Our studies on the resistance mechanisms and chemical modifications of aminoglycoside antibi-otics led to the synthesis of arbekacin (ABK), which was refractory to most aminoglycoside-modifying enzymes in resistant bacteria. In 1990, ABK was launched into clinical uses in Japan as a chemotherapeutic agent for the treatment of infections caused by methicillin-resistant Staphylo-coccus aureus (MRSA).
By 1993 only a few MRSA strains moderately resistant to ABK (MIC, 6.25-12.5μg/ml) had clinically been isolated. ABK was modified by the reaction with an excess of an enzyme preparationextracted from an ABK-resistant strain (12.5μg/ml) and three inactivated products were produced, consisting mainly of ABK 2-phosphate along with small amounts of 6'-N-acetyl-ABK and the doubly modified ABK.
Based on these results, replacement of the 2-hydroxyl by amino group in dibekacin (DKB) or in ABK was designed to obtain potent active derivatives against MRSA. Conversion of the 2-hydroxyl group by DMSO-DCC oxidation followed by reductive amination with NH₄OA_c-N_aBH₃CN gave 2-amino-2-deoxy-DKB (D1) and-ABK (A1). Their 5-deoxy (D2 and A2), 5-epifluoro (D3 and A3) and 5-epiamino (D4 and A4) derivatives were also synthesized. All 2-amino-2-deoxy-ABK derivatives (Al, A2, A3 and A4) showed excellent activities against MRSA and Gram-negative bacteria, as expected. Among them, A4 having low acute toxicity and nephrotoxicity was selected as a new candidate for anti-MRSA agent.

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Isolation frequency of MRSA in Japan increased up to 60% until 1993. The therapy of infectious diseases usually begins empirically, then doctors would verify or change their regimen according to laboratory data. But the hospitally-infected MRSA strains are now highly resistant to β-lactams, and strains resistant to other antibiotics such as, macrolides, quinolones and minocycline are also increasing. MRSA strains in infected focus are often mixtures of strains expressing different patterns of multiple resistance, and often exist with other pathogens such as Pseudomonas aeruginosa. Relying upon laboratory data alone, often results in emergence of new resistant bacteria or replacement of pathogens, hence ineffectiveness of chemotherapy. Now only arbekacin and vancomycin are the antibiotics to which resistant strains are less than 3%. Other antibiotics should be used after considering the resistance pattern of isolates from the patient and in the hospital. Most of the MRSA-infected patients are compromised hosts, and the in vivo efficacy does not always reflect the in vitro results. Even arbekacin and vancomycin are sometimes recommended to be used in combination therapies with other drugs.

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Eight hundred and seventy-two isolates of clinically significant methicillin-resistant Staphylo-coccus aureus (MRSA) with their clinical information were obtained between 1992 and 1993 from thirty-four hospitals in Japan. The isolation frequency of MRSA was high in sputum (42.9%), pus (33.1%) and blood (14.0%). Pseudomonas aeruginosa was a major bacterial species in poly-microbial infections with MRSA. Enterobacteriaceae and Candida sp. were also frequently isolated with MRSA. Four different coagulase types were identified. Coagulase type II was found in 85.6% of all MRSA strains tested. The isolation frequencies of coagulase type III, type IV and type VII were 3.1%, 3.6% and 3.2%, respectively. The strains of MRSA contained coagulase type II were prevalent in all geographical areas of Japan, but other coagulase types were limited in western areas of the country. The strains of MRSA were tested for their susceptibility to twelve antimicrobial agents and for production of penicillinase. More than 80% of MRSA strains were highly resistant to methicillin, and were also resistant to macrolide antibiotics and tobramycin. Frequencies of resistance to gentamicin, minocycline or ofloxacin were approximately 60%, 50% or 70%, respec-tively. But only a small parcentage of strains were resistant to arbekacin and all of the MRSA testedwere susceptible to vancomvcin.

