The prevalence of ofloxacin-resistant strains in Japan was assessed in a collaboration of 18 university hospitals and the Metropolitan Geriatric Hospital, Tokyo.
Of 14 species (4, 560 strains) of bacteria collected from 1986 to 1988, increase in ofloxacin-resistance was demonstrated in two species: Staphylococcus aureus (resistant strains, 11%) and Pseudomonas aeruginosa (44%). Most of the ofloxacin-resistant S. aureus strains were MRSA, which were still susceptible to minocycline or imipenem. Ofloxacin-resistant P. aeruginosa strains were isolated in urine, pus, bile and sputum with a percentage of more than 40%. Imipenem, ceftazidime and tobramycin were active against these strains. Although floxacin-resistant strains were prominent also in Streptococcus pneumoniae, Serratia rnarcescens and Bacteroides fragilis, in these species there was no tendency towars increasing resistance.

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During the period from April 1987 to March 1989 we examined 242 isolates of Staphylococcus aureus isolated from skin and skin structure infections for susceptibility to various antimicrobial agents, coagulase-types and β-lactamases by the nitrocefin broth method. Multi-resistant isolates of S. aureus increased remarkably during the period from September 1988 to March 1989. The incidence of methicillin-resistant S. aureus (MRSA) was 24.5% during the period from April 1987 to August 1988, but soared up to 61.0% during the period from September 1988 to March 1989. High resistance (MIC≥100μg/ml) of S. aureus to methicillin, cloxacillin, amoxicillin cephalexin, cefaclor, cefatrizine, cephaloridine, fucidic acid and was seen in more than 50% of S. aureus isolates, but the incidence of high resistance of S. aureus to gentamicin obviously decreased during the period from September 1988 to March 1989.
Medium resistance (12.5≤MIC5≤50μg/ml) of S. aureus to minocycline (MINO) remarkably increased but no high MINO resistance was found. Most isolates were susceptible to ofloxacin. As to coagulases, type IV was most frequently isolated. In deep-seated pyoderma such as furuncle and furunculosis, type N S. aureus was most frequently isolated. In superficial pyoderma, such as impetigo, types I and V were most frequently isolated. No other diseases were superficially related to particular coagulase types.β-Lactamase production of S. aureus was determined by the nitrocefin broth method and after 30 min reaction, 63.6% of the isolates were positive.

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We investigated 19 patients with drug-induced fever (22 incidences) due to antibacterial drugs.
1.β-Lactam agents were considered to be the cause of fever in most cases and aminoglycosides as well as other antibacterial drugs were involved in the remaining casas.
2. 1) The types of fever were classified as follows: gradual onset type, cataplectic type, mild type. The majority of cases were diagnosed as having gradual onset type fever.
2) Drug-induced fever occurred on day 4 to 42 of antibacterial treatment, but in most cases on day 11 to 15.
3) The fever subsided 1 to 5 days after drug administration was terminated, while symptoms disappeared after only one day.
3. 1) Clinical examination of inflammatory changes showed both increase and decrease in the number of leukocytes, CRP and the erythrocyte sedimentation rate in some cases; but no definite trend was recognized.
2) Further clinical examination showed that the values for LDH concentration and platelet count before and after fever were not significantly different. Various disorders result in fever; and the different types of fever, as well as different clinical manifestations, make diagnosis difficult. It is therefore important to understand fully the patient's clinical process.

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There have been reports of hemorrhagic manifestations associated with the administration of antibiotics, mainly beta-lactams recently introduced into the market.
During the course of a clinical study to assess the safety of a new quinolone, norfloxacin (NFLX) in children, we investigated the drug's influence on blood coagulation and platelet functions.
ADP-induced platelet aggregation was measured in seven pediatric patients from 6 months ‘to 10 years’ old being treated with NFLX. The mean values were 51.0±13.1% before administration and 63.8±17.2% during the treatment, showing an improvement in platelet function differing from cases commonly treated with other oral antibacterials.
In parallel, tests on blood coagulation and PIVKA II were performed, and no abnormalities caused by NFLX were observed.
Our results suggest that NFLX in children has less adverse effect on the normal function of hemostasis and blood coagulation.

