Oedema and angioneurotic oedema

CNS effects: dizziness, headache

Facial paraesthesia

Muscle cramps

Visual disturbances

Tinnitus

Dyspnoea

Fever

Eosinophilia

Irreversible ototoxicity (vestibular and cochlear) (wide range of incidence, 7–90%) (26)

Reversible nephrotoxicity (10–20%; higher incidence in critical patients due to affectation of the renal function)

Potentiation of myasthenia gravis

Teratogenic (irreversible bilateral congenital deafness)

Oedema

CNS effects: dizziness, headache

Muscle cramps

Visual disturbances

Dyspnoea

Ototoxicity (hearing loss and tinnitus) (26)

Nephrotoxicity

Neuromuscular block (muscle paralysis and apnoea)

Potentiation of myasthenia gravis

Gastrointestinal symptoms: diarrhoea, nausea, vomiting, anorexia, weight loss, cramps, dysphagia, abdominal pain (1–5%)

Photosensitivity, usually mild (unclear incidence)

Tooth discoloration

Tinnitus

Exanthema

Urticaria and angioneurotic oedema

Oral candidiasis

Gastrointestinal inflammation and ulceration, oesophagitis, pseudomembranous colitis

Intracranial hypertension, pseudotumour cerebri (<1%)

Hypersensitivity reactions (<1%): exfoliative dermatitis, Stevens–Johnson syndrome

Delayed skeletal development in infants

Gastrointestinal disorders, generally mild: diarrhoea (5%), nausea (7%), vomiting (2%), constipation (3%), abdominal pain (2%), dyspepsia (2%)

Photosensitivity (moxifloxacin most associated with phototoxic reaction), rash (2%), pruritus (1%)

CNS disorders: dizziness (3%), headache (6%), insomnia (4%), restlessness

Dyspnoea (1%)

Vaginitis (1%)

Hypoglycaemia (more with moxifloxacin) (27)

The incidences given above correspond to adverse reactions of levofloxacin, from a safety profile in adults based on 29 Phase III trials including 7537 patients.

Tendonitis, tendon rupture: risk increases with age, renal disease, female sex, non-obese (28)

Peripheral neuropathy

QTc prolongation (RR 1.7–3.3, higher with moxifloxacin) (29)

Torsade de pointes

Exacerbation of myasthenia gravis

Clostridium difficile-associated diarrhoea

Severe hepatic disorders, including fulminant hepatitis

Seizure risk in susceptible patients (such as those with epilepsy, renal insufficiency or brain injury) (with ciprofloxacin) (30)

Mental health effects: agitation, nervousness, disorientation, attention disturbances, memory impairment, delirium

Aortic rupture (OR 2.71), especially with exposure >14 days (31)

CNS effects: confusion, delirium, headache

Gastrointestinal effects: diarrhoea, nausea, vomiting

Bone marrow suppression

Hypersensitivity reaction

Serious and fatal blood dyscrasias: aplastic anaemia, leukopenia, thrombocytopenia, haemolytic anaemia, leukaemia; idiosyncrasy reaction; incidence of 1/40 000

Grey baby syndrome

Ciprofloxacin: 70%

Levofloxacin: 99%

Moxifloxacin: 89%

Oflofloxacin: 98%

Ciprofloxacin: 26%

Levofloxacin: 30–50%

Moxifloxacin: >50%

Oflofloxacin: >50%

2.5

Streptomycin: 1–2

Gentamicin: 4

6–12

Doxycycline: 18

Ciprofloxacin: 4–6.6

Levofloxacin: 7

Moxifloxacin: 10–14

Oflofloxacin: 7

This was a randomized, blinded placebo-controlled trial.

Participants: 20 African green monkeys (10 males and 10 females).

Challenge: pneumonic plague from Y. pestis CO92 strain by aerosol exposure.

Intervention:

-

initiated when the animal presented at least 4 hours of sustained fever;

-

administration: not described;

-

treatment regimen: moxifloxacin, dose not specified;

-

placebo: not specified; and

-

duration of treatment: 10 days.