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A clinical investigation on MRSA infections, and the determination of the efficacy and usefulness of arbekacin (ABK) were performed an “MRSA Forum” composed of 18 groups including 115 institutions in Japan.
Patients with infectious diseases clearly related with MRSA, a total of 348 (males: 237, females: 111), were evaluated, 74/274 patients were treated with ABK alone/combination with ABK.
Most of them (94.6%/96.4%) had underlying diseases and they had pneumonia (38/175), sepsis (6/35) or other infections (30/64). Infections by MRSA alone were noted in 41/159 and polymicrobial infections including with MRSA were in 33/115. 53.6%/56.4% of MRSA were eradicated and bacteriological clinical efficacies were 75.6%/67.9% in single infections and 63.6%/ 71.3% in polymicrobial infections.
The clinical efficacies were obtained in 70.3%/69.3% of total and in 60.5%/72.0% of pneumonia and in 90.0%/80.8% of the patients pretreated with other drugs within 3 days previously.
Efficacy rates were 78.6%/71.4% in 30 minute's div and 63.2%/66.4% in 60 minute's div.
Adverse effects were found in 4.76%/5.70% including renal function disorder (2/11) but no case was serious. Abnormal laboratory test results were noted in 15.4%. ABK is effective against MRSA infections.
Combined therapies with ABK and other drug are effective against refractory infections.

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Changes in properties of MRSA and the status of MRSA infections in the last two years were investigated by an MRSA Forum composed of 18 groups including 115 medical institutions in Japan. And an opinion poll regarding MRSA was taken by professional doctors (41) and general clinical doctors (323).
Points of discussion
1. Did properties of MRSA change?
2. Did the pattern of MRSA infections change?
3. Did the understanding of MRSA change?
4. What is the relationship between MRSA and the 3rd cephems?
5. Howis MRSA related to polymicrobial infections?
6. Is ABK useful against MRSA infections?
7. What will be future trend in characteristics of MRSA and MRSA infections?
Conclusions
1. MRSA has become more resistant to methicillin however it seemed to have become less toxic.
2. Severe MRSA infections are decreasing and colonizations are increasing.
3. There were some differences in attitude against MRSA between professional doctors and general clinical doctors.
4. The 3rd cephem should be used reasonably.
5. MRSA infections should be treated with polymicrobial infections in consideration.
6. MRSA did not gain resistance against ABK and ABK is useful against MRSA infections.
7. Problems of MRSA will cool down but they should always be kept in our mind.

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Data on Staphylococcus aureus strains isolated at various areas in Japan during 1992 and 1993 were collected and analysed. Among 7, 033 strains examined, 60.3% were methicillin-resistant S. aureus (MRSA), 86% of which were isolated from inpatients. MRSA were isolated most often (38%) from departments of internal medicine, followed by departments of surgery (13%). The most frequent source of MRSA was sputa (38%), followed by pus (18%). As for coagulase types, 69% of MRSA were Type II and next most frequent was Type VII (24%). Among MSSA strains, Type VII (35%) and Type III (32%) were the most frequent. Frequencies of β-lactamaseproducing strains were 68% in MRSA and 59% in MSSA. More than 80% of MRSA strains were resistant to β-lactams. The frequencies of resistance to fosfomycin, ofloxacin, minocycline and gentamicin were 88%, 72%, 19% and 66%, respectively. Less than 3% of MRSA strains were resistant to arbekacin or vancomycin.

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We surveyed 387 clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) obtained from 26 hospitals isolated in 1993 to determine whether they became resistant to arbekacin (ABK). Twenty-five ABK-resistant MRSA(6.5%)were isolated from 9 hospitals. Analysis of genomic DNA fingerprinting by pulsed-field gel electrophoresis was used to confirm the classification by resistance patterns, phage typing and other biological characters. After digestion with endonuclease SmaI, two or three types of restriction patterns were found in ABK-resistant MRSA isolated from each hospital. We concluded that ABK-resistant MRSA may spread through nosocomial MRSA infections.

