Flomoxef (FMOX, 6315-S), a new parenteral oxacephem antibiotic, was evaluated for its safety, efficacy and pharmacokinetics in children. Twenty-six patients with bacterial infections were treated with FMOX. Clinical efficacy rate was 92% and bacteriological cure rate was 85%. Three cases of infections due to methicillin-resistant Staphylococcus aureus were cured with FMOX therapy. No severe adverse reactions or abnormalities of laboratory test data were associated with FMOX therapy, although loose stools and diarrhea occurred frequently (23%).
Serum half-lives of FMOX after a single bolus injection of 9 infants and children were 0.77±0.31 hour and excretion into urine was rapid. From these experiences, FMOX appeared to be a safe and effective antibiotic when used in children with susceptible bacterial infections.

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Flomoxef (FMOX; 6315-S), a new synthetic oxacephem antibiotic, was studied in the pediatric field and pharmacokinetic and clinical results obtained were summarized below.
1. The activity of FMOX against Staphylococcus aureus isolated from clinical patients, including latamoxef resistant strains was very high and MIC was approximately <0.39 μg/ml. This MIC value was lower than other cephem antibiotics such as cefotaxime, cefotiam, cefmetazole, cefamandole. The distribution of MIC's of FMOX against Escherichia coli and Salmonella spp. ranged from 0.05 to 0.78 μg/ml and from 0.05 to 0.39 μg/ml, respectively.
2. Serum concentrations of FMOX after dosages of 20 mg/kg and 40 mg/kg with 1 hour intravenous drip infusion were 21.5-27.5 μg/ml, 6.00 7.81 μg/ml, 0.37-0.59 μg/ml at 1, 2, 5 hours after administration, respectively, and T 1/2 (β) were 0.61-0.83 hour. Serum concentrations after one shot intravenous injection of 20 mg/kg FMOX were 56.7-90.2 and 0.20-0.26 μg/ml at 3-10 minutes and 6 hours after administration, respectively, T 1/20) was 1.22 hours and urinary excretion rate was 66.7-69.8% in 6 hours.
3. FMOX was administered to 32 cases (upper and lower respiratory tract infection, and purulent infections) at 3-4 times daily for 4-13 days. In these cases the daily dosage amounted to 41-119 119 mg/kg. Clinical effectiveness was 97% overall including resistance cases upon other cephem antibiotic treatment. All bacterial species identified including Branhamella catarrhalis, Streptococcus pyogenes, S. aureus, Streptococcus agalactiae, and Haemophilus influenzae were eradicated upon the treatment with FMOX.
4. Only 3 cases of soft stool, 1 case of elevated GOT and GPT, and 1 case of elevated GPT were observed, and all of these adverse reactions were normalized after the completion of treatment.

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Bacteriological and clinical studies on flomoxef (FMOX, 6315-S) were performed and the results obtained are summarized below.
1. The MIC values of FMOX against 307 clinically isolated strains of Staphylococcus aureus were 0.024 to 100 μg/ml with a peak MIC of 0.39 μg/ml, and the MIC₉₀ value was 1.56μg/ml. The MIC₉₀ against methicillin resistant S. aureus (MRSA) was 25 μg/ml.
2. FMOX was administered to 15 children with pediatric bacterial infections, and the effectiveness was rated excellent or good in all cases.
3. In bacteriological evaluation, 7 of 11 strains identified prior to the treatment were eliminated (63.6%).
4. As side effects, diarrhea or soft stool was found in 3 cases and eruption in 1 case. As abnormal laboratory values, eosinophilia and thrombocytosis were found in 1 case each.
5. On the intestinal bacterial flora, FMOX had a marked influence just as did other Group 4 and 5 cephems antibiotics.
6. FMOX interfered little with the coagulation system or platelet aggregation.

