Differentiation between responders and non-responders to antibiotic treatment in mice using 18F-Fluorodeoxysorbitol/PET

doi:10.21203/rs.3.rs-4669916/v1

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Differentiation between responders and non-responders to antibiotic treatment in mice using ¹⁸F-Fluorodeoxysorbitol/PET

https://doi.org/10.21203/rs.3.rs-4669916/v1

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Purpose Bacterial infection causes significant mortality and morbidity worldwide despite the availability of antibiotics. Differentiation between responders and non-responders early on during antibiotic treatment will be informative to patients and healthcare providers. Our objective was to investigate whether PET imaging with ¹⁸F-Fluorodeoxysorbitol (¹⁸F-FDS) or ¹⁸F-FDG can be used to differentiate responders from non-responders to antibiotic treatment.

Procedures NTUH-K2044 was used for infection in Albino C57 female mice. Each mouse was inoculated intratrachealy with NTUH-K2044 to induce lung infection (n=8). For treatment studies, two bacterial doses for animal inoculation and two treatment starting times were compared to optimize treatment profiles. ¹⁸F-FDS or ⁸F-FDG /PET imaging was performed to monitor treatment progression.

Results Our results demonstrated that the treatment profiles for using mice infected with 25 CFU hvKp and antibiotic treatment starting at 24 p.i. were not ideal due to no evidence of lung infection and lack of treatment efficacy. The optimal scheme is to use 250 CUF for infection and start antibiotic treatment at 24 h p.i. to monitor antimicrobial efficacy. 75% of the mice were classified as responders to antibiotic treatment. 25% of the mice were classified as non-responders. ¹⁸F-FDG was used to compare with ¹⁸F-FDS, but all mice showed increased lung uptake of ¹⁸F-FDG during 3-day treatments.

Conclusions ¹⁸F-FDS is a promising PET tracer to image bacterial infection. It can be used to monitor response to treatment, and differentiate responders from non-responders to antibiotic treatment, but ¹⁸F-FDG cannot, probably due to the presence of high degree of inflammation before and after treatment.

18F-FDS

bacterial infection

PET

antibiotic treatment

Bacterial infections represent a major clinical challenge in most medical fields. Klebsiella pneumoniae (Kp) is a Gram-negative opportunistic pathogen that is responsible for a variety of community and hospital infections with mortality rates of up to 22.7% [1, 2]. Hypervirulent K. pneumoniae (hvKp) is an evolving pathotype that is more virulent than classical K. pneumoniae. HvKp is a more easily transmitted, more pathogenic, and a more fatal variant of classical KP. HvKp have higher potential to cause more severe and disseminated infections than classic Kp. hvKp can infect nearly every site of the body and can cause invasive community-acquired infections in healthy patients of all ages. A few examples of these infectious syndromes include nonhepatic abscesses, pneumonia, necrotizing fasciitis, endophthalmitis, and meningitis [3, 4].

It is critical to determine the causative pathogen in bacterial infections clinical management rapidly, and accurately. However, the conventional diagnosis of most infections has limitations such as time-consuming, high contamination rates, not specific to infection and unable to differentiate bacterial infection from inflammation, etc. [5]. Fluorine-18-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET) has been widely used for the detection of inflammatory and infectious diseases, but it is not able to differentiate infection from sterile inflammation [6]. ¹⁸F-Fluorodeoxysorbitol (¹⁸F-FDS) has been well documented as a promising PET tracer specifically targeting gram-negative bacteria and can differentiate infection from sterile inflammation [5, 7–9]. Our published data have demonstrated that ¹⁸F-FDS, in comparison with ¹⁸F-FDG, is a pathogen-specific marker in distinguishing bacterial infection caused by K. pneumoniae from sterile lung inflammation [5].

The evaluation of early treatment response is critical for patient prognosis and successful therapy of bacterial infection [10]. Categorization of responders and non-responders early on during antibiotic treatment is meaningful to develop personalized treatment by improving efficacy and minimizing the toxicity of antimicrobial treatment for patients [11]. However, there are many cases in which it is difficult for clinicians to determine the clinical effectiveness of antibiotics. An effective monitoring tool in assessment of early responders to antibiotic treatment can help prevent long-term use of unnecessary antibiotics, thereby reducing the risk of developing multidrug-resistant bacteria. Our objective was to investigate whether PET imaging with ¹⁸F-FDS or ¹⁸F-FDG can be used to distinguish responders from non-responders to antibiotic treatment in a mouse lung infection model infected with hypervirulent K. pneumoniae (hvKp).