20 African green monkeys included: 10 received placebo, 10 received levofloxacin.

Main outcome measured: survival/death at 30 days after completion of treatment:

-

placebo group: 10/10 (100%) died between 83 and 139 hours post-treatment; and

-

moxifloxacin group: 0/10 (0%) died.

Funding: not mentioned.

Competing interests: not reported.

This was a randomized, placebo-controlled trial. Randomization was performed using a computerized system, using a random number generator. It was unclear whether randomization was performed for the three cohorts receiving different doses of exposure, or for attribution of placebo versus intervention.

Participants:

-

26 African green monkeys, weight 3–8 kg, aged 2 years and older, with no systemic antibiotics or topical mupirocin ointment received in the 28 days and 14 days before Y. pestis challenge exposure, retrospectively;

-

SC implanted telemetry allowing continuous monitoring of body temperature, intrathoracic pressure, respiratory rate, heart rate and electrocardiographic activity; and

-

femoral venous catheter inserted into each participant.

Intervention:

-

initiated within 6 hours of the onset of fever (≥39 °C for >1 hour);

-

administration: IV through a 30-minute infusion;

-

treatment regimen: levofloxacin, daily dose of 8 mg/kg followed by 2 mg/kg 12 hours later;

-

placebo: 5% dextrose in water; and

-

duration of treatment: until death/euthanasia or completion of 20 doses of the intervention (10 days).

26 African green monkeys included: 7 received placebo, 17 received levofloxacin; 2 were removed from analysis (one before and one after Y. pestis challenge exposure, due to health reasons for the first case and due to start of treatment before presenting fever for the second case).

Main outcome measured: survival/death at 28 days post-challenge exposure:

-

placebo group: 7/7 (100%) died/were euthanized before day 5 post-challenge exposure;

-

levofloxacin group: 1/17 (6%) died:

-

16 survived with 10 days of treatment until euthanasia on day 28 post-challenge exposure, no evidence of clinical relapse between end of treatment and time of euthanasia; and

-

1 case was euthanized on day 9 post-challenge exposure due to a gastric complication (vomiting and inability to retain food); blood culture for Y. pestis was positive at the start of the treatment, but negative on days 4–7 and at post-mortem, showing no evidence of treatment failure.

Conducted at the Lovelace Respiratory Research Institute, Albuquerque (NM), USA.

Funding: “This project was funded by the National Institute of Allergy and Infectious Diseases, www​.niaid.nih.gov, contract N01-AI-4000951. The funding agency’s Project Officer approved the study design and manuscript. The Project Officer did not have a role in data collection and analysis, decision to publish, or conclusions.”

Competing interests: “The authors have declared that no competing interests exist.”

This manuscript summarizes the assessment of plazomicin through six cohorts from three studies.

The total number of African green monkeys were randomized into six exposure cohorts, using a computerized system with a random number generator.

Participants:

-

64 African green monkeys (at least 2 males and 2 females per cohort);

-

telemetry implanted within the peritoneum for continuous monitoring of fever, respiratory rate and heart rate; and

-

femoral venous catheter inserted in each participant.

Intervention:

-

initiated within 6 hours of the onset of sustained fever (>39 °C for 1 hour for the first 2 studies; >1.5 °C above baseline body temperature for 1 hour for the third study);

-

administration: IV through a 30-minute infusion;

-

treatment regimen: plazomicin, daily dose of 6.25, 12.5 or 25 mg/kg, divided into two doses: 90% of the daily dose followed by 10% 12 hours later;

-

placebo: saline for injection; and

-

duration of treatment: 5 or 10 days, depending on the study cohort.