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Pharmacokinetical, bacteriological and clinical studies of flomoxef (FMOX, 6315-S), a new cephem antibiotic, were conducted in the pediatric field.
1. Mean drug concentrations in the blood after intravenous one shot injection of FMOX 20 mg/kg to 5 children (aged 5-8 years) were 39.7 μg/ml at 1/4 hour, 24.1 μg/ml at 1/2 hour, 12.2 μg/ml at 1 hour, 4.7 μg/ml at 2 hours, 1.1 μg/ml at 4 hours, and 0.3 μg/ml at 6 hours. The mean half-life in blood was 0.65 hour. Mean concentrations in urine was 3,558 μg/mI during 0-2 hours after intravenous injection, 568 μg/ml during 2-4 hours, and 117 μg/ml during 4-6 hours. The mean 6-hour urinary recovery rate was 72.8%.
2. Clinically, FMOX was administered to 32 children (5 months to 9 years) with infections, i.e. 29 with pneumonia, 1 each with acute purulent tonsillitis, acute purulent lymphadenitis and cellulitis. The treatment was excellent in 24 cases and good in 8. Thus, the efficacy rate was 100%.
3. The bacteriological effect of FMOX was investigated using 11 clinical isolates which were considered to be causative organisms, i.e. 1 strain of Staphylococcus aureus, 1 strain of Streptococcus pneumoniae, 8 strains of Haemophilus influenzae and 1 strain of Haemophilus parainfluenzae. Except one strain (H. influenzae) which was just decreased, all the bacteria were eliminated.
4. No side effect was found at all. As abnormal laboratory findings, elevation of GOT was found in 1 case, thrombocytosis in 2, and eosinophilia in 1 but all the changes were slight and were normalized by the time of re-examination.
The above results suggest that FMOX is a useful and safe drug for the pediatric practice just as in the adult field.

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Bacteriological and clinical studies with fiomoxef (FMOX, 6315-S), a new oxacephem antibiotic, were carried out in the field of pediatrics and the results obtained are summarized as follows:
1. The antimicrobial activity of FMOX against clinically isolated organisms was determined. FMOX had a good antimicrobial activity against Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae and especially against Staphylococcus aureus (including methicillin resistant S. aureus).
2. Mean serum concentrations of FMOX following intavenous bolus injection of 20 and 40 mg/kg (in 7 and 4 cases, respectively) were 35.3 and 77.7 μg/ml at 15 minutes after administration with mean serum half-lives (T1/2) of 0.75 and 0.95 hours and mean urinary recovery rates up to 6 hours after administration were 71.9 and 65.1%, respectively.
3. Twenty-five pediatric patients (19 cases of pneumonia, 1 case of pyothorax and 5 cases of urinary tract infection) were treated with FMOX in doses ranging from 50 to 138 mg/kg divided into 3 or 4 times a day. The rate of clinical effectiveness was 100% and the bacterial elimination rate was 90.6%.
4. No adverse reactions were observed. Abnormal laboratory findings were eosinophilia in 1, thrombocytosis in 2 and slight elevations of GOT and GPT in 3 patients.
These results indicate the usefulness and the safety of FMOX in the treatment of bacterial infections in the pediatric field.

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The new antibiotic flomoxef (FMOX, 6315-S) was administered to 38 children. The results obtained are summarized as follows.
1. In 3 cases of children administered with FMOX (20 mg/kg) by intravenous drip infusion for 30 minutes, the mean T 1/2 (p) was 0.96 hour and the mean 6-hour urinary excretion was 95.5%.
2. The antibiotic was administered to a total of 38 patients with bronchopneumonia, lacunar tonsillitis, upper respiratory tract infection complicated with brain tumor, otitis media, urinary tract infection, purulent meningitis, subcutaneous and hyponychial abscess, cervical lymphadenitis, or bacterial enteritis. The treatment was markedly effective in 24 cases, effective in 13, fair in 1, and ineffective in none. The efficacy rate was 97.4%.
From our results, this drug appears to be particularly effective to bronchopneumonia, upper respiratory tract infection and urinary tract infection.
3. None of the children showed clinical symptoms indicating side effects of the drug.
These results showed that FMOX is a drug that can be safely used in the pediatric field as well as for adults.