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We studied the efficacy of arbekacin (ABK) against MRSA that were resistant to gentamicin (GM). ABK was fairly active against most of the GM-resistant MRSA strains. Against highly GM-resistant strains, however, ABK was slightly less active than it was against the low level GM-resistant strains. ABK-resistant mutants were isolated from GM-resistant MRSA at a frequency of 10^-4to 10^-5 when the selection was made with MIC of ABK. But the frequency decreased with higher concentration of ABK or with a use of 1/2 MIC of β-lactam antibiotics, such as cefazolin, cefotiam, cefamandole or flomoxef, together with ABK.
We isolated a ABK-resistant mutant from a laboratory strain MS353/pMS91 which possess a GM-resistant gene on a plasmid. The gene encodes a modifying enzyme, AAC-6/APH-2. We compared the enzyme activities between the mutant MS353/pMS91M and MS353/pMS91. The mutant strain showed enzyme activity six times as much as the primary strain. This result suggests that the increase of AGs-modifying enzymes was responsible for the ABK-resistance of MRSA.

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Bactericidal activity of arbekacin (ABK) against methicillin-resistantStaphylococcusa ureus(MRSA) was compared with that of vancomycin (VCM). MIC₈₀, of VCM against 1,056 clinical isolates was 2μg/ml and not a single strain of those in of which MIC above 4μg/ml was detected. Whereas MIC₈₀, of ABK against the isolates was 1μg/ml, but a few strains of which showed MIC of 8μg/ml or 16μg/mi.
A killing-curve study indicated that bactericidal activity of ABK was critically dependent on its concentrations. ABK, at higher concentrations, showed excellent killing effects against all the tested isolates, and the effects were superior to those of VCM because of following reasons; great reduction CFU was attained within short time incubation, and the effects were not remarkably influenced by different inoculum sizes of MRSA. At lower concentrations of ABK, between a half and four times MIC, the re-increaseo f CFU of MRSAw ith appearanceo f characteristics mall coloniesw as observed. Considering the concentration of ABK in usual dose, the significance of the re-growth should be carefully assessed. It showed be recommended that the peak concentration of ABK be elevated to higher level if adverse effects do not appear.

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The activities of arbekacin (ABK) and vancomycin (VCM) against MRSA were compared, and the results are as follows.
1. In antibacterial activities (MIC value) against 142 strains of MRSA, MIC₅₀ of ABK was two times less than that of VCM. MIC₉₀'s were both 1.56μg/ml.
2. ABK was also superior to VCM in bactericidal activities within a short time against 100strains of MRSA. After 4 hours, 42 strains were killed to below 10^-2 by 2 MIC of ABK, but 6 strains were killed to 10^-2 by 4 MIC of VCM.
3. Against the MRSA 1936 strain, neither ABK nor VCM was active, when an inoculum size of about 10₈ CFU/ml was used. At an inoculum size of 10₅ CFU/ml, ABK showed strong bactericidal activity in a dose dependent manner, while bacteria killing activity of VCM was time dependent.
4. In experimental infections with the MRSA 1936 strain, ABK showed high bactericidal activity rapidly, and area of body that showed bacterial inhibition appeared to be large compared to that obtained with VCM.
5. As to protection from MRSA infections, ABK was significantly superior to VCM in activities against 3 out of 4 strains of MRSA tested. ABK showed more pronounced efficacy when administered in a single dose than in divided doses.
These results indicated that ABK would exhibit therapeutic efficacy in a short time.

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The bactericidal activities of arbekacin (ABK), vancomycin (VCM), gentamicin (GM) and netilmicin (NTL) in mixed culture with Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa were examined using an in vitro computer programmed pharmacokinetic simulation system and also the protective effect of these agents on systemic infection in neutropenic mice was examined. In a mixed culture of S. aureus No.235 (MRSA) and P. aeruginosa E7, ABK showed a strong bactericidal activity and an inhibition of regrowth against both bacteria, and GM and NTL showed similar effects. On the other hand, VCM showed a bactericidal activity against S. aureus No.235, but not against P. aeruginosa. In the protective study, ABK was evidently more effective than GM, NTL or VCM against a systemic mixed infection of mice with S. aureus No.235 and P. aeruginosa E7. In brief, the ED₅₀ values of ABK, VCM, GM and NTL were 19.5,>100, 40.5 and 45.2mg/kg, respectively.