Unless noted otherwise, all chemicals were of analytic grade and purchased from Sigma-Aldrich. ¹⁸F-FDG was purchased from PETNET Solutions Inc. The K. pneumoniae strain (NTUH-K2044, a drug sensitive hvKp (LD₅₀ < 100 CFU) was kindly provided by Jin-Town Wang, NTUCM and Valley Stewart, UC Davis [2]. ¹⁸F-FDS was prepared from commercially available ¹⁸F-FDG using published methods [5]. In a typical run, 10 mCi (370 MBq) of ¹⁸F-FDG (0.5–0.6 ml saline) was mixed with 2–3 mg of solid sodium borohydride at 35^oC for 15 min. The sample was then carefully quenched with acetic acid and adjusted to pH 6–7 with sodium bicarbonate. About 6–7 mCi (222–259 MBq) of ¹⁸F-FDS was collected after passaging through a Sep-Pak Alumina N cartridge (Waters) and 0.2-mm filter. Radiochemical purity was verified by thin-layer chromatography.

Bacterial Uptake Assays

Kp NTUH-K2044 was cultured using a previously published method [2]. Briefly, one week prior to animal infection, bench batch of NTUH-K2044 was prepared by preculturing in Lennox Broth (LB) at 37°C in a shaking bed overnight, and then left at R.T.. For preparation of kp sample for animal inoculation, 100 µl NTUH-K2044 from bench batch was mixed with 3*830 µl TSBDC and 50 mM monosodium glutamate (50 µl) and incubated at 37°C for 3 h. CFUs were enumerated by dilution and plated onto solidified LB medium. Tracer uptake was performed by incubating different bacterial colony-forming units (CFUs) (10⁵-10⁹ in 10-fold increments, n = 5 each) with either ¹⁸F-FDS (20 kBq/mL) or ¹⁸F-FDG at 37^oC for 1 h. As a control, heat-killed (90^oC for 30 min) bacteria were similarly incubated with each tracer. Bacteria were pelleted by centrifugation and washed twice with phosphate buffer, and radioactivity was counted using an automated gamma-counter. Percentage uptake in bacteria was calculated by 100·(counts in pellet/total counts).

Animal Models

Murine infection studies were approved by the University of Louisville Institutional Animal Care and Use Committee in accordance with the National Institutes of Health guidelines. Albino C57 female mice (8–10 wk old; Charles River) were inoculated with NTUH-K2044 (25 or 250 CFUs/50 µL/mouse) using a previously published intubation-mediated intratracheal instillation method [2]. For body temperature monitoring, a temperature transponder was subcutaneously implanted into each mouse one week before infection. Body weight (BW) and body temperature (BT) were measured twice a day to evaluate health status of infected mice.

PET/CT imaging in infected mice

A 7.4-MBq dose of a radiotracer (¹⁸F-FDS or ¹⁸F-FDG) was injected intravenously into each mouse via the tail vein. The mice were then anesthetized with 1.5% isoflurane and placed at the center of the field of view. PET imaging was performed 1 h after inoculation using a microPET-R4 scanner (Siemens) and then followed by CT (microCAT-II; Siemens). Images were reconstructed using an ordered-subsets expectation-maximum algorithm. ROIs were expressed as percentage injected dose (%ID)/g. CT imaging was performed for 10 min immediately after PET imaging for anatomic co-registration and attenuation correction. Mice were sacrificed immediately after imaging, and then tissues and organs of interest were removed, weighed, and counted. Bacterial enumeration from infected lungs were performed using published methods [2]. Briefly, lungs were collected, weighed, and homogenized in 1 ml PBS. 10 µl aliquots were spotted onto a LB-agar plates to allow bacterial growth for up to 2 days. Bacterial CFUs were back calculated based on dilution factor, lung weight, and estimated tissue density [2].

Monitoring disease progression in hv kp infection mice

Albino C57 female mice were intratrachealy inoculated with 25 CFU NTUH-K2044/mouse to induce lung infection (n = 8). ¹⁸F-FDS/PET/CT was performed to monitor disease progression in lungs for up to 3 days post infection (p.i.). Lung regions of interests (ROIs) were calculated based on PET images.

