Transient intestinal colonization by a live-attenuated oral cholera vaccine induces protective immune responses in streptomycin-treated mice

AbstractCurrent mouse models for evaluating the efficacy of live oral cholera vaccines (OCVs) have important limitations. Conventionally raised adult mice are resistant to intestinal colonization by Vibrio cholerae, but germ-free mice can be colonized and have been used to study OCV immunogenicity. However, germ free animals have impaired immune systems and intestinal physiology; also, live OCVs colonize germ free mice for many months, which does not mimic the clearance kinetics of live OCVs in humans. Here, we leverage antibiotic-treated, conventionally raised adult mice to study the effects of transient intestinal colonization by a live OCV V. cholerae strain. In a single dose vaccination regimen, we found that HaitiV, a live-attenuated OCV candidate, was cleared by streptomycin treated adult mice within a week after oral inoculation. This transient colonization elicited far stronger adaptive immune correlates of protection against cholera than did inactivated whole-cell HaitiV. Infant mice from HaitiV vaccinated dams were also significantly protected from choleric disease than pups from inactivated-HaitiV dams. Our findings establish the benefits of antibiotic treated mice for live OCV studies as well as its limitations and underscore the immunogenicity of HaitiV.ImportanceOral cholera vaccines (OCVs) are being deployed to combat cholera but current killed OCVs require multiple doses and show little efficacy in young children. Live OCVs have the potential to overcome these limitations but small animal models for testing OCVs have shortcomings. We used an antibiotic treatment protocol for conventional adult mice to study the effects of short-term colonization by a single dose of HaitiV, a live OCV candidate. Vaccinated mice developed vibriocidal antibodies against V. cholerae and delivered pups that were resistant to cholera, whereas mice vaccinated with inactivated HaitiV did not. These findings demonstrate HaitiV’s immunogenicity and suggest that this antibiotic treatment protocol will be useful for evaluating the efficacy of live OCVs.

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Transient Intestinal Colonization by a Live-Attenuated Oral Cholera Vaccine Induces Protective Immune Responses in Streptomycin-Treated Mice

Journal of Bacteriology ◽

10.1128/jb.00232-20 ◽

2020 ◽

Vol 202 (24) ◽

Cited By ~ 1

Author(s):

Bolutife Fakoya ◽

Brandon Sit ◽

Matthew K. Waldor

Keyword(s):

Single Dose ◽

Antibiotic Treatment ◽

Treatment Protocol ◽

Small Animal ◽

Intestinal Colonization ◽

Content Type ◽

Immune Correlates ◽

Adult Mice ◽

Clearance Kinetics ◽

Cholera Vaccines

ABSTRACT Current mouse models for evaluating the efficacy of live oral cholera vaccines (OCVs) have important limitations. Conventionally raised adult mice are resistant to intestinal colonization by Vibrio cholerae, but germfree mice can be colonized and have been used to study OCV immunogenicity. However, germfree animals have impaired immune systems and intestinal physiology; also, live OCVs colonize germfree mice for many months, which does not mimic the clearance kinetics of live OCVs in humans. In this study, we leveraged antibiotic-treated, conventionally raised adult mice to study the effects of transient intestinal colonization by a live OCV V. cholerae strain. In a single-dose vaccination regimen, we found that HaitiV, a live-attenuated OCV candidate, was cleared by streptomycin-treated adult mice within 2 weeks after oral inoculation. This transient colonization elicited far stronger adaptive immune correlates of protection against cholera than did inactivated whole-cell HaitiV. Infant mice from HaitiV-vaccinated dams were also significantly more protected from choleric disease than pups from inactivated-HaitiV-vaccinated dams. Our findings establish the benefits of antibiotic-treated mice for live-OCV studies as well as their limitations and underscore the immunogenicity of HaitiV. IMPORTANCE Oral cholera vaccines (OCVs) are being deployed to combat cholera, but current killed OCVs require multiple doses and show little efficacy in young children. Live OCVs have the potential to overcome these limitations, but small-animal models for testing OCVs have shortcomings. We used an antibiotic treatment protocol for conventional adult mice to study the effects of short-term colonization by a single dose of HaitiV, a live-OCV candidate. Vaccinated mice developed vibriocidal antibodies against V. cholerae and delivered pups that were resistant to cholera, whereas mice vaccinated with inactivated HaitiV did not. These findings demonstrate HaitiV’s immunogenicity and suggest that this antibiotic treatment protocol will be useful for evaluating the efficacy of live OCVs.

