Mechanisms of Antibiotic Failure During Staphylococcus aureus Osteomyelitis

Abstract

Staphylococcus aureus is a highly successful Gram-positive pathogen capable of causing both superficial and invasive, life-threatening diseases. Of the invasive disease manifestations, osteomyelitis or infection of bone, is one of the most prevalent, with S. aureus serving as the most common etiologic agent. Treatment of osteomyelitis is arduous, and is made more difficult by the widespread emergence of antimicrobial resistant strains, the capacity of staphylococci to exhibit tolerance to antibiotics despite originating from a genetically susceptible background, and the significant bone remodeling and destruction that accompanies infection. As a result, there is a need for a better understanding of the factors that lead to antibiotic failure in invasive staphylococcal infections such as osteomyelitis. In this review article, we discuss the different non-resistance mechanisms of antibiotic failure in S. aureus. We focus on how bacterial niche and destructive tissue remodeling impact antibiotic efficacy, the significance of biofilm formation in promoting antibiotic tolerance and persister cell formation, metabolically quiescent small colony variants (SCVs), and potential antibiotic-protected reservoirs within the substructure of bone.

Keywords: SCVs; Staphylococcus aureus; antibiotic failure; antibiotic tolerance; biofilm; intracellular survival; osteomyelitis; persisters.

Figure 1

Mechanisms of Antibiotic Failure in S. aureus Infection. (A) Abscesses are the characteristic tissue lesions of invasive staphylococcal infection. The bacteria within the core of abscesses are referred to as staphylococcal abscess communities (SACs), which are surrounded by a pseudocapsule made of fibrin and other host extracellular matrix proteins. The SAC is surrounded by immune cells, including both viable and non-viable neutrophils. Bacteria within a SAC exhibit increased tolerance to antibiotic treatment. (B) Abscess formation and exuberant inflammation during osteomyelitis compromise the blood supply to the bone leading to bone necrosis. Necrotic bone fragments result in the formation of tissue lesions known as sequestra, which are characteristic of chronic osteomyelitis and serve as a nidus for persistent infection. In response to the sequestrum, new bone formation occurs resulting in the formation of a pathologic lesion known as an involucrum. Vascular impairment resulting from infection significantly diminishes the effectiveness of systemic antibiotics. (C) Biofilm formation on bone greatly contributes to bacterial persistence during bone infection, and biofilm-associated bacteria exhibit increased tolerance to antibiotics. Biofilms may act as diffusion barriers for antibiotics, thereby reducing the penetrance of antibiotics toward the deeper layers of the biofilm. The biofilm environment, which is characterized by significant nutrient and oxygen gradients, is thought to promote the production of antibiotic tolerant bacterial cells (e.g., small colony variants [SCVs] and persisters) (SCVs are illustrated as pink cocci; persisters are illustrated as orange cocci). (D) S. aureus has been shown to invade and survive within professional phagocytes (e.g., macrophages) and resident bone cells (e.g., osteoclasts and osteoblasts). Intracellular survival contributes to antibiotic tolerance given that most antibiotics act extracellularly, and the intracellular host environment is thought to enrich the formation of SCVs and persisters. (E) Osteocytes, the major cell type embedded within the bone matrix, reside in structures known as lacunae, and connect to one another via a three-dimensional network of channels known as canaliculi. Colonization of the osteocyte lacuno-canalicular network (OLCN) is believed to promote chronicity of S. aureus osteomyelitis as the antibiotic concentrations needed for bacterial eradication may not be possible to achieve within the infected OLCN. Bacteria within the OLCN might also be protected from the host response.