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We studied the in vitro and in vivo synergistic effect of ceftizoxime in combination with amikacin, tobramycin, isepamicin, piperacillin, aztreonam or carumonam against Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae.
1. The MICs and FIC indexes of ceftizoxime with amikacin, piperacillin or aztreonam were superior in activity to those of each alone. The bactericidal activity of ceftizoxime and amikacin in combination against P. aeruginosa was synergistic, and the activity of ceftizoxime in combination with amikacin, piperacillin or aztreonam against E. coli and K.pneumoniae was also synergistic.
2. In treatment against infection with P. aeruginosa or E. coli in mice, ceftizoxime and amikacin in combination had synergistic or additive effect, but ceftizoxime combined with piperacillin or aztreonam did not.
3. In an in vitro model simulating human serum levels of ceftizoxime (2g/1h) and amikacin (200mg, i.m.), ceftizoxime and amikacin in combination markedly inhibited regrowth of P. aeruginosa treated by amikacin alone for a long time. The bactericidal time of ceftizoxime combined with amikacin or aztreonam was shorter than that of ceftizoxime alone, but there was no such effect in the combination of ceftizoxime and piperacillin.

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The influence of ceftazidime (CAZ) on the synergetic bactericidal effect withserum complement was investigated. One-fourth of the minimal inhibitory concentration (MIC) ofCAZ increased the killing activity of gram-negative bacteria, such as Escherichia coli, Pseudomonas aeruginosa and Serratia marcescens, but no synergetic bactericidal effect of CAZ with serum complement was observed on gram-positive Staphylococcus aureus.
E. coli was killed by congenitally deficient C 9 serum (C 9 D). The killingactivity of C 9 D was weaker than that of normal human serum (NHS). But P. aeruginosa was not entirely killed by C 9 D.
A sub-MIC of CAZ increased the killing activity of P. aeruginosa by C 9 D. Wesuspect that a sub-MIC of CAZ increases the susceptibility of the bacterial cell wall against membrane attack complex (C 5 b-8).
We conclude that CAZ has a synergetic effect with serum complement on P. aeruginosa before C 9 activation.

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We studied the synergistic interaction of some new cephem antibiotics and fresh serum against a clinical isolate of Serratia marcescens.
Bacterial growth was dose-dependently inhibited by the addition of 20%-30% fresh serum to the broth.
Its activity was lost by the inactivation of the fresh serum and the additionof specific antibody for the strain, while the complement activity (CHSO) of the broth was consumed.
Bacterial growth was strongly inhibited by simultaneous incubation with freshserum and some new cephems. The most potent synergistic bactericidal effect was observed with cefbuperazone, followed by latamoxef, ceftizoxime, cefotaxime and cefotetan. No regrowth of the strain after 24h was observed in a broth of 1/2 MIC of cefbuperazone or latamoxef with 10% serum, or in a broth of 1/2 MIC of ceftizoxime or cefotaxime with 20% serum.
Interestingly, after 10 and 24 hours incubation, the MIC levels of the cephems in the broth with sub-MIC antibiotic and fresh serum increased 2-4 times more than those in thebroth with sub-MIC antibiotic only. This suggests that the drug resistance of this organism might have been induced during the simultaneous incubation with cephem antibiotics and fresh serum.

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We studied the safety and efficacy of aztreonam lg by single-dose intramuscular injection in acute uncomplicated cystitis by prospective randomized trial and compared it to oral ofloxacin 300 mg/day for 3 consecutive days.
1) The patients, in whom efficacy was judged on day 3 in accordance with the Japanese UTI Comittee's criteria, numbered 41 in the aztreonam and 44 in the ofloxacin group.
The overall clinical efficacy of aztreonam was 95.1%(excellent and moderate), and that of ofloxacin was 93.2%(excellent and moderate), showing no difference between the two groups.
2) The effect on bacteriuria of aztreonam was 86.4%(38/44, eradicated) and that of ofloxacin was 91.1%(41/45, eradicated), showing no difference between the two groups.
3) The recurrence rate, as judged by the doctors, was 0%(0/16) and 14.3%(2/14) in the aztreonam and ofloxacin group, respectively.
There was no evidence of side effects or abnormal laboratory findings in any patients of either groups.
From these results, we conclude that aztreonam 1g by single-dose intramuscular injection is highly safe and effective against acute uncomplicated cystitis.

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We studied ceftriaxone (CTRX), a cephem antibiotic, for its bacteriological and clinical effects in male gonorrhoeal urethritis.
One gram of CTRX in an i. v. single-dose injection was given to 23 patients with gonorrhoeal urethritis, and the following results were obtained:
1. The MICs for Neisseria gonorrhoeae were evaluated for 18 of 23 isolates. The MIC was ≤0.05 geml in all 18, and ≤ 0.025 geml in 16 of these 18 strains. Two strains (8.7%) of 23 clinical isolates were β-lactamase producing, but their MICs were not in the high value range.
2. N. gonorrhoeae was eradicated in all cases both on days 3 and 7.
3. Clinical efficacy was good in 58% and excellent in 42% on day 3, and good in 75% and excellent in 25% on day 7.
4. No subjective or objective adverse reactions occurred.

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In an open, prospective, multicenter trial we investigated the clinical efficacy of Imipenem/cilastatin sodium (IPM/CS) for the treatment of pulmonary infection.
Out of 129 cases collected, 103 could be evaluated for utility of IPM/CS: 83 with pneumonia (49 moderate and 34 severe cases), 6 with lung abscess, 5 with empyema, 9 with chronic bronchial infection caused by Pseudomonas aeruginosa.
In 83 cases of pneumonia, the mean age was 67.6 years old, significant underlying diseases were present in 87.9%, and 21 cases (25.3%) were hospital-acquired. Causative organisms were determined in 36 cases (43.4%), and multiple causative organisms were isolated in 5 cases.
The principal pathogens were Streptococcus pneumoniae (8), Staphylococcus aureus (8), P. aeruginosa (8), Haemophilus influenzae (6), Klebsiella pneumonia (6).
The efficacy rate of the cases of pneumonia in monotherapy with IPM/CS was 84.6%: moderate 87.2%, severe 80.6%, community-acquired 91.7%, and hospital-acquired 61.1%. Monotherapy with IPM/CS was highly effective in cases of aspiration pneumonia. The efficacy rate in cases in which the causative organism was P. aeruginosa was low (50.0%).
The efficacy rate of the cases of lung abscess was 100% and of empyema was 50.0%.
Of 9 cases of chronic bronchial infection due to P. aeruginosa, in 5 cases treated with IPM/CS combined with tobramycin and I case treated combined with amikacin, the efficacy rate was 66.6% and the eradication rate 33.3%.
We consider monotherapy with IPM/CS to be highly effective in cases of moderate and severe pneumonia, with the exception of disease due to imipenem-resistant P. aeruginosa.

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1. Methicillin-resistant Staphylococcus aureus (MRSA) was investigated for its isolation frequency from clinical materials from 1980 to 1988. The rapid increase of MRSA from the beginning of 1980 coincided with the introduction into the market of new antipseudomonal penicillins and second-and third-generation cephems.
2. The change in the rate of isolates obtained from blood culture in the aforementioned period showed that S. aureus, of gram-positive cocci, was evidently increasing, whereas the isolation rate of gram-negative bacilli changed little or, in some species, even showed a slight decrease.
3. MRSA strains isolated from blood culture during the past five years were epidemiologically classifiable into three major groups: gentamicin-resistant (GM^r) MRSA, group 1, was typed using bacteriophage group I and coagulase IV, which produced enterotoxin A or B. Chromosomal DNA encoding the mecA gene was a 4.0 kb Hind III fragment; tobramycin-resistant (TOB^r) MRSA, group 2, was typed using phage group III and coagulase II, which produced toxin shock syndrome toxin 1 (TSST-1) alone or TSST-1 and enterotoxin C. The DNA encoding the mecA gene was a 4.3 kb Hind III fragment; GM^r+TOB^r-MRSA, group 3, was similar to group 2 epidemiologically. These MRSA strains indicated rapid changes from group 1 to group 2, then to group 3.
4. Induction of penicillin-binding protein (PBP)-2' in MRSA of these three groups by β-lactam antibiotics was investigated. Ingroup 1, GM^rMRSA, the induction degree by cefazolin or flomoxef was low, whereas in the other MRSA groups, PBP-2' induction was prevalent with all the compounds tested.
5. From these results, it appears that MRSA are acquiring more adaptability to new environments along with the change in the use of antibiotics.

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