Assessment of response to antibiotic treatment in mice

For treatment studies, meropenem, a clinically available antibiotic was injected IP with q12h of 400 mg/kg/day for up to 3 days. Two different inoculums (25 vs. 250 CFU/mouse) and two different time points for the first dose of meropenem (24 h vs. 36 h post infection (p.i.)) were used in our studies (n = 8). ¹⁸F- FDS)/PET, followed by CT imaging was performed at 48 h or 72 h p.i. to monitor treatment efficacy. Regions of interests (ROIs) in the lung were estimated based on PET/CT fused images.

Differentiation between responders and non-responders to antibiotic treatment in mice

Each mouse was intratrachealy inoculated with 250 CFU of NTUH-K2044 to induce lung infection (n = 8). For treatment studies, meropenem was injected IP with q12h of 400 mg/kg/day for 3 days (a total 6 doses) and the first dose started at 24 h post infection (p.i.).¹⁸F-FDS/PET or ⁸F-FDG/PET imaging followed by CT imaging was performed once daily for up to 3 days to monitor treatment progression. Regions of interests (ROIs) in the lung were estimated from the PET-CT fused images for ¹⁸F-FDS uptake. Biodistribution studies were performed after the imaging on day 4 p.i..

Preliminary studies in monitoring the degree of antibiotic treatment adequacy.

Albino C57 female mice were intratrachealy inoculated with 250 CFU/mouse NTUH-K2044 to induce lung infection (n = 8). To test adequacy degree of antibiotic treatment, the meropenem was IP injected with q12h of 400 mg/kg/day for 3 or 6 doses of meropenem and the first dose started at 24 h p.i., respectively. ¹⁸F-FDS PET/CT imaging was performed to monitor treatment. Lung regions of interests (ROIs) were calculated based on PET images.

Statistical analyses

Statistical comparisons were performed using the one-way analysis of variance (ANOVA) (GraphPad Software Inc., City, State) or T test. P < 0.05 was considered statistically significant. P > 0.05 was considered statistically not significant.

Bacterial Uptake Assays

Similar with the results obtained from JSKP0001 [5], uptakes of ¹⁸F-FDS and ¹⁸F-FDG in NTUH-K2044 were increased over bacteria CUFs in vitro, reaching a plateau at about 10⁸ CFUs/mL (10% vs. 15% for ¹⁸F-FDS and ¹⁸F-FDG, respectively). Both radiotracers could detect as few as 10⁶ CFUs/mL in vitro. There was no uptake of either ¹⁸F-FDS or ¹⁸F-FDG accumulated in dead bacteria.

Monitoring disease progression in hvKp infection mice

Results were shown in Fig. 1. Consistent with our previous studies using JSKP0001, CT clearly showed increased area of lung consolidation over infection time, ¹⁸F-FDS/PET also showed enhanced lung uptake on the corresponding lung consolidation area. Moreover, dramatic tracer uptake was detected on day 3 p.i., with the average uptake of 2.5 ± 1.2% ID/g. The lung uptake ratios were 3.7 (day 2/day 1 p.i.) and 11.5 (day 3 to day 1), respectively. Half mice survived for 2 days, and the other half survived for 3 days p.i., indicating the high virulence of NTUH-K2044. Average bacterial burdens in infected lungs for moribund mice after 3 days p.i. were 8.5 ± 2.1*10^8 CFU/mL (n = 3). BW and BT slowly dropped from day 2 to day 3 p.i., reaching endpoints on day 3 p.i..

Assessment of antibiotic treatment response in mice

For mice infected with 25 CFU NTUH-K2044 and the first dose of meropenem given at 24 h p.i., all mice were healthy for 3 more days after infection without significant changes in BW and BT. No visible lung uptake was seen on ¹⁸F-FDS/PET images for all the mice. For mice infected with 250 CFU hvKp, all mice rapidly developed obvious infection symptoms at 24 p.i., with up to a 10% reduction in BT and BW. When the first dose of the antibiotic treatment was given at ~ 36 h p.i., the subsequent ¹⁸F-FDS/PET/CT imaging (performed at 48 h p.i.) showed serious lung infection with high ¹⁸F-FDS uptake in lungs for all mice (3.2 ± 2.2%ID/g). However, the health situation for all mice deteriorated sharply with no mice survived beyond 48 h p.i., indicating the high virulence of NTUH-K2044. The infection failed to be prohibited if the treatment was started later. However, when the first dose of meropenem was given at 24 h p.i. instead, the infection progression was highly reduced. ~90% mice did not show any significant reduction in BW and BT for 2 days and showed great improvement on day 3 after a total of 6 doses of meropenem treatment. Overall, 87.5% of the mice survived for 3 days post treatment. BT increased significantly from 26 ± 2 to 35 ± 2 ^oC on day 3 post meropenem injection, indicating the effectiveness of antibiotic treatment. The first dose of meropenem treatment introduced at different infection times greatly altered the treatment profiles. Lung uptake of ¹⁸F-FDS dropped quickly from 3.2 ± 2.2 to 0.62 ± 0.24% ID/g at 48 h p.i., when the first dose of meropenem was introduced at 36 h vs. 24 h p.i. (Fig. 2), indicating the importance of the optimal time window for introducing the treatment. In summary, an optimal treatment profile was obtained with a better survival rate: animal was infected with 250 CFU/mouse and antibiotic treatment was initiated at 24 h p.i..