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Nephrotoxicities of arbekacin (ABK) and/or vancomycin (VCM) were examined by administrating rats intravenously with single doses or 10 times repeated daily doses. ABK was found less toxic to kidney than VCM, and the toxicity was strengthened by combined treatment with VCM and ABK. Fosfomycin decreased the nephrotoxicity when added to the single or combined treatment with ABK and VCM.

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Experimental and phase I clinical studies were performed to evaluate the efficacy and safety of once-daily administration of arbekacin (ABK). The results obtained were as follows:
1. ABK displayed dose-dependent, excellent antibacterial activity and post-antibiotic effects (PAE) against MRSA.
2. No significant difference was found between once-daily and divided administration regimens in protection against an experimental MRSA infection in mice.
3. There was no significant difference between once-daily and twice-daily administration of ABK in ototoxicity in guinea pigs or in nephrotoxicity in rats.
4. In the phase I clinical study using 200 mg single daily administration of ABK, no abnormal laboratory test results or symptoms were observed.
5. In the phase I clinical study of 5-day repeated administration of 200 mg/day of ABK, headache and increase in WBC sediment in the urine was noted in 1 volunteer; however these were not confirmed to be attributable to ABK. No abnormal laboratory test results were obtained other than increases in β₂-microglobulin, NAG and γ-GTP levels, each of which returned to normal after the completion of ABK administration.
No abnormality was observed in the audiometry examination.
6. Maximum serum concentration(C_max), serum half-life(T1/2β)and urinary recovery rate (0-48 hours)after single administration of 200mg of ABK, were 13.20μg/ml,2.30 hours and 86.75%, respectively.
There were no significant differences in pharmacokinetic parameters or urinary recovery rates between day 1 and day 5 in the 5-day repeated administration study. These findings suggest that once-daily administration regimen of ABK may be as effective and safe as divided administration regimen for the treatment of MRSA infection. Further clinical evaluation is required, however.

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Efficacies of combined uses of arbekacin(ABK)with other antibiotics against between 57 and 76 clinically isolated methicillin-resistant Staphylococcus aureus(MRSA) were examined. Other antibiotics tested were fosfomycin(FOM),5 cephems(CEPs), 2 penicillins(PCs) and imipenem. Percentages of strains that grew at various combination of serially diluted drugs in a microdilution method were scored, and for each pair of drugs ≥MIC₅₀ or ≥MIC₉₀ was determined. FIC-indices were calculated at ≥MIC₅₀.Bacterial growth was inhibited by low concentrations of ABK dose-dependently,while most of the strains tested were resistant to 9 other drugs. FIC-indices with ABK were lowest when used together with ampicillin (ABPC)(0.516) followed by combinations with cefotiam(CTM) and cefuzonam(CZON)(each, 0.53), and FOM(0.625). When combined with 0.5μg/ml of ABK,0.5μg/ml of ABPC inhibited more than 50% of MRSA strains. CTM or CZON in combination with the same amount of ABK to 2μg/ml inhibited more than 50% of MRSA. Thus ABPC was found to be the most efficient in combined use with ABK to inhibit clinical MRSA strains.

