in paired sera.
• Bedside cold-agglutinin clue: blood clumps in an EDTA tube refrigerated/on ice and disperses on warming.
• Non-specific — also seen in EBV (infectious mononucleosis), CMV, lymphoma, SLE — so it supports but does not confirm Mycoplasma.

High-yield: A rising cold agglutinin titre ≥ 1:32 (or 4-fold rise) in a young patient with atypical pneumonia points to M. pneumoniae. The autoantibody is anti-I (capital I), distinguishing it from the anti-i seen in infectious mononucleosis.

Microbiological & serological work-up

• Culture: on Eaton's agar / PPLO (pleuropneumonia-like organism) medium enriched with horse serum and yeast extract; needs glucose + phenol red (glucose fermentation turns medium yellow). Very slow (1–3 weeks) → impractical for routine diagnosis.
• Investigation of choice for confirmation: NAAT / PCR of throat swab, nasopharyngeal aspirate or sputum — most sensitive and rapid; the modern gold standard.
• Serology: paired (acute + convalescent) complement fixation or ELISA for IgM (recent infection in children) and IgG. Single IgM useful early in children.
• Routine clues: Gram stain shows neutrophils but no organisms; sputum often scant.

Identification & differentiation tests

Test	M. pneumoniae	M. hominis	U. urealyticum
Glucose fermentation	+	–	–
Arginine hydrolysis	–	+	–
Urea hydrolysis (urease)	–	–	+
Haemadsorption (guinea-pig RBCs)	+	–	–
Tetrazolium reduction	+ (aerobic)	variable	–
Growth/colony	Granular "mulberry"	Fried-egg	Tiny "T" colonies

High-yield: Use the biochemical triad — M. pneumoniae ferments glucose, M. hominis hydrolyses arginine, Ureaplasma splits urea (urease positive). This is the single most efficient way to tell the three apart in an MCQ.

Management & drug of choice

Because there is no cell wall, cell-wall-active agents (penicillins, cephalosporins, carbapenems, vancomycin) are useless. Target protein synthesis or DNA gyrase.

Approach (M. pneumoniae):

1. Macrolide (azithromycin / clarithromycin / erythromycin) → drug of choice, especially in children.
2. If macrolide-resistant (rising globally, esp. East Asia) or in adults → doxycycline (tetracycline).
3. Respiratory fluoroquinolone (levofloxacin, moxifloxacin) → alternative in adults; avoided in children/pregnancy.

Stepwise drug logic: Wall-less organism → β-lactams fail → choose macrolide → if resistant or adult → tetracycline → if both unsuitable → fluoroquinolone.

Organism	First-line	Notes
M. pneumoniae	Macrolide (azithromycin); doxycycline	Self-limiting; treatment shortens illness/shedding
M. hominis	Clindamycin / doxycycline	Intrinsically macrolide-RESISTANT (lacks erythromycin target site)
M. genitalium	Azithromycin, then moxifloxacin for resistance	Resistance-guided therapy now standard
U. urealyticum	Doxycycline / azithromycin	Tetracycline resistance (tetM) emerging

High-yield: Macrolides do NOT work against M. hominis (intrinsic resistance) — use clindamycin or doxycycline. Conversely M. pneumoniae is macrolide-sensitive (first line). This reversal is a favourite trap.

High-yield: All mycoplasmas are resistant to penicillin, cephalosporins, vancomycin and trimethoprim/sulfa — anything acting on the cell wall or folate pathway is ineffective.

Genital mycoplasmas

Mycoplasma hominis

• Commensal of the lower genital tract; pathogenic in pyelonephritis, pelvic inflammatory disease, post-partum and post-abortal fever, and neonatal sepsis/meningitis.
• Arginine-positive, urease-negative, glucose-negative.
• Intrinsically macrolide-resistant → treat with clindamycin/doxycycline.

Mycoplasma genitalium

• Increasingly recognised cause of non-gonococcal/non-chlamydial urethritis, cervicitis, PID and possibly tubal-factor infertility.
• Extremely slow/fastidious — diagnosed almost exclusively by NAAT/PCR.
• Notable for rising macrolide resistance (23S rRNA mutations) → resistance-guided therapy (azithromycin then moxifloxacin).

Ureaplasma urealyticum / parvum

• Urease-positive ("T-strain", T = tiny colonies) — splits urea to generate energy; the urease raises local pH and contributes to struvite stone formation.
• Causes non-gonococcal urethritis (a leading cause after Chlamydia), epididymitis, and is implicated in chorioamnionitis, premature rupture of membranes, preterm labour, and neonatal bronchopulmonary dysplasia/pneumonia and meningitis in low-birth-weight infants.
• Treat with doxycycline (or azithromycin); note emerging tetracycline (tetM) resistance.

High-yield: Urease positivity = Ureaplasma among the mycoplasmas. It is a recognised cause of NGU and of neonatal lung disease/BPD in preterm infants — and its urease can promote infection (struvite) stones.

Complications

• M. pneumoniae: prolonged cough, post-infectious asthma exacerbation/reactive airways, autoimmune haemolytic anaemia, SJS/MIRM, encephalitis, GBS, myocarditis, rarely ARDS (CARDS toxin), and DIC/multiorgan in fulminant cases.
• Genital mycoplasmas: PID with tubal scarring → ectopic pregnancy and infertility; in pregnancy → chorioamnionitis, preterm birth; neonatal pneumonia, BPD and meningitis.

Key differentials

Atypical pneumonia mimics (the "atypical" triad to compare):

Feature	M. pneumoniae	Chlamydophila psittaci	Legionella pneumophila
Source	Person-to-person droplets	Birds (psittacine)	Water/AC, soil; no person-to-person
Age	Young/school-age	Bird exposure history	Older, smokers, immunosuppressed
Hyponatraemia / GI / confusion	Mild	–	Marked (Na↓, diarrhoea, ↑LFTs, relative bradycardia)
Cold agglutinins	+	–	–
Diagnosis	PCR; cold agglutinins	Serology	Urinary antigen (serogroup 1); silver stain; BCYE agar
Treatment	Macrolide/doxycycline	Doxycycline	Macrolide/fluoroquinolone

Other differentials: viral pneumonia (influenza, RSV, adenovirus, SARS-CoV-2), early tuberculosis, Q fever (Coxiella), and Chlamydophila pneumoniae. The combination of young patient + dry cough + clinico-radiological dissociation + cold agglutinins + extrapulmonary autoimmune features is the giveaway for M. pneumoniae.

Mnemonics & eponyms

• Eaton agent = M. pneumoniae (named after Monroe Eaton, who isolated it; grows on Eaton's agar).
• "PPLO" = pleuropneumonia-like organism (historical name).
• "Walking pneumonia" — ambulatory patient, mild systemic upset.
• Mnemonic for genital mycoplasma biochemistry — "Harry hominis Argues, Urea-plasma Urinates": Hominis = Arginine; Ureaplasma = Urea/urease.
• Cold agglutinin: anti-I in Mycoplasma vs anti-i in infectious mononucleosis (EBV).

Recently asked / exam angle

• "Smallest free-living organism / only bacterium without a cell wall / only bacterium with sterols in membrane" → Mycoplasma.
• Sterol requirement & fried-egg colonies on Eaton/PPLO agar are repeat single-best-answer items.
• Cold agglutinin titre ≥ 1:32 / four-fold rise, anti-I specificity, optimal at 4 °C — classic discriminator vs EBV (anti-i).
• "Atypical pneumonia + bullous myringitis / SJS in a child" → M. pneumoniae.
• Drug-of-choice questions: macrolide for M. pneumoniae, but clindamycin/doxycycline for M. hominis (macrolide-resistant) — examiners flip these.
• Urease-positive genital mycoplasma causing NGU / neonatal BPD → Ureaplasma urealyticum.
• Mechanism-based: P1 adhesin → ciliary base attachment → ciliostasis; CARDS toxin; immune-mediated damage.
• "Why are beta-lactams/vancomycin ineffective?" → no peptidoglycan/cell wall.

Rapid revision

1. Mycoplasma = smallest free-living bacterium, no cell wall, sterol-containing membrane → resistant to all beta-lactams & vancomycin.
2. Not seen on Gram stain; pleomorphic; passes through bacterial filters.
3. M. pneumoniae = Eaton agent → atypical "walking" pneumonia in young/school-age patients with a dry hacking cough.
4. Clinico-radiological dissociation + bullous myringitis are classic clues.
5. Cold agglutinins (anti-I IgM), titre ≥ 1:32 / 4-fold rise, react at 4 °C → cold AIHA; mononucleosis gives anti-i.
6. Extrapulmonary: SJS/MIRM, encephalitis, GBS, myocarditis, haemolysis.
7. PCR/NAAT is the confirmatory investigation of choice; culture on Eaton/PPLO agar gives fried-egg colonies but is too slow.
8. Biochemistry: M. pneumoniae ferments glucose, M. hominis splits arginine, Ureaplasma splits urea (urease +).
9. DOC for M. pneumoniae = macrolide (azithromycin), doxycycline in adults/resistance.
10. M. hominis is intrinsically macrolide-RESISTANT → use clindamycin/doxycycline.
11. Ureaplasma & M. genitalium → NGU; Ureaplasma also causes neonatal pneumonia/BPD and chorioamnionitis.
12. Differential: contrast with Legionella (hyponatraemia, urinary antigen, water source) and psittacosis (bird exposure).