Differentiation between responders and non-responders to antibiotic treatment in mice using ¹⁸F-FDS/PET or ¹⁸F-FDG/PET.

75% of the mice were classified as responders to antibiotic treatment. Lung uptake of ¹⁸F-FDS was 0.74 ± 0.23, 0.43 ± 0.14, and 0.41 ± 0.16% ID/g for day 2, 3, and 4 p.i., respectively. Reduction of > 40% in ¹⁸F-FDS uptake was observed with significant reduction from day 2 to day 3 p.i. (p < 0.05). No further significant reduction in ¹⁸F-FDS uptake was seen after two additional doses of meropenem (p > 0.5) (Figs. 3 and 4). 25% of the mice were classified as non-responders (Fig. 4). ¹⁸F-FDG was also used to compare with ¹⁸F-FDS, but all mice showed increased lung uptake of ¹⁸F-FDG throughout 4 days p.i. (Fig. 4). Average lung uptake of ¹⁸F-FDG was 6.32 ± 1.98, 7.53 ± 2.44, and 9.35 ± 2.14% ID/g on day 2, 3, and 4 p.i., respectively. Biodistribution data at day 4 p.i. for ¹⁸F-FDS showed the radioactivity localized mainly in large intestine (3.39 ± 2.84%ID/g) and kidney (2.90 ± 1.85% ID/g). The average lung uptake was 0.48 ± 0.30% ID/g. ¹⁸F-FDG uptake mainly accumulated in heart (29.96 ± 24.55% ID/g) and lung (13.28 ± 4.02% ID/g) (Fig. 5). The biodistribution data were comparable to results obtained with PET.

Monitoring the degree of antibiotic treatment adequacy using ¹⁸F-FDS/PET.

When treatments with total 3 doses of meropenem were used, 7 out of 8 mice survived for 3 days p.i., with similar lung takes of 1.2 ± 0.5 and 1.3 ± 0.4% ID/g on day 2 and 3 p.i., respectively. All those 7 mice showed clear infection symptoms with average BT of 25 ± 4 and 31 ± 1 oC on day 2 and 3 p.i., respectively, further indicating that lung infection progression on day 3 was temporarily inhibited by 3-dose antibiotic treatment. However, 6 out of 7 mice died in the morning of day 4 p.i. and only one mouse survived for PET imaging on day 4 p.i.. Lung uptake for this mouse was firstly decreased from 0.8 to 0.4% ID/g on day 2 to day 3 p.i., but rapidly increased to 23% ID/g on day 4 p.i. (Fig. 6).

HvKp is an emerging variant of classical kp that is known to cause serious debilitating infections in immunocompetent individuals, including bacteremia, pneumonia, and soft tissue infections. It was reported that the mortality rate was very high in hvKp associated infections (87.5%) than classical kp associated infections (35.7%) due to multidrug resistance [12, 13]. Therefore, it is important to monitor disease progression of HvKp patients, especially those with underlying conditions like diabetes and respiratory disorders and prolonged hospital stay to prevent possible spread of Hv-Kp infections [13].

For most animal studies with bacterial infections, antibiotic treatment was usually initiated either immediately or within a few hours after infection, probably due to the rapid infection progression in mice [14]. However, patients do not get antibiotic treatment until clear infection symptoms are diagnosed. To better mimic clinical settings, it is of the upmost importance to monitor response to antibiotic treatment early enough to allow successful therapy, but not too early, to allow evidence of clinical response for patients with bacterial infections [11]. Thus, we tried to start the treatment when visible lung infection was developed based on ¹⁸F-FDS PET. At first, we tried to use JSKP0001 for treatment studies because this strain was bioluminescent emitting kp strain and our lab has established a good infection model with a series of successful ¹⁸F-FDS PET imaging data published [5]. But 100% death rate was obtained within 2 days p.i. when the treatment was started on the day with detectable lung uptake of ¹⁸F-FDS (usually around 24-36 h p.i.). Based on the published data by our collaborators, NTUH-K2044 was reported to be a highly virulent strain of K. pneumoniae with a LD₅₀ of 23.3 but was very drug sensitive to meropenem. Full protection from respiratory disease was achieved with the 400 mg/kg/day treatment, and meropenem ED50 was estimated to be 221 mg/kg/day [14]. We then decided to use NTUH-K2044 for this study.

Our in vitro tracer uptake demonstrated binding affinity of both ¹⁸F-FDS and ¹⁸F-FDG to live NTUH-K2044, but not dead one, was dose dependent in a range of 10^6-10^8 CFU/mL, indicating that the uptakes were NTUH-K2044 specific. Due to low LD₅₀ of NTUH-K2044, low bacterial inoculum (25 CFU/mouse) were used for animal inoculation for disease progression studies. ¹⁸F-FDS /PET/CT imaging showed increased lung uptake over 3 days p.i. with the highest lung uptake at day 3 p.i.. Up to 10^9 CFU/mL bacterial loads were obtained for those lungs with the highest tracer uptake, further indicating the correlation between ¹⁸F-FDS uptake and bacterial loads in vivo. Our imaging data demonstrated ¹⁸F-FDS to be a promising PET tracer to monitor disease progression [5]. Even with such a low inoculum (25 CFU/mouse), 50% death rate was seen for mice at 3 days p.i., indicating the high virulence of this strain [2, 14]. For the following treatment studies, at first we used this same infection model and started the treatment at 24 h p.i.. All mice kept active and healthy for the next 3 days with only 2 to 3 doses of meropenem treatments. ¹⁸F-FDS lung uptake was similar to that of normal lungs from day 1 to day 4 p.i.., indicating that the treatment might be introduced too early so that disease progression was effectively prohibited by antibiotic treatment. To better mimic clinic settings, the treatment should be started when clear lung infection was developed. According to Fig. 1, mild infection was seen on day 2 p.i., but if we started the treatment at this time or later, the study would be hindered by factors such as limited weekday left during that week, the animal infection usually happens on each Tuesday, and no ¹⁸F-FDG production during weekend. Therefore, we chose to use higher dose CFUs for animal infection to speed up disease progression for the following antibiotic treatment studies.

It has been well documented that the overuse and misuse of antibiotics has been a significant driver in causing antibiotic resistance. CDC estimates that at least 28% of antibiotics prescribed in the outpatient setting are unnecessary [15]. Therefore, it is critical to evaluate the effect of the timing of therapeutic intervention after infection and to get optimal treatment regimens in ensuring the prolonged effectiveness of these antibiotics [16,17]. When 250 CFU/mouse were used for infection, all mice developed lung infection with clear ¹⁸F-FDS uptake within 2 days p.i.. No mice survived for more than 2 days p.i. if no antibiotic was applied. To get optimal treatment regimens in minimizing the usage and maximizing the effect of antibiotic, we compared two different time points to initiate meropenem treatment. When treatment was started at 24 h p.i., at which all mice experienced up to 10% reduction in BT and BW, most animals survived for 3 days p.i. with highly improved health situations such as increased activity and BT. But BW was either dropping or not seen increase. When the treatment was initiated at 36 h p.i., no animals survived beyond 48 h with both over 20% of BW loss and BT reduction, which reached endpoints for animal euthanasian. Both BW and BT were used to evaluate health status for infected mice in this study, and they fluctuated over infection process. BT, however, was found to be a better indicator to predict infection progression. 10% BT reduction might be used as the indicator to start the treatment.

Studies have demonstrated that early failure of treatment within 48-72 h is associated with high morbidity and mortality rates and most cases occur due to inadequate response [18, 19]. The categorization of responders and non-responders is useful in screening endpoints for non-responders at the early stage, which allows the selection of an alternative antimicrobial therapy and avoiding prolonged use of inappropriate treatment [19]. This process will minimize the misuse of antibiotics and reduce the likelihood of drug resistance developing. ¹⁸F-FDG has been a reliable means of noninvasively response monitoring in various treatments such as infectious diseases, but it was not specific and cannot distinguish bacterial infections from sterile inflammation [5, 20, 21]. Studies have shown that ¹⁸F-FDS was a specific PET tracer that accumulated in gram-negative kps with high affinity and specificity [5, 22]. To distinguish responders from non-responders early on during antibiotic treatment, ¹⁸F-FDS/PET imaging was performed in lung infected mice using the optimal treatment regimens obtained above. There were 25% animals not responsive to meropenem treatments with about 2-fold increased lung uptake on day 3 to day 1 p.i.. For those non-responders, meropenem might not be the optimal antibiotic. Contrary to ¹⁸F-FDS, ¹⁸F-FDG/PET imaging demonstrated completely different pattern: instead of decreased lung uptake, PET ROIs demonstrated significantly increased lung uptake over treatment (Fig. 4). Our data clearly showed ¹⁸F-FDS/PET was useful in differentiating between responders and non-responders, but not ¹⁸F-FDG. On day 4 p.i. after the 6^th dose of meropenem, lung tissues were collected at the end of imaging for biodistribution. Serious lung inflammation was seen for all mice, which explained the high ¹⁸F-FDG uptake in lungs during all the treatment processes. This indicates that ¹⁸F-FDG was not an optimal tracer to monitor treatment efficacy in kp infection model.

The global rise in antibiotic resistance poses a significant threat, diminishing the efficacy of common antibiotics against widespread bacterial infections [23]. It is essential to minimize the total amount of antibiotics used. However, inadequate antibiotic treatment might increase the total bacterial burden on the host over the length of the infection and increase the risk of antibiotic resistance [24]. To test this, we treated the animals using 3-dose versus 6-dose meropenem plans and performed ¹⁸F-FDS PET imaging to monitor the treatment response. It was found lung infection was only temporarily inhibited by 3-dose antibiotic treatment, but most mice died in the morning of day 4 p.i.. The surviving mouse had a decreased lung uptake first but quickly bounced back with a 58-fold uptake increase on day 4 p.i., which indicates that enough antibiotic treatment is critical to ensure all the bacteria are killed, otherwise bacteria would grow significantly greater than before and become resistant afterwards. More studies are needed to further confirm the findings.

In summary, our study was limited by factors such as the number of animals studied, the availability of ¹⁸F-FDG, high virulence and rapid disease progression of NTUH-K2044 (when higher inoculum was used), overall poor animal health status, and low survival rates, etc.. Based on the data from disease progression studies (Fig. 1), animals did not develop high degree of lung infection until day 3 p.i. when 25 CFU/mouse was used for infection. Therefore, in the future, we might choose to use 25 CFU as inoculum on Friday late afternoon, then start the antibiotic treatments on the following Monday. This treatment profile would expand our study up to 5 days which might reduce some of the limitations mentioned above.

¹⁸F-FDS/PET/CT imaging was able to monitor disease progression over infection time. It was feasible to use 250 CUF for infection and treatment starting point of 24 h p.i. to monitor antibiotic efficacy. ¹⁸F-FDS was a promising PET tracer that can be used to differentiate responders from non-responders to antibiotic treatment, but ¹⁸F-FDG not, mostly due to the presence of high degree of sterile inflammation before and after treatment.

Author contributions Li, Junling:designed experiments, performed bacterial culture and biodistribution, analyzed data, interpreted results, and wrote manuscript. Zheng, Huaiyu: performed PET/CT imaging. Olson, Jenna: performed bacterial culture and analyzed bacterial enumeration data. Warawa, Jonathan B: performed mouse lung infection. Ng, Chin K: interpreted imaging data and designed the experiment. All authors reviewed the final manuscript and approved submissions.

Funding This study was supported by NIH NIAD R21 Al156332-01. No other potential conflict of interest relevant to this article was reported.

Data Availability Data are available from the authors on request.

Conflict of Interest The authors declare no competing interests.

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Differentiation between responders and non-responders to antibiotic treatment in mice using ¹⁸F-Fluorodeoxysorbitol/PET

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Abstract

Figures

Introduction

Materials and Methods

Bacterial Uptake Assays

Animal Models

PET/CT imaging in infected mice

Assessment of response to antibiotic treatment in mice

Differentiation between responders and non-responders to antibiotic treatment in mice

Statistical analyses

Results

Bacterial Uptake Assays

Monitoring disease progression in hvKp infection mice

Assessment of antibiotic treatment response in mice

Discussion

Summary

Declarations

References

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