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Combination effects were studied with arbekacin(ABK)and β-lactam antibiotics including imipenem/cilastatin(IPM/CS), flomoxef(FMOX), and cefotiam(CTM)for bactericidal activities, post-antibiotic effects(PAE's)and bactericidal activities of β-lactam antibiotics after removal of ABK using methicillin-resistant Staphylococcus aureus (MRSA)strain1936. The following results were obtained.
1. When ABK was administered in combination with IPM/CS, FMOX or CTM against MRSA strain 1936, low FIC index was not obtained.
2. Higher bactericidal activity was observed when ABK was given before β-lactam than when β-lactam was given before ABK.
3. Combination of ABK and each of β-lactam antibiotic led a longer PAE than ABK alone.
4. When each β-lactam antibiotic was administered after a treatment and removal of ABK, greater bactericidal activity and growth inhibition were observed than when administered each β-lactam alone.A
These findings basically demonstrated that ABK was effectively bactericidal against MRSA when administered in combination with β-lactam antibiotic such as IPM/CS, FMOX or CTM, even when the FIC index did not indicate a favorable effect.

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We determined the in vitro activities of arbekacin in combination with other antibiotics against 96 clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA). Efficacies were evaluated by comparing frequencies of susceptible strains at concentrations of antibiotics present in serum 3 hours after intravenous administration of recommended dosages with those obtained with addition of 1 or2 μg/ml of arbekacin. The addition of arbekacin significantly increased the antibacterial activities of cefotiam, cefuzonam, flomoxef and fosfomycin, but had no effect on the activity of either imipenem or minocycline. Arbekacin in combination with fosfomycin was found to have the greatest activity against MRSA among combinations tested. In addition, arbekacin had excellent antimicrobial activity against Pseudomonas aeruginosa, compared to other anti-pseudomonal agents such as piperacillin, ceftazidime and imipenem.

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We investigated the clinical efficacy of arbekacin (ABK) in patients with methicillin-resistant Staphylococcus aureus (MRSA) infections, and also studied coagulase types, β-lactamase producing activity and drug sensitivity of MRSA isolated from various clinical specimens. A total of23 patients with MRSA infections (13cases of pneumonia, 1case of sepsis, 1case of pneumonia and sepsis and8cases of the others) who were hospitalized from April1992to September1993were enrolled in this study. They were14males and9females, and the mean age was66.9years (range, 18-91years). All patients had underlying diseases (mainly malignant tumors and cerebrovascular diseases). ABK was given intravenously at doses ranging from75to100mg twice daily. The clinical efficacy rate was90%; 8cases showed excellent responces, 10cases good, 1case fair, 1case poor and3cases were unevaluable. The eradication rate of MRSA was81.8%; 16cases were judged as eradicated, 3cases decreased, 2cases replaced, 1case unchaged and in 1 case the bacteriological response was unknown. Side effects were not observed, but S-GPT was elevated in 1case. Coagulase types of MRSA (123 strains) isolated at the institutes involved in the study were type II (56 strains), type IV (12 strains), type VII (13 strains) and other types (2 strains), but coagulase types of40strains could not be determined. Eighty-four strains (68.3%) produced β-lactamases. MICs of ABK were0.5μg/ml against43strains and1μg/ml against37strains, and all of the MICs were under4μg/ml. In summary, ABK showed high antimicrobial activity against MRSA and clinical usefulness in the infections investigated.

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Clinical efficacy of arbekacin (ABK) was examined on patients with MRSA infection during hospitalization in Nagoya University Hospital. A total of 15 analysed cases of 5 sepses, 3 pneumonias, 6 wound infections and one abdominal abscess. ABK was administered intravenously by drip infusion of 200 mg per day divided into 2 doses with or without other antibiotics. Overall clinical efficacy rate was 76.9%, and eradication rate for the MRSA was 54.5%. Adverse effects were noted in 3 cases (one each case of urticaria, disorder of liver function, and renal disorder). The renal disorder was found in the case where ABK was used in combination with vancomycin.

