Pulmonary Infection of Mice with
            <i>Staphylococcus aureus</i>

DeMaria, Thomas F.; Kapral, Frank A.

doi:10.1128/iai.21.1.114-123.1978

Cited by 20 publications

(8 citation statements)

References 30 publications

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“…However, while rodent models of chronic infection have been well characterized for Gram-negative pathogens such as Pseudomonas and nontuberculous mycobacteria ( 37 , 38 ), development of a reliable chronic MRSA model has been challenging ( 39 ), in part due to the steep mortality curve associated with the infection. As such, we and others in this field have resorted to using acute pulmonary infection models to establish initial in vivo proof of concept ( 34 , 40 – 42 ).…”

Section: Discussionmentioning

confidence: 99%

Development and Preclinical Evaluation of New Inhaled Lipoglycopeptides for the Treatment of Persistent Pulmonary Methicillin-Resistant Staphylococcus aureus Infections

Plaunt

Rose

Kang

et al. 2021

Antimicrob Agents Chemother

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Chronic pulmonary MRSA disease in cystic fibrosis (CF) has a high probably of recurrence following treatment with standard-of-care antibiotics and represents an area of unmet need associated with reduced life expectancy. We developed a lipoglycopeptide therapy customized for pulmonary delivery that not only demonstrates potent activity against planktonic MRSA but also against protected colonies of MRSA both in biofilms and within cells, the latter of which have been linked to clinical antibiotic failure. A library of next-generation potent lipoglycopeptides were synthesized with an emphasis on attaining superior pharmacokinetics (PK) and pharmacodynamics to similar compounds of their class. Our strategy focused on hydrophobic modification of vancomycin where ester and amide functionality were included with carbonyl configuration and alkyl length as key variables. Candidates representative of each carbonyl attachment chemistry demonstrated potent activity in vitro with several compounds being 30-60 times more potent than vancomycin. Several compounds were advanced into in vivo nose-only inhalation PK evaluations in rats where RV94, a potent lipoglycopeptide that utilizes an inverted amide linker to attach a 10-carbon chain to vancomycin, demonstrated the most favorable lung residence time after inhalation. Further in vitro evaluation of RV94 showed superior activity to vancomycin against an expanded panel of gram-positive organisms, cellular accumulation and efficacy against intracellular MRSA, and MRSA biofilm killing. Moreover, in vivo efficacy of inhaled nebulized RV94 in a 48-h acute model of pulmonary MRSA (USA300) infection in neutropenic rats demonstrated statistically significant antibacterial activity that was superior to inhaled vancomycin.

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Section: Discussionmentioning

confidence: 99%

Development and Preclinical Evaluation of New Inhaled Lipoglycopeptides for the Treatment of Persistent Pulmonary Methicillin-Resistant Staphylococcus aureus Infections

Plaunt

Rose

Kang

et al. 2021

Antimicrob Agents Chemother

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“…When the organisms are instilled intratracheally, they are eliminated rapidly by phagocytic ingestion (9,10) and other extracellular killing mechanisms (11,24). For example, DeMaria and Kapral (5) demonstrated that elimination of at least 99% of the inoculum occurs within 48 h in mice inoculated with 10 8 CFU of staphylococci by this method. However, the lack of a satisfactory animal model, in which pathogens remain in the lung in adequate numbers for a sufficient period of time, manifesting clear pathologic features of infection, has been one of the major impediments to the study of the pathogenesis and therapy of staphylococcal pulmonary infection.…”

mentioning

confidence: 99%

Role of coagulase in a murine model of hematogenous pulmonary infection induced by intravenous injection of Staphylococcus aureus enmeshed in agar beads

et al. 1997

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We describe a novel mouse model of acute staphylococcal pneumonia induced by intravenous injection of Staphylococcus aureus enmeshed in agar beads. For comparison, we also used various strains of bacteria, including three strains of S. aureus, two strains of Staphylococcus epidermidis, one strain of Streptococcus pyogenes, three strains of Pseudomonas aeruginosa, and one strain of Klebsiella pneumoniae. All except two strains of S. aureus were cleared rapidly from the lungs. When S. aureus NUMR1 enmeshed in agar beads was injected intravenously, the organisms concentrated and remained in the lung for a period longer than several weeks. Multiple lung abscesses were evident macroscopically, and histological examination of the infected lung showed multiple lung abscesses around the pulmonary arterioles, consisting of bacterial colonies encircled with fibrin filaments and surrounded by inflammatory cells of neutrophils and macrophages. When 14 strains of clinically isolated S. aureus were injected intravenously, the number of bacteria recovered from the lung tissue 7 days after infection correlated with the titer of staphylocoagulase (P < 0.01) but not with the titer of clumping factor. Injection of coagulase-deficient mutant strain DU5843 was associated with a markedly reduced number of viable bacteria isolated from the lung, compared with its coagulase-positive parental strain DU5789. Our results suggest that coagulase may play a role in the development of blood-borne staphylococcal pneumonia in our model. Our animal model is simple and reproducible and resembles blood-borne staphylococcal pneumonia in humans, and it could be useful for investigating the pathogenicity or treatment of staphylococcal pulmonary infection, including infections with methicillin-resistant S. aureus.

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“…We and others think that extracellular killing of staphylococci occurs in murine lungs (3,12) and suggest that steroid-induced defects may involve this extracellular killing activity. The mechanism for extracellular killing is unknown but could involve, for example, the production of reactive oxygen species during prostaglandin synthesis (12).…”

Section: Discussionmentioning

confidence: 86%

Chronic glucocorticosteroid therapy impairs staphylococcal clearance from murine lungs

Nugent¹,

Pesanti²

1982

Infect Immun

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Since the clearance of Staphylococcus aureus from murine lungs after aerosol exposure depends only on regional defense processes and does not require the recruitment of neutrophils or other systemic factors, we used this model for pulmonary clearance to evaluate the effect of chronic glucocorticosteroid therapy on intrinsic pulmonary defense responses. Mice treated with oral prednisolone for 2 or more weeks had delayed clearance of S. aureus at both 6 and 22 h after aerosol exposure. Mice treated with prednisolone for 1 week had delayed clearance at 22h, and mice treated for 2 days had normal clearance. In mice that had been treated for 2 weeks, clearance returned to normal after 2 weeks off therapy, but not after 1 week. Prednisolone did not appear to alter the number of phagocytes in bronchoalveolar spaces or their ingestion capacity. These results suggest that chronic steroid therapy can alter pulmonary clearance functions independent of any effect on immune or inflammatory responses.

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Pulmonary Infection of Mice with Staphylococcus aureus

Cited by 20 publications

References 30 publications

Development and Preclinical Evaluation of New Inhaled Lipoglycopeptides for the Treatment of Persistent Pulmonary Methicillin-Resistant Staphylococcus aureus Infections

Development and Preclinical Evaluation of New Inhaled Lipoglycopeptides for the Treatment of Persistent Pulmonary Methicillin-Resistant Staphylococcus aureus Infections

Role of coagulase in a murine model of hematogenous pulmonary infection induced by intravenous injection of Staphylococcus aureus enmeshed in agar beads

Chronic glucocorticosteroid therapy impairs staphylococcal clearance from murine lungs

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