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Flomoxef (FMOX, 6315-S), a newly synthesized antibiotic which belongs to the oxacephem group, was clinically evaluated for its efficacy and safety in 17 patients with ages ranging from 1 month to 9 year-8-month who had bacterial infections. The results obtained were summarized as follows.
1. A pharmacokinetic study following 20 mg/kg FMOX administration by intravenous bolus injection showed that the half-life of FMOX (β phase) was 39.8 minutes and the urinary excretion of FMOX in the first 6 hours was 76.5%.
2. FMOX was administered to 3 patients with pneumonia, 8 patients with bronchopneumonia, 2 patients with tonsillitis, 2 patients with pyelonephritis, one patient each with cervical lymphadenitis, and pustulosis associated with severe varicella at daily dosage levels of 61.9-87.2 mg/kg, divided into 3 or 4 administrations by intravenous bolus injection or by 30 minutes drip infusion. The clinical results of these 17 patients were as follows; excellent: 14 patients, good: 2 patients, poor: 1 patient. The efficacy rate was 94.1%.
3. No clinical adverse reaction was observed in any of the 17 patients. Neutropenia, eosinophilia, a slight elevation of GPT and slight elevations of GOT & GPT were observed in 1, 1, 1, and 2 patients, respectively. No abnormality in coagulation system was observed in any of 10 evaluable patients.
4. MICs of FMOX against 13 strains isolated from patients were as follows.
MIC against 2 out of 3 strains of Streptococcus pneumoniae was 0.20 μg/ml and that of the remaining 1 strain was 0.39 μg/ml. MICs against 1 strain each of Staphylococcus aureus, Staphylococcus sp. and Streptococcus agalactiae were 0.20 μg/ml, 0.20 μg/ml and 0.78 μg/ml, respectively. MIC against 2 out of 3 strains of Haemophilus influenzae was 0.39 μg/ml and MIC of remaining 1 strain was 0.20 μg/ml. MIC against 2 strains of Branhamella catarrhalis was 0.20 μg/ml. MICs against 1 strai n of Klebsiella pneumoniae and 1 strain of Acinetobacter calcoaceticus were 0.20 μg/ml and 50 μg/ml, respectively.
5. These data show that FMOX has an excellent bactericidal capacity against Gram-positive bacteria as well as Gram-negative bacteria and anaerobes and suggest that FMOX is a useful antibiotic in pediatric patients, although extreme attention should be paid to the possibility of inducing liver dysfunction.

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We have carried out laboratory and clinical studies on fiomoxef (FMOX, 6315-S).
The results were summarized as follows.
FMOX was given by 5-minute intravenous administration to 3 children at a single dose of 20 mg/kg. After the intravenous administration, mean serum levels of FMOX were 110.1±30.95 μg/ml at the end of injection, 44.4±10.55 μg/ml at 15 minutes, 11.0±1.72, ug/ml at 1 hour and 0.42±0.17 μg/ml at 6 hours. The mean half-life was 1.14±0.30 hours. The mean urinary excretion rate was 68.8±17.4% up to 6 hours after the intravenous administration.
FMOX was given by 30-minute drip infusion to 2 children at a single dose of 20 mg/kg and to 3 children at a single dose of 40 mg/kg. After the 30-minute drip infusion, mean peak serum levels of FMOX obtained for the 2 dose levels were 45.5±0.45 μg/ml and 87.4±18.35μg/ml at the end of injection, respectively, and mean half-lives were 0.63±0.23 hours and 0.70±0.27 hours, respectively.
The mean urinary excretion rate was 53.4±6.1% up to 6 hours after the 30-minute drip infusion of 40 mg/kg FMOX.
Treatment with FMOX was made in 24 cases of pediatric bacterial infections; 5 cases of purulent tonsillitis, 2 cases of bronchopneumonia, 12 cases of pneumonia, and 1 case each of lymphadenitis, pyothorax, purulent meningitis, cellulitis, and abscess. Results obtained were excellent in 15 cases and good in 9 cases.
No significant side effect due to the drug was observed in any cases.

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Flomoxef (FMOX, 6315-S), a new parenteral oxacephem antibiotic was investigated for its clinical efficacy and pharmacokinetics. The results obtained are summarized below.
1. Twenty-eight patients were treated with 39-152 mg/kg per day of FMOX by intravenous administration. Diagnosis of patients were pneumonia in 15 patients, acute upper respiratory tract infection in 5, acute enterocolitis in 3, urinary tract infection in 2 and cholangitis, suppurative lymphadenitis and suspicious sepsis in 1 patient each.
Clinical effect was excellent in 7 cases, good in 8, fair in 5, poor in 2 and 6 cases were excluded because therapy periods were too short and other antibiotics were used together.
Efficacy rate was 68% and the rate of bacterial disappearance was 83%.
2. Rash was found in 5 cases and thrombocytosis was found in 1 out of 28 cases. However, no severe adverse reaction was encountered.
3. The peak serum level of FMOX was 51.0 μg/ml after 20 mg/kg of drip infusion for 30 minutes and the half-life was 17.2 minutes in a-phase and 58.2 minutes in β-phase.