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Effect of Parenteral Antibiotic Administration on Establishment of Intestinal Colonization by Candida glabrata in Adult Mice

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.1.438-440.2005 ◽

2005 ◽

Vol 49 (1) ◽

pp. 438-440 ◽

Cited By ~ 32

Author(s):

Nicole J. Pultz ◽

Usha Stiefel ◽

Mahmoud Ghannoum ◽

Marion S. Helfand ◽

Curtis J. Donskey

Keyword(s):

Antibiotic Treatment ◽

Candida Glabrata ◽

Antibiotic Administration ◽

Intestinal Colonization ◽

Parenteral Antibiotic ◽

Adult Mice

ABSTRACT We examined the effect of antibiotic treatment on establishment of intestinal colonization by Candida glabrata in adult mice. Subcutaneous ceftriaxone, piperacillin-tazobactam, clindamycin, and metronidazole promoted increased density of stool colonization, whereas cefepime, levofloxacin, and aztreonam did not. These findings suggest that antibiotics that inhibit intestinal anaerobes promote C. glabrata colonization.

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Measurement of the Intestinal pH in Mice under Various Conditions Reveals Alkalization Induced by Antibiotics

Antibiotics ◽

10.3390/antibiotics10020180 ◽

2021 ◽

Vol 10 (2) ◽

pp. 180

Author(s):

Kouki Shimizu ◽

Issei Seiki ◽

Yoshiyuki Goto ◽

Takeshi Murata

Keyword(s):

Antibiotic Treatment ◽

High Protein Diet ◽

Intestinal Bacteria ◽

High Protein ◽

Protein Diet ◽

Germ Free ◽

Treatment Regimens ◽

Ph Values ◽

Specific Pathogen ◽

The Stability

The intestinal pH can greatly influence the stability and absorption of oral drugs. Therefore, knowledge of intestinal pH is necessary to understand the conditions for drug delivery. This has previously been measured in humans and rats. However, information on intestinal pH in mice is insufficient despite these animals being used often in preclinical testing. In this study, 72 female ICR mice housed in SPF (specific pathogen-free) conditions were separated into nine groups to determine the intestinal pH under conditions that might cause pH fluctuations, including high-protein diet, ageing, proton pump inhibitor (PPI) treatment, several antibiotic treatment regimens and germ-free mice. pH was measured in samples collected from the ileum, cecum and colon, and compared to control animals. An electrode, 3 mm in diameter, enabled accurate pH measurements with a small amount of gastrointestinal content. Consequently, the pH values in the cecum and colon were increased by high-protein diet, and the pH in the ileum was decreased by PPI. Drastic alkalization was induced by antibiotics, especially in the cecum and colon. The alkalized pH values in germ-free mice suggested that the reduction in the intestinal bacteria caused by antibiotics led to alkalization. Alkalization of the intestinal pH caused by antibiotic treatment was verified in mice. We need further investigations in clinical settings to check whether the same phenomena occur in patients.

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Antibiotic treatment with one single dose of gentamicin at admittance in addition to a β-lactam antibiotic in the treatment of community-acquired bloodstream infection with sepsis

PLoS ONE ◽

10.1371/journal.pone.0236864 ◽

2020 ◽

Vol 15 (7) ◽

pp. e0236864 ◽

Cited By ~ 1

Author(s):

Karolina Liljedahl Prytz ◽

Mårten Prag ◽

Hans Fredlund ◽

Anders Magnuson ◽

Martin Sundqvist ◽

...

Keyword(s):

Single Dose ◽

Bloodstream Infection ◽

Antibiotic Treatment ◽

Lactam Antibiotic

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Corrigendum: A Single Dose of 5-MeO-DMT Stimulates Cell Proliferation, Neuronal Survivability, Morphological and Functional Changes in Adult Mice Ventral Dentate Gyrus

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2019.00079 ◽

2019 ◽

Vol 12 ◽

Author(s):

Rafael Vitor Lima da Cruz ◽

Thiago C. Moulin ◽

Lyvia Lintzmaier Petiz ◽

Richardson N. Leão

Keyword(s):

Cell Proliferation ◽

Single Dose ◽

Dentate Gyrus ◽

Functional Changes ◽

Adult Mice

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452. Antibiotic Duration, but Not Size, Impacts Clinical Cure of Limited Skin and Soft-Tissue Infection After Incision and Drainage

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.525 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S222-S223

Author(s):

Jason G Lake ◽

Stephanie Fritz

Keyword(s):

Antibiotic Therapy ◽

Antibiotic Treatment ◽

Clinical Cure ◽

Day Treatment ◽

Treatment Protocol ◽

Chi Square ◽

Incision And Drainage ◽

Exact Test ◽

Days Of Therapy ◽

Antibiotic Duration

Abstract Background Incision and drainage (I&D) is the most common treatment for skin abscesses. A recent randomized clinical trial (RCT) of outpatients with limited (≤5 cm) skin abscesses demonstrated antibiotic therapy with clindamycin or trimethoprim-sulfamethoxazole (TMP-SMX) was superior to I&D alone. We performed a subgroup analysis to measure the effect of antibiotic duration and abscess size on clinical cure at 7–10 days after antibiotic completion. Methods Participants with complete data regarding adherence to the 10-day treatment were included. Demographic and baseline clinical features were compared using t-test, Pearson’s chi-square or Fisher’s exact test, or a non-parametric equivalent where appropriate. Largest abscess dimension (cm) was dichotomized by median size. The effect of antibiotic duration, abscess size (≤ median vs. >median) and covariates on clinical cure were measured using logistic regression. Breslow-Day Test for Homogeneity was used to assess the interaction between treatment and abscess size. Results Of 786 participants in the intention-to-treat analysis, complete adherence data were available for 680 (87%) participants. Of these, 463 (68%) received either antibiotic: 421 (91%) completed 10 days of therapy, 29 (6.3%) ≤7 days and 20 (4.3%) ≤5 days. Only antibiotic treatment duration was associated with clinical cure (table). Odds of clinical cure were 1.7 (95% CI: 1.5, 2.0) times higher for each additional day of treatment. Median abscess size was 2.5 cm (range: 0.2–5); 364 participants had abscesses ≤ median vs. 316 >median. Assessed continuously, abscess size was not associated with cure within antibiotic groups (table) or between placebo and treatment groups (OR 0.94, 95% CI: 0.58–1.5). Stratifying on size, no significant interaction was observed with antibiotic treatment (Breslow-Day P = 0.13). Conclusion Adherence to the treatment protocol was high. These data suggest that longer courses of antibiotic therapy in conjunction with I&D are associated with successful treatment of limited skin abscesses. Size was not associated with clinical cure. Prospective RCTs to determine the optimal length of treatment are needed. Disclosures All authors: No reported disclosures.

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Prospective study of Clostridium difficile intestinal colonization and disease following single-dose antibiotic prophylaxis in surgery.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.35.1.208 ◽

1991 ◽

Vol 35 (1) ◽

pp. 208-210 ◽

Cited By ~ 106

Author(s):

G Privitera ◽

P Scarpellini ◽

G Ortisi ◽

G Nicastro ◽

R Nicolin ◽

...

Keyword(s):

Single Dose ◽

Clostridium Difficile ◽

Prospective Study ◽

Antibiotic Prophylaxis ◽

Intestinal Colonization

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PICs in motoneurons do not scale with the size of the animal: a possible mechanism for faster speed of muscle contraction in smaller species

Journal of Neurophysiology ◽

10.1152/jn.00045.2017 ◽

2017 ◽

Vol 118 (1) ◽

pp. 93-102 ◽

Cited By ~ 7

Author(s):

Seoan Huh ◽

Ramamurthy Siripuram ◽

Robert H. Lee ◽

Vladimir V. Turkin ◽

Derek O’Neill ◽

...

Keyword(s):

Electrical Properties ◽

Muscle Fibers ◽

Small Animal ◽

Spinal Motoneurons ◽

Persistent Inward Currents ◽

Firing Rates ◽

Adult Mice ◽

Inward Currents ◽

Animal Size

The majority of studies on the electrical properties of neurons are carried out in rodents, and in particular in mice. However, the minute size of this animal compared with humans potentially limits the relevance of the resulting insights. To be able to extrapolate results obtained in a small animal such as a rodent, one needs to have proper knowledge of the rules governing how electrical properties of neurons scale with the size of the animal. Generally speaking, electrical resistances of neurons increase as cell size decreases, and thus maintenance of equal depolarization across cells of different sizes requires the underlying currents to decrease in proportion to the size decrease. Thus it would generally be expected that voltage-sensitive currents are smaller in smaller animals. In this study, we used in vivo preparations to record electrical properties of spinal motoneurons in deeply anesthetized adult mice and cats. We found that PICs do not scale with size, but instead are constant in their amplitudes across these species. This constancy, coupled with the threefold differences in electrical resistances, means that PICs contribute a threefold larger depolarization in the mouse than in the cat. As a consequence, motoneuronal firing rate sharply increases as animal size decreases. These differences in firing rates are likely essential in allowing different species to control muscles with widely different contraction speeds (smaller animals have faster muscle fibers). Thus from our results we have identified a possible new mechanism for how electrical properties are tuned to match mechanical properties within the motor output system. NEW & NOTEWORTHY The small size of the mouse warrants concern over whether the properties of their neurons are a scaled version of those in larger animals or instead have unique features. Comparison of spinal motoneurons in mice to cats showed unique features. Firing rates in the mouse were much higher, in large part due to relatively larger persistent inward currents. These differences likely reflect adaptations for controlling much faster muscle fibers in mouse than cat.

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