64 African green monkeys included across the six cohorts: 12 received placebo, 52 received plazomicin.

Main outcome measured: survival/death at 28 to 30 days post-challenge exposure:

-

placebo: 12/12 (100%) died/were euthanized between 71 and 129 hours post-challenge exposure; and

-

intervention group (plazomicin): 16/52 (30.7%) died:

-

25 mg/kg per day for 5 days: 5/16 (31.3%) died; two animals succumbed before the end of the 5-day treatment;

-

12.5 mg/kg per day for 5 days: 4/6 (66.7%) died; one animal succumbed after receiving all but one treatment doses;

-

6.25 mg/kg per day for 5 days: 5/6 (83.3%) died;

-

25 mg/kg per day for 10 days: 1/12 (8.3%) died; for the only animal that died in this cohort, the animal’s implanted temperature probe failed between time of challenge exposure and treatment and temperature was therefore measured in an alternative way (according to the authors, “this potentially delayed therapy initiation significantly, although it is difficult to know by how long”);

-

12.5 mg/kg per day for 10 days: 0/6 (0%) died; and

-

6.25 mg/kg per day for 10 days: 1/6 (16.7%) died.

Among the 16 animals treated with plazomicin that died, the cause of death was attributed to meningitis in four cases, and to CNS infection in a fifth case. Among the remaining cases, the cause of death was pneumonia (6), pneumonia/sepsis (1), resurgence of pneumonia (3) and lung damage (1).

Funding: “Federal funds from the Biomedical Advanced Research and Development Authority, Office of the Assistant Secretary for Preparedness and Response, Office of the Secretary, Department of Health and Human Services, under Contract No. HHSO100201000046C.”

Competing interests: not reported.

This manuscript summarizes the assessment of different antibiotic regimens in eight cohorts of baboons from a first experiment (A). There are no details on randomization or allocation of the monkeys to the different cohorts, and no details on whether investigators were blinded.

This manuscript also summarizes the findings in a group of baboons infected with plague after starting antibiotic therapy with a group of healthy baboons, to assess contagiousness (B).

Participants:

-

19 baboons (males and females), weight 3.8–12 kg for (A); and

-

49 baboons for (B), including 43 infected and 6 healthy baboons.

Intervention:

-

initiated immediately or within 12, 24 or 48 hours of the onset of fever;

-

administration: orally or IM;

-

treatment regimen:

-

(A): streptomycin 100 mg/day IM, or amikacin 100 mg/day, IM, or tetracycline 100 mg/day, IM, or ceftriaxone 60 mg/day, IM, or doxycycline 32 mg/day, orally, or rifampicin 160 mg/day, orally, or ofloxacin 80 mg/day, orally, or ciprofloxacin 60 mg/day, orally; daily dose divided in two doses and administered every 12 hours;

-

(B): streptomycin 100 mg/day, IM, or amikacin 100 mg/day, IM, or netilmicin 20 mg/day, IM, or ceftriaxone 60 mg/day, IM, or cefotaxime 60 mg/day, IM, or rifampicin 160 mg/day, orally, or ofloxacin 80 mg/day, orally or ciprofloxacin 60 mg/day, orally; daily dose divided in two doses and administered every 12 hours;

-

control: for (B): six baboons did not receive a challenge dose by aerosol or antibiotics but were exposed to infected baboons; and

-

duration of treatment: 5–7 days.

(A) 19 baboons included: 8 groups of 2 or 3 baboons, each receiving one of the 8 antibiotics cited under Methods.

(B) 49 baboons included: 1 group of 8 baboons receiving streptomycin; 7 groups of 5 baboons, each receiving 1 of the remaining 7 antibiotics cited under Methods; 1 group of 6 baboons that did not receive a Y. pestis challenge dose and received no antibiotics (control group).

Main outcome measured:

-

(A): survival/death at 96 hours after starting treatment, and number of bacteria isolated from blood culture and oropharyngeal culture at 0, 12, 24, 36, 48 and 96 hours after starting treatment:

-

all 19 baboons survived;

-

from 12 hours onwards, cultures were negative for baboons that received streptomycin, amikacin, ceftriaxone, ofloxacin or ciprofloxacin;

-

the 2 animals that received tetracycline had a positive oropharyngeal culture at 36 and 48 hours, after negative cultures at 12 and 24 hours, with posterior negative culture at 96 hours;

-

among the 3 animals that received doxycycline, 1 presented negative cultures from 12 hours; the other 2 animals presented positive oropharyngeal culture at 12 and 24 hours with subsequent negative cultures; and

-

in the 2 animals that received rifampicin, all cultures were negative from 24 hours onwards.

Conducted at the Research Institute of Microbiology, Kirov, Russian Federation.

Funding: Ministry of Defence of the Russian Federation.

Competing interests: not reported.

This manuscript summarizes the assessment of different antibiotic regimens in 12 cohorts of baboons with no details on randomization or allocation of the baboons to the different cohorts, and no details on whether investigators were blinded.

Participants:

-

48 baboons (males and females), weight 4.1–5.6 kg.

Intervention:

-

initiated immediately after the onset of fever, inguinal adenopathy or erythema at the inoculation site;

-

administration: orally or IM;

-

treatment regimen: streptomycin 100 mg/day, IM, or kanamycin (dosage not reported), IM, or tetracycline 100 mg/day, IM, or amikacin 100 mg/day, IM, or netilmicin 20 mg/day, IM, or ceftizoxime 100 mg/day, IM, or cefotaxime 100 mg/day, IM, or ceftriaxone 60 mg/day, IM, or doxycycline 32 mg/day, orally, or ofloxacin 80 mg/day, orally, or ciprofloxacin 60 mg/day, orally, or rifampicin 160 mg/day, orally; daily dose divided in two doses and administered every 12 hours;

-

placebo: four baboons did not receive treatment; and

-

duration of treatment: 5 days for all antibiotics except tetracycline and rifampicin (7 days).

48 baboons included: groups of 4 baboons, each of which received one of the 11 antibiotics cited under Methods except kanamycin (kanamycin is cited in the text but does not appear in the findings); one group of 4 baboons with no antibiotics.

Main outcome measured: survival/death (time not specified, probably at the end of the 5- or 7-day treatment):

-

control group: all 4 baboons that did not receive any antibiotics died; and

-

all 44 baboons that received any antibiotic survived.

Conducted at the Research Institute of Microbiology, Kirov, Russian Federation.

Funding: Ministry of Defence of the Russian Federation.

Competing interests: not reported.

This was a randomized, placebo-controlled trial, not blinded. Randomization stratified by sex and day of challenge exposure (method used for randomization not provided).

Participants:

-

12 African green monkeys (6 males and 6 females), weight 3–6 kg;

-

SC implant for monitoring of body temperature, pulse and pressure every 30 minutes; respiratory rate assessed manually; and

-

central venous catheter inserted in each participant.

Intervention:

-

treated as a group, initiated when fever for 2 hours in most of the animals (fever defined as >1.5 °C above baseline body temperature for 2 hours);

-

administration: IV through a 60-minute infusion;

-

treatment regimen: ciprofloxacin, 15 mg/kg twice daily;

-

placebo: not specified; and

-

duration of treatment: 10 days.

12 African green monkeys included: 2 received placebo, 10 received levofloxacin.

Main outcome measured: survival/death at 28 days post-challenge exposure:

-

placebo group: 2/2 (100%) died at 99 and 98.5 hours post-challenge exposure; and

-

ciprofloxacin group: 1/10 (10%) died; the animal that succumbed after receiving 8 doses of ciprofloxacin had catheter failure.

Study conducted by the United States Army Medicam Research Institute of Infectious Diseases.

Sponsors: FDA/NIAID/USAMRIID Interagency Agreements.

Competing interests: not reported.

Animal: female mice.

Challenge: Y. pestis CO92 delivered by aerosol → PP; and SC → BP.

Intervention: streptomycin, gentamicin (12 or 20 mg/kg), ciprofloxacin, ofloxacin or other antibiotic not addressed in this review, IP, every 6 hours for 5 days:

-

early treatment, initiated 24 hours post-challenge exposure

-

late treatment, initiated 42 hours post-challenge exposure.

Cohort size: 15–20 (usually 20).

-

CFR for PP, early treatment:

-

streptomycin: 0/20 (0%)

-

gentamicin: 8/40 (20%) for 12 mg/kg dose; 4/20 (20%) for 20 mg/kg dose

-

ciprofloxacin: 0/35 (0%)

-

ofloxacin: 0/20 (0%)

-

CFR for PP, late treatment:

-

streptomycin: 35/85 (41%)

-

gentamicin: 26/38 (68%) for 12 mg/kg dose; 3/20 (15%) for 20 mg/kg dose

-

ciprofloxacin: 17/45 (38%)

-

ofloxacin: 8/20 (40%)

-

CFR for BP treated with streptomycin:

-

24 hours post-challenge exposure: 0/20 (0%)

-

42 hours post-challenge exposure: 6/20 (30%)

-

48 hours post-challenge exposure: 15/20 (75%)

-

54 hours post-challenge exposure: 11/20 (55%).

Animal: female outbred mice.

Challenge: intranasal fully virulent Y. pestis Kimberley53 strain (Kim53) → PP.

Intervention: initiated 24 and 48 hours post-challenge exposure, for 5 days:

-

gentamicin (3.5 mg/kg per day), by inhalation; or

-

gentamicin (3.5 mg/kg per day), SC; or

-

tobramycin (1.5 mg/kg per day), by inhalation.

Control: untreated.

Cohort size: 8 per cohort.

-

when started 24 hours post-challenge exposure, simulating PEPT:

-

gentamicin, by inhalation: 0/8 (0%); 1/8 (13%) for increased Y. pestis infection dose

-

gentamicin, SC: 5/8 (60%); 6/8 (75%) for increased Y. pestis infection dose

-

tobramycin, by inhalation: 0/8 (0%)

-

control: 8/8 (100%).

-

when started 48 hours post-challenge exposure:

-

gentamicin, by inhalation: 0/8 (0%)

-

gentamicin, SC: 8/8 (100%)

-

control: 8/8 (100%).

Animal: female BALB/c neutropenic (N) and non-neutropenic (nonN) mice.

Challenge: Y. pestis CO92 delivered by aerosol → PP.

Cohort size: 10 mice.

Intervention: levofloxacin (15 mg/kg every 12 hours) or doxycycline (40 mg/kg every 6 hours) or gentamicin (12 mg/kg every 6 hours or 24 mg/kg every 12 hours or 48 mg/kg every 24 hours), IP, initiated 24 hours post-challenge exposure, for 5 days.

Control: placebo with saline.

-

levofloxacin: nonN 0%; N 0%; control 100%

-

doxycycline: nonN 10%; N 100%; control 100%

-

gentamicin: nonN 10% (12 mg/kg every 6 hours), 0% (24 mg/kg every 12 hours) and 20% (48 mg/kg every 24 hours); N 30%, 20% and 20%, respectively; control 100%.

Animal: female BALB/c mice.

Challenge: Y. pestis CO92 delivered by aerosol → PP.

Intervention: ciprofloxacin (30 mg/kg every 12 hours) or imipenem (data not collected for this review) or ceftazidime (data not collected for this review), IP, initiated 24 hours (PEPT experiment) and 42 hours post-challenge exposure (treatment experiment), for 5 days.

Cohort size: 10 mice in the ciprofloxacin cohort.

Control: 0.85% saline.

-

ciprofloxacin as PEPT: 0%

-

ciprofloxacin as treatment: 50%.

Animal: Swiss-Webster mice.

Challenge: Y. pestis CO92 by nasal instillation → PP.

Intervention: levofloxacin at various doses from 0.1 to 15 mg/kg per day, IP, initiated 24, 36 or 48 hours post-challenge exposure for 6 days.

Control: no antibiotics.

Cohort size: not reported.