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Flomoxef (FMOX, 6315-S), a new parenteral oxacephem antibiotic, was studied bacteriologically and clinically.
1. The MIC and MBC values of FMOX and cefuzonam (CZON) were determined against strains of Staphylococcus aureus recently isolated from clinical materials. In MICs against methicillin-and cefazolin (CEZ)-sensitive strains, FMOX and CZON were almost equivalent. In MBC, FMOX showed lower values than CZON. Against resistant strains, both MIC and MBC values indicated that FMOX was superior to CZON, and particularly, values showed large differences in MBC.
2. FMOX was administered intravenously at doses of 20.0-35.1 mg/kg 3 or 4 times daily to 17 children aged 2 months to 8 years. The therapeutic effect was determined in 16 cases (pneumonia 9 cases, pyothorax 1, urinary tract infection 2, staphylococcal scalded skin syndrome 1, cellulitis 2 and arthritis 1). One remaining case was unevaluable and later found to be mycoplasmal pneumonia. The effect was determined as excellent in 10 cases and good in 6 cases. All the causative organisms detected in these evaluable cases were eliminated.
3. There were no symptoms or findings that suggested the occurrence of side effects of the drug in any of the 17 cases. With regard to laboratory values, a slight elevation of GPT was found in 1 case only.
4. In a case with pyothorax, the concentration of the drug in the pleural fluid determined on the day following the initiation of treatment was 18.2 μg/ml at 30 minutes after intravenous injection of the drug at 33 mg/kg. The concentration was 46.7 times as high as the MIC (0.39μg/ml) against the causative organism S. aureus.
5. Two doses of FMOX were intravenously administered at the dose of 50 mg/kg to a female infant ventriculoperitoneal shunt infection which had been treated with other drugs. In this case showing relatively low cell counts of 171-240/mm8 in the ventricular fluid, concentrations of the drug measured by HPLC were as low as 0.53 and 0.98 μg/ml 1 hour after intrave nous injection of the drug.
6. The above results suggested that FMOX is a new antibiotic drug easy to use and effective for the treatment of general infections in children.

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Pharmacokinetic and clinical studies were performed on flomoxef (FMOX, 6315-S), a new oxacephem antibiotic, as follows.
1. Pharmacokinetics
Serum concentrations of FMOX were measured in 2 cases given 20 mg/kg bolus injection. In the 2 cases, peak concentrations of the drug were 44.3 and 197 μg/ml at 15 minutes, T1/2 (9) were 0.76 and 0.47 hour and AUC were 44.8 and 169.5 μg·hr/ml, respectively. Urinary recovery rates for these cases during 6 hours were 83.1 and 54.9%, respectively. The extremely high peak serum concentration in one case may be attributed to dehydration.
2. Clinical efficacy
FMOX was administrated intravenously to 12 patients, 6 with pneumonia, 2 with cellulitis, 1 each with bronchitis, tonsillitis, purulent lymphadenitis and subcutaneous abscess, in doses of 55.0-120.0 mg/kg (average 82.2 mg/kg) t.i.d. for 4-13 days (average 6.2 days).
The overall efficacy rate was 100%, with excellent responses in 10 and good in 2.
Bacteriological efficacy was excellent; 4 of 5 strains were eradicated and 1 strain was decreased.
No clinical side effect was observed. Laboratory abnormality was observed in 1 case with transient eosinophilia.
The above results suggested that FMOX would be an useful antibiotic for treating pediatric bacterial infections.

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Flomoxef (FMOX, 6315-S) was given intravenously to 21 children with the following acute bacterial infections; 10 cases of bronchopneumonia, 3 cases each of purulent lymphadenitis and urinary tract infection, 2 cases of staphylococcal scalded skin syndrome and 1 case each of peritonsillar abscess, pyothorax and purulent meningitis. Good clinical responses were obtained in 18 out of 21 patients, and bacteriologically, all of the 17 isolated strains were eradicated.
No side effect was observed except for 1 case with soft stool and 2 cases of eosinophilia.
From the above clinical results, it is apparent that FMOX is a useful antibiotic for treating pediatric patients with various bacterial infections.

