Cross-susceptibility among tetracyclines in Gram-positive infections: microbiological basis, EUCAST/CLSI guidance and...

Tetracyclines remain useful options for Gram-positive infections, particularly when prolonged oral therapy is required. Doxycycline is attractive because of its oral bioavailability and tolerability, but many susceptibility systems report tetracycline or minocycline rather than doxycycline, creating uncertainty about within-class extrapolation.

To examine the microbiological, pharmacokinetic/pharmacodynamic (PK/PD), interpretive and clinical evidence supporting cross-susceptibility among tetracycline-class agents in clinically relevant Gram-positive organisms and to define when surrogate results may reasonably support doxycycline use.

We performed a narrative review of PubMed/MEDLINE and ScienceDirect (1990-2025), supplemented by current European Committee on Antimicrobial Susceptibility Testing (EUCAST) and Clinical and Laboratory Standards Institute (CLSI) documents. Predefined search concepts covered resistance mechanisms, cross-susceptibility, PK/PD and clinical outcomes. Primary microbiological, surveillance, PK/PD and clinical studies and systematic reviews/meta-analyses were prioritized.

Cross-susceptibility is not uniform across the tetracycline class. Efflux mechanisms such as tet(K) and tet(L) may permit retained doxycycline or minocycline activity, whereas ribosomal protection mechanisms such as tet(M) and tet(O) are associated with broader reduced susceptibility. Interpretation is organism-, phenotype-, method- and breakpoint-dependent. Free-drug Area Under the Concentration-Time Curve (AUC)/Minimun Inhibitory Concentration (MIC) is the principal PK/PD index, but exposure targets vary by agent, pathogen, model and endpoint. Direct clinical evidence is heterogeneous and is strongest for selected staphylococcal osteoarticular infections and suppressive therapy.

Organism-specific EUCAST or CLSI surrogate rules may provide sufficient microbiological support for doxycycline use without routine agent-specific MIC confirmation when the clinical context is appropriate. Direct doxycycline testing is particularly valuable when surrogate interpretation is unsupported, results are resistant or discordant or uncertainty could materially affect management of severe or deep-seated infection.