-

when started 24 hours post-challenge exposure:

-

5, 10 or 15 mg/kg: 0% died

-

1 mg/kg: 20% died

-

0.5 or 0.1 mg/kg: 100% died

-

when started 36 hours post-challenge exposure: 5 or 10 mg/kg: 10% died

-

when started 48 hours post-challenge exposure:

-

10 mg/kg: 80% died

-

5 mg/kg: 90% died

Animal: female OF1 mice.

Challenge: virulent Y. pestis strain 6/69 IV → SP.

Intervention: initiated 24 hours post-challenge exposure:

-

streptomycin (30 mg/kg every 8 hours), SC, for 2, 3 or 4 days; or

-

chloramphenicol (100 mg/kg every 8 hours), IM, for 2, 3 or 4 days; or

-

OCm (100 mg/kg or 200 mg/kg per dose), IM, as a single injection at 24 hours post-challenge exposure; or

-

OCm (200 mg/kg per dose), IM, as two injections at 24 and 48 hours post-challenge exposure.

Cohort size: 5.

-

streptomycin, SC: 1/5 (20%), 0/5 (0%) and 0/5 (0%) after 2, 3 and 4 days of treatment, respectively

-

chloramphenicol, IM: 1/5 (20%) after 4 days of treatment (no results given for 2 and 3 days)

-

OCm, IM, single injection:

-

100 mg/kg: 7/10 (70%)

-

200 mg/kg: 5/5 (100%)

-

OCm, IM, two injections: 3/5 (60%).

Animal: female Brown Norway rats.

Challenge: Y. pestis CO92 by intranasal inoculation at day 0, and at day 43 or 34 → PP PP.

Intervention: levofloxacin at various doses from 0.5 to 15 mg/kg per day, IP, or 20 mg/kg per day, orally, initiated 24 hours post-challenge exposure, for 6 days.

Delayed start at 36, 42 and 48 hours post-challenge exposure with doses of 5 and 10 mg/kg per day, IP, for 6 days.

Control: phosphate-buffered saline.

Cohort size: 6 rats per group for treatment started at 24 hours, 9 rats per group for delayed treatment and control.

-

when started 24 hours post-challenge exposure:

-

15 mg/kg: 0/6 (0%) and 2/6 (33%) at 42 and 60 days, respectively

-

10 mg/kg: 0/6 (0%) at 42 and 60 days

-

5 mg/kg: 2/6 (33%) at 42 and 60 days

-

1 mg/kg: 5/6 (83%) at 42 and 60 days

-

0.5 mg/kg: 6/6 (100%) at 42 days

-

control: 9/9 (100%) at 42 days.

-

CFR for delayed treatment:

-

at 24, 36 and 42 hours post-challenge exposure, for 10 or 5 mg/kg: 0/9 (0%) at 34 days

-

at 48 hours post-challenge exposure for 10 or 5 mg/kg: 6/9 (66%) at day 34.

Animal: Porton outbred mice. Challenge: IP Y. pestis strain GB with 5 or 6 challenge doses → SP.

Intervention:

-

ciprofloxacin, SC, 40 or 20 mg/kg every 12 hours, administered from 48 hours pre-challenge exposure to 5 days post-challenge exposure, or

-

ciprofloxacin, SC, 40 or 20 mg/kg every 12 hours, initiated 24 hours post-challenge exposure, for 5 days, or

-

doxycycline, SC, 40 or 20 mg/kg every 12 hours, administered from 48 hours pre-challenge exposure to 4 days post-challenge exposure, or

-

doxycycline, SC, 40 or 20 mg/kg every 12 hours, initiated 24 hours post-challenge exposure, for 4 days.

Cohort size: 30 mice for each dose cohort of ciprofloxacin, 25 mice for each dose cohort of doxycycline, 10 mice untreated.

-

ciprofloxacin as pre-exposure prophylaxis: 0/30 (0%) for each dose

-

ciprofloxacin as PEPT: 14/30 (46.7%) for each dose

-

doxycycline as pre-exposure prophylaxis: 15/25 (60%) for 40 mg/kg dose, 24/25 (96%) for 20 mg/kg dose

-

doxycycline as PEPT: 23/25 (92%) for 40 mg/kg dose, 25/25 (100%) for 20 mg/kg dose.

Animal: Porton outbred mice.

Challenge: Y. pestis strain GB and strain CO92 delivered by aerosol → PP.

Intervention: ciprofloxacin or doxycycline given at 40 mg/kg every 12 hours, SC, in one of the four regimens:

-

prophylaxis: administered from 48 hours pre-challenge exposure to 5 days post-challenge exposure

-

initiated immediately post-challenge exposure, for 5 days

-

initiated 24 hours post-challenge exposure, for 5 days

-

initiated 48 hours post-challenge exposure, for 5 days.

Cohort size: not reported.

-

doxycycline 100%; ciprofloxacin 0%

-

doxycycline 100%; ciprofloxacin 0%

-

doxycycline 90% and 100% for GB and CO92 strains, respectively; ciprofloxacin 0%

-

doxycycline 100%; ciprofloxacin 100%.

Animal: female BALB/c mice.

Challenge: Y. pestis CO92 delivered by aerosol → PP.

Intervention: omadacycline (5, 10, 20 or 40 mg/kg every 12 hours) or doxycycline (5, 10, 20 or 40 mg/kg every 12 hours) or ciprofloxacin (15 mg/kg every 12 hours), IP, initiated 1 hour post-challenge exposure, for 7 days.

Control: saline (0.2 mL every 12 hours), IP, for 7 days.

Cohort size: 10 mice.

-

omadacycline: 10% (40 mg/kg), 0% (other doses)

-

doxycycline: 10% (40 mg/kg), 0% (other doses)

-

ciprofloxacin: 0%.

Animal: female BALB/c inbred mice.

Challenge: Y. pestis strain GB delivered SC and by aerosol → SP and PP.

Intervention: ciprofloxacin, gatifloxacin or moxifloxacin: 2 mg every 12 hours, orally, for 7 days:

-

systemic challenge (SP): initiated 1 hour pre-challenge exposure, or 6, 18 or 24 hours post-challenge exposure

-

aerosol challenge (PP): initiated 6, 18, 30 or 48 hours post-challenge exposure.

Cohort size: 18 mice per cohort; 252 mice for each of infection route.

-

systemic challenge (SP):

-

ciprofloxacin: 1 hour pre-challenge exposure: 0/18 (0%); 6 hours post-challenge exposure: 0/18 (0%); 18 hours post-challenge exposure: 3/18 (17%); 24 hours post-challenge exposure: 13/18 (72%); control: 18/18 (100%)

-

gatifloxacin: 1 hour pre-challenge exposure: 0/18 (0%); 6 hours post-challenge exposure: 0/18 (0%); 18 hours post-challenge exposure: 2/18 (11%); 24 hours post-challenge exposure: 5/18 (28%); control: 18/18 (100%)

-

moxifloxacin: 1 hour pre-challenge exposure: 0/18 (0%); 6 hours post-challenge exposure: 0/18 (0%); 18 hours post-challenge exposure: 8/18 (45%); 24 hours post-challenge exposure: 12/18 (67%); control: 18/18 (100%)

-

aerosol challenge (PP):

-

ciprofloxacin: 6, 18 and 30 hours post-challenge exposure: 0/18 (0%); 48 hours post-challenge exposure: 17/18 (94%); control: 18/18 (100%)

-

gatifloxacin: 6, 18 and 30 hours post-challenge exposure: 0/18 (0%); 48 hours post-challenge exposure: 12/18 (67%); control: 18/18 (100%)

-

moxifloxacin: 6, 18 and 30 hours post-challenge exposure: 0/18 (0%) each; 48 hours post-challenge exposure: 10/18 (56%); control: 18/18 (100%).