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The transfer to cerebrospinal fluid of a new oxacephem antibiotic flomoxef (FMOX, 6315-S) and its clinical efficacy against bacterial infections were investigated.
1. In 3 cases of purulent meningitis, cerebrospinal fluid concentrations of FMOX after one shot intravenous injection of 100 mg/kg during the acute stage of infections were 5.12-6.32μg/ml and ratios of FMOX in cerebrospinal fluid in serum were about 5%. During the recovery stage, cerebrospinal fluid concentrations were about 3.8 μg/ml and cerebrospinal fluid/serum ratios were about 3.5%.
2. In 1 case of purulent meningitis, the treatment with FMOX was clinically effective but this case was classified as “unevaluable” because other drug was used concomitantly. FMOX was rated effective in other 2 cases of pululent meningitis. Of 9 cases of pneumonia, FMOX was rated very effective in 8 cases and it was rated only effective in the other. Of 4 cases of bronchitis, the drug was rated very effective in 3 cases and only effective in the other. FMOX was rated very effective against 2 cases of tonsillitis, also.
3. As side effects, thrombocytosis was observed in 3 of 20 cases examined. All cases, however, were deemed unrelated to the FMOX treatment and the side effect was only transient as are often found in courses of recovery from infections.

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Flomoxef (FMOX, 6315-S) was evaluated pharmacologically and clinically in its application to bacterial infections in children.
1. Pharmacokinetics
A bolous intravenous injection of FMOX at 20 mg/kg body weight gave a peak serum concentration of 114.6±34.4 μg/ml in 1 minute after the injection and T1/2 of β-phase was 0.86±0.15 hours.
2. Bacteriological effectiveness
MIC of FMOX against Staphylococcus aureus except resistant strains (10⁶ cells/ml) was below 0.39 μg/ml and against Haemophilus influenzae, Escherichia coli and Klebsiella pneumoniae (10⁶ cells/ml) were below 0.78 μg/ml.
3. Clinical effectiveness
Clinical effectiveness of FMOX was excellent in 14 cases, good in 2 cases and fairly good in 1 case among 17 cases of bacterial infections examined. An increase in eosinophilic leukocytes was observed in 1 case but no other clinical adverse effects were detected.
These findings indicate that FMOX is a useful and safe antibiotic as a first choice against bacterial infections in children.

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A new oxacephem antibiotic, flomoxef sodium (FMOX, 6315-S), was studied for its clinical efficacy in the field of pediatrics. The treated patients were infants and children ranging from 6 months to 14 years old suffering from bacterial pneumonia in 3 cases, acute tonsillitis in 2 cases, acute enterocolitis in 2 cases, and cellulitis and urinary tract infection in 1 case each, a total of 9 cases. FMOX was administered at (levels of) 57-150 mg/kg in daily dose with durations of treatment ranging from 5 to 18 days. Clinical efficacies of good or excellent results were obtained in all cases (excellent in 4, good in 5). As an adverse reaction, eosinophilia was observed in 1 patient. This elevation is, however, normalized with the cessation of the treatment.

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Fundamental and clinical studies of flomoxef (FMOX, 6315-S) were conducted and the obtained results are summarized as follows.
For the pharmacokinetic investigation, FMOX at 10 or 20 mg/kg was administered by intravenous drip infusion over 30 minutes. In the 10 mg/kg group, the maximum blood concentration was reached just after completion of the drip infusion with the mean concentration of 30.3±4.5μg/ml, and the mean half-life was 0.734±0.196 hour. The 6-hour urinary excretion rate was 72.3%. In the 20 mg/kg group, which also showed the peak concentration immediately after completion of the drip infusion, the mean peak blood concentration was 54.3±9.7 μg/ml and the mean half-life was 0.628±0.185 hour. The 6-hour urinary excretion rate was 69.3%. The urinary recovery tended to be lower in children than in adults. Between 10 mg/kg and 20 mg/kg, a definite correlation was observed between dose levels and blood concentrations.
In the clinical investigation conducted with a total of 30 patients (22 with respiratory tract infection, 3 with lymphadenitis, 2 each with urinary tract infection and cellulitis, and 1 with acute osteomyelitis), FMOX was found to be excellent in 14 cases, good in 9, fair in 1, poor in 1, and not evaluable in 5. The efficacy rate was, therefore, 92.0%. In the bacteriological evaluation, 8 out of 12 clinically isolated strains were eradicated, 2 unchanged and 2 unknown. The elimination rate was 80.0%.
Regarding side effects, no abnormal clinical symptoms were observed. As abnormal laboratory values, eosinophilia, prolongation of APTT, increased platelet count, and a slight elevation of GOT were observed.

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Flomoxef (FMOX, 6315-S), a new intravenous cephem antibiotics, was administered to a total of 11 cases with their ages ranging from 7 years and 4 months to 10 years and 10 months. Among them, two were administered with (FMOX at) a dose level of 10 mg/kg, three each with 20 mg/kg and 40 mg/kg using one shot intravenous injection, and the remaining 3 with 40 mg/kg by intravenous drip infusion over 30 minutes. Plasma concentrations, urine concentrations and urinary recovery rates were determined.
The clinical efficacy of FMOX was evaluated in 2 cases with tonsillitis, 45 with acute pneumonia, 10 with urinary tract infections, 2 with purulent lymphadenitis, and 2 with abscess, a total of 61 cases. Of these cases, one case of pneumonia in which a side effect occurred was excluded from the evaluation because the treatment was interrupted short of the required period. In the remaining 60 cases, the mean daily dose was 79.3 mg/kg in 3 or 4 divided doses and, except one case treated by 30-minute intravenous drip infusion, all cases were treated by one shot intravenous injection for a mean period of 6 days.
Bacteriological effects of FMOX, its side effects and influences on laboratory test values were also investigated.
1. Maximum plasma concentrations after one shot intravenous injections of FMOX occurred at 5 minutes after administration regardless of dose levels (10 mg/kg in 2 cases, 20 mg/kg in 3 and 40 mg/kg in 3). Mean peak values obtained upon the 3 different dose levels were 62.5, 103.1 and 244.7 μg/ml, respectively. Mean plasma half-lives were 0.670, 0.915 and 0.595 hour, and mean AUCs were 33.0, 65.2 and 133.1μg·hr/ml, respectively. Thus, a positive dose-response relation ship was found among the 3 doses.
2. Plasma concentrations after 30-minute intravenous drip infusions of FMOX at 40 mg/kg always reached a peak at 30 minutes after the initiation of infusion, i.e. at the completion of infusion, and the mean value for 3 administrations was 151.0 μg/ml. The mean half-life was 0.973 hour and the mean AUC was 149.1μg·hr/ml.
3. Maximum concentrations in urine after one shot intravenous injections of FMOX were always obtained in 0-2 hours after administration regardless of dose levels (10 mg/kg, 2 cases, 20 mg/kg, 3 cases and at 40 mg/kg, 3 cases) and mean values for the 3 dose levels were 2,570, 4,410 and 6,290 μg/ml, respectively. Thus, urine concentrations were also dose-dependent. Because of a failure to collect a urine sample, a 6-hour analysis was not done in 1 of the 3 cases to which FMOX was given at 40 mg/kg. In the remaining cases, namely, 2 at 10 mg/kg, 3 at 20 mg/kg and 2 at 40 mg/kg, mean 6-hour recovery rates were 92.2, 72.0 and 77.9%, respectively.
4. Maximum urine concentrations of FMOX after 30-minute intravenous drip infusions in 3 cases given 40 mg/kg occurred invariably during 0-2 hours after administration and the mean value was 7,083 μg/ml. The mean urinary recovery during a 6-hour period after the completion infusion was 77.3%.
5. Clinical efficacy of FMOX was evaluated in 60 cases consist of 5 categories of bacterial infections. The drug was effective or very effective against all cases of pneumonia which accounted for the majority of illness. In the total population, a very high efficacy rate of 98.3% was obtained.
6. Bacteriological effect was evaluated in 22 cases. The elimination rate was very high, 95.5%.
7. Among the 61 ch ildren treated with FMOX, urticaria developed in 2 cases (3.3%) and the causal relation to the drug was considered “probable” in 1 case and “possible” in the other. With regard to laboratory test values, eosinophilia was found in 3 out of 50 cases (6.0%) examined for this parameter in the peripheral blood, and the causal relation of the abnormality to this drug was considered “definite” in 1 case and “possible” in the other 2 cases.

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