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Aged or immuno-compromized patients were mostly affected, by pneumonia caused by infection of MRSA, and more than half of the cases were superinfected with glucose-nonfermentative Gram-nagative rods including Pseudomonas aeruginosa. These patients were treated with a monotherapy of arbekacin (ABK) by intravenous drip administration or with a combination of ABK and imipenem/cilastatin, ceftazidime or antifungals. The clinical efficiencies were 55.6% in 11 mono-therapy cases and 83.3% in combined therapy. MRSA was eradicated in 31.9% of the patients. These results are comparable with, or superior to the vancomycin therapy in the treatment of MRSA pneumonia. When MRSA is isolated from sputum of pneumonia patients, the discrimination between colonization and infection is important, but the diagnosis is very difficult in many clinical cases before the initiation of chemotherapy. The number of bacteria and the grade of inflammation should be carefully scored before starting a chemotherapy.

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Arbekacin sulfate (ABK) was administered by intravenous drip to pneumonia patients infected with methicillin-resistant Staphylococcus aureus (MRSA), and the efficacy and the safety were objectively evaluated by the executive committee. The daily dose was determined in principle as 150-200 mg, two times a day, 30-90 minutes drip infusion, and the dose was to bechanged at each special occasion. Combined therapy with other antibiotics was scheduled in severe cases at a decision of the physician in charge. Data of 18 cases were accumulated. The efficacy could be evaluated for 12 cases (4 cases with ABK alone, and 8 cases with combined therapy), and the safety was evaluated for 18 cases. The clinical efficacy was: excellent, 1; good, 4; fair, 5; and poor, 2. The efficacy rate was 41.7%. The bacteriological effect was: eradicated, 2 (16.7%) ; decreased, 2; and no change, 8. There found no side effects except 3 cases of abnormal laboratory data, two abnormal renal functions (11.1%) and one abnormal hepatic function (5.5%). In one of the renal disorders, decreased dose of ABK improved the function. In the other case, the impaired renal function lasted until death by heart failure. In the case of abnormal function, discontinuing the ABK therapy improved the hepatic function. In the 4 out of 5 cases that showed excellent or good clinical efficacy, patients recovered within relatively early days of ABK therapy. The average days for recovery was 7.8.

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Availability of arbekacin (ABK) was analyzed in the chemotherapy of 24 MRSA-infected patients with symptoms of pneumonia (12), sepsis (6) and others (6). Most patients had background diseases such as malignant tumors or cerebrovascular disorders. 47% (7/15) of them were immunologically abnormal. 17 of them had been previously treated with cephems, imipenem, minocycline or fosfomycin. The ABK therapy was performed with doses ranging 50-400mg a day, devided into 1-3 times (mostly 100mg×2), and for 5-24 days.(18 patients were treated between 5 and 14 days). 14 patients (58%) received combined therapy with other antibiotics (mostly with β-lactams, 12). The clinical efficacy rate of the ABK therapy was 62% (good, 13; fair, 4; ineffective, 4; unknown, 3). The bacteriological efficacies were: eradicated, 7 (44%); decreased, 4; no change, 5; unknown, 8. Side effects were found in 3 patients (oliguria, 2; eruption due to drug, 1) and one case resulted in serious renal disorder. Abnormal laboratory data were found in 7 cases. Above results have indicated that ABK is a useful antibiotic in chemotherapy of MRSA-infections.

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Arbekacin (ABK) was administered to 17 patients with MRSA infections that complicated underlying hematopoietic disorders, and the efficacy and safety were evaluated. The underlying diseases included acute myelocytic leukemia (8 cases), acute lymphocytic leukemia (1) myelodysplastic syndrome (3), chronic myelocytic leukemia (1), non-Hodgkin's lymphoma (2), Hodgkin's disease (1) and adult T cell leukemia (1). The infections consisted of septicemia (5cases), pneumonia (4), upper respiratory tract infections (6) and urinary tract infections (2). ABK was administered by i. v. drip infusion in daily doses of 150-200 mg, given in two divided dosages. The therapeutic efficacies were: excellent in 2 (2 septicemias), good in 7 (1 septicemia, 4 upper respiratory infections, 2 urinary tract infections), fair in 2 (septicemia and pneumonia) and poor in 6 (1septicemia, 3 pneumonias, 2 upper respiratory infections). As a side effect, reversible renal dysfunction was detected in four cases. Causative bacteria were isolated from six cases. They were all coagulase type II and MIC's of ABK were from 0.25μg/ml to 4.0μg/ml. Arbekacin therapy was found to be effective even in patients with hematopoietic disorders accompanied by MRSA infections.

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We analyzed the efficacy of arbekacin (ABK) using monotherapy or combined therapy on deep MRSA infection to find the most adequate usage of the drug.
We also followed-up the isolation incidence of MRSA after the end of chemotherapy.
The results are summarized as follows:
1. Clinical efficacy of ABK on 29 pneumonia and 3 septicemia due to MRSA was 42.9%in ABK monotherapy (9 patients), 62.5%in combined therapy with ABK and minocycline (9 patients), 100% with ABK and imipenem/cilastatin (IPM/CS)(7 patients), and 100% with ABK and other drugs (7 patients).
2. As for microbiological efficacy, combined therapy with ABK and IPM/CS or other drug was superior to other methods. Among patients from whom two or more species of bacteria were isolated, causative bacteria persisted in many cases, and some replacements occurred.
3. Kidney functions deteriorated in two patients that anderwent monotherapy or combined therapy with ABK and IPM/CS, but they recovered when therapy was completed the completion.
4. In the three month follow-up study after ABK therapy, we found four cases of renewed infections after disappearance of MRSA. When just decreases in the number of MRSA resulted upon the chemotherapy, the relapse occurred in all cases.
5. Above results indicate that ABK is effective in MRSA infection, and combined therapy with β-lactams is superior to other methods in serious MRSA infections. We also suggest that chemotherapy should be continued until the complete disappearance of MRSA is achieved.

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Clinical efficacies of fosfomycin (FOM) or arbekacin (ABK) plus β-lactam combination therapies against methicillin-resistant Staphylococcus aureus (MRSA) infections were examined in 15 major hospitals in Ibaraki Prefecture. The subjects were 54 inpatients from January 1991 to April 1993, and most of them showed moderate to severe infections with underlying diseases. MRSA alone was isolated from23patients and the other 31 patients had polymicobes including MRSA Pseudomonas aeruginosa was the most frequent among the co-isolated strains. The number of patients treated with FOM and cefmetazole (CMZ) was22 (Group C) and that with FOM and flomoxef (FMOX) was25 (Group F). CMZ or FMOX was administrated 60minutes after FOM administration. To 8 nonresponding patients in Groups C and F and 7 nonresponders to the other therapies, ABK and ceftazidime (CAZ) or ABK and piperacillin (PIPC) were treated simultaneously (Group A).
The clinical efficacies of Groups C and F were63.6%and 64%, respectively. The bacteriological efficacies (eradication rates) of both groups including microbial substitutions were 42.9% in the former and56.5%in the latter. No statistical differences were observed in the clinical and the bacteriological efficacies between Groups C and F. The clinical and bacteriological efficacies in Group A were 66.7%and 46.2%, respectively.
No side effects were observed in any cases. Mild disturbances of hepatic functions were observed in2 cases of Groups C and F, and there were no abnormal laboratory test results in Group A.
The combination therapy with FOM plus β-lactam may be useful for the treatment of MRSA infections, but the ABK plus CAZ or PIPC combination is more effective to the patients with multi-drug-resistant MRSA infections.

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Bacteriological and clinical studies were carried out on staggered intensive chemotherapy regimen for methicillin-resistant Staphylococcus aureus (MRSA) infections combined with Gramnegative opportunistic pathogens as polymicrobial infections. The regimen consisted of administering ceftazidime (CAZ) 30 minutes after infusion of arbekacin (ABK) and a bolus injection of fosfomycin (FOM). The combination of these drugs strongly inhibited the growth of MRSA and Pseudomonas aeruginosa. By this combination treatment, both of MRSA and P. aeruginosa in mixed culture became more susceptible to killing by macrophages. We evaluated the clinical efficacy and safety of combination of ABK, FOM and CAZ in the treatment of 15 patients with MRSA infections. The total efficacy rate was 80.0% and the bacterial eradication rate of MRSA was 60.0%. It is considered that staggered intensive chemotherapy with ABK, FOM and CAZ is useful for such polymicrobial infections involving MRSA.

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We examined the clinical efficacy of a combination of arbekacin and fosfomycin in the treatment of various methicillin-resistant Staphylococcus aureus (MRSA) infections. The combination ofarbekacin plus fosfomycin displayed 65.4% (17/26) clinical efficacy and 65.4% (17/26) bacteriological efficacy. This combination thus appeared to be an effective regimen for the treatment of MRSA infections. However, its bacteriological efficacy against concomitant Pseudomonas aeruginosa strains was only 16.7% (1/6). In addition, in 4 episodes of superinfection involving P. aeruginosa strains developed during the combination therapy.

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We evaluated the efficacy of combined therapy of arbekacin (ABK) and imipenem/cilastatin (IPM/CS) against infections by methicillin-resistant Staphylococcus aureus (MRSA).
The MICs of ampicillin, cefmetazole, cefotiam, cefuzonam, flomoxef, fosfomycin, ofloxacin. minocycline, ABK and IPM/CS against clinically isolated strains of MRSA were examined. Almost all strains of MRSA were resistant to these antibiotics except ABK. Furthermore, combination of ABK and IPM/CS showed smaller MICs than that of ABK or IPM/CS alone. All fractional inhibitory concentration indices (FIC indices) of ABK plus IPM/CS were lower than 0.75.
The efficacy rate of combined therapy of ABK and IPM/CS in 22 patients with MRSA infections (15 patients with pneumonia, 3 patients with chronic bronchitis, 2 patients with sepsis, a patient with subcutaneous abscess and a patient with DPB) was 68%. And no patients had adverse reactions. Six (27%) of 22 strains of MRSA were eradicated. Significant correlations were found between bacteriological effect and severity of disease, and between serum albumin level and clinical effect.

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Susceptibilities to antibiotics were determined in 36 strains of methicillin-resistant Staphylococcus aureus (MRSA) isolated from clinical specimens from 1990 to 1992. Rates of resistance to arbekacin and minocycline were 31% and 53%, respectively. However, all MRSA isolates were susceptible to vancomycin.
MRSA was found in 12 out of 35 cases. Three infections caused by MRSA included enterocolitis (3), abscess (5), pneumonia (1), cholangitis (1), peritonitis (1) and catheter related sepsis (1). In two cases patients died with bacteremia within two years after the onset of MRSA infections.

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The clinical efficacy of a new aminoglycoside antibiotic, arbekacin (ABK), was studied in surgical patients who had been infected with methicillin-resistant Staphylococcus aureus (MRSA). Six cases of pneumonia, 2 of wound infections and 2 of intra-abdominal infections were treated by ABK alone or ABK together with β-lactam antibiotics such as imipenem/cilastatin or cefotiam.
The overall clinical efficacies against these MRSA infections were excellent in one case, good in 6 and poor in 3. In six cases treated by ABK alone, good clinical responces were obtained in 4 cases. Among 4 cases that received combination therapy with ABK, good responces were obtained in 3 cases.
No adverse reactions were found in ABK monotherapy or in combinated therapy.
These data suggested that ABK is an effective antibiotic on surgical infections caused by MRSA.

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The frequency of infection by methicillin-resistant Staphylococcus aureus (MRSA) is high in Japan and control of such strains is urgently needed. Arbekacin (ABK), a semisynthetic aminoglycoside, has potent activity against S. aureus, including resistant strains, and against Gt am-negative bacteria as well. For this reason, in surgical infections (which are often caused by more than one bacterium), this drug might be particularly effective. We calculated the MIC and the decrease in the MIC when cultures of 59 resistant strains of S. aureus isolated in our wards at Osaka City University Hospital, contained arbekacin in the medium. We also used the drug to treat 12 infections caused by resistant strