Pathogens Considered True Infection at Low Copy Numbers (<10³)
At low copy numbers (<10³), Bordetella pertussis, Bordetella holmesii, Legionella pneumophila, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Coxiella burnetii, and Pneumocystis jirovecii should be considered true infections, while Haemophilus influenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes typically represent colonization at these levels.
Pathogens That Are True Infections at Low Copy Numbers
Obligate or Fastidious Pathogens (Always Significant)
Bordetella pertussis and Bordetella holmesii should always be considered true pathogens when detected, regardless of copy number, as they are not normal respiratory flora 1, 2, 3.
Legionella pneumophila is never part of normal flora and any detection represents true infection, particularly important in critically ill patients, those over 40 years, immunocompromised individuals, or those nonresponsive to β-lactam antibiotics 4.
Mycoplasma pneumoniae is an obligate pathogen that does not colonize the respiratory tract; detection at any level indicates infection 1, 2, 3.
Chlamydophila pneumoniae should be considered a true pathogen when detected, as it is not part of normal respiratory flora 1, 2, 3.
Coxiella burnetii (Q fever) is never a colonizer and any detection represents true infection, particularly in patients with appropriate epidemiologic exposures 4.
Pneumocystis jirovecii is particularly important in immunocompromised patients and bronchoscopy may be especially useful for its detection; it should be considered a true pathogen when identified 4.
Pathogens That Typically Represent Colonization at Low Copy Numbers
Common Colonizers Requiring Higher Thresholds
Haemophilus influenzae is frequently encountered in respiratory specimens and may represent colonization of the upper airways; distinction between pathogen and colonizer is facilitated by detection as the dominant flora on direct Gram stain or recovery in moderate or heavy growth 4, 5.
Streptococcus pneumoniae requires quantitative assessment, as it can colonize the upper airways; the distinction between pathogen and colonizer is facilitated by detection as dominant flora on Gram stain or moderate to heavy growth 4.
Staphylococcus aureus is frequently encountered in respiratory specimens and may represent colonization; it becomes more significant in the context of influenza infection or ICU patients 4.
Klebsiella pneumoniae and other Enterobacteriaceae are frequently encountered in respiratory specimens and may represent contaminants that colonize the upper airways 4.
Moraxella catarrhalis is commonly found in respiratory specimens and may represent colonization rather than true infection at low copy numbers 4.
Streptococcus pyogenes requires clinical correlation and higher bacterial loads to distinguish from colonization 4.
Critical Clinical Considerations
Quantitative Culture Interpretation
Quantitative cultures of bronchoscopic or other lower airway specimens facilitate the distinction between colonizing bacteria and pathogens, though clinical interpretation may be hampered by previous antibiotic administration, which can lower the observed quantitative inoculum after 24 hours of ongoing therapy and up to 72 hours after cessation 4.
The multiplex PCR assays can detect down to 10 copies/ml for atypical pathogens, demonstrating high sensitivity and specificity (100% and 98.5% respectively) 1.
Common Pitfalls to Avoid
Do not dismiss low copy numbers of obligate pathogens like Bordetella, Legionella, Mycoplasma, Chlamydophila, or Coxiella as contamination—these organisms do not colonize and any detection is clinically significant 1, 2, 3.
Do not automatically treat low copy numbers of typical bacterial pathogens (S. pneumoniae, H. influenzae, S. aureus, K. pneumoniae, M. catarrhalis) without correlating with Gram stain findings showing dominant flora or clinical severity 4, 5.
Consider the clinical context: Isolation of enterococci, viridans streptococci, coagulase-negative staphylococci, and Candida species should rarely if ever be considered the cause of respiratory dysfunction regardless of copy number 4.
Previous antibiotic use matters: Quantitative cultures are less reliable after 24 hours of antibiotic therapy, potentially underestimating true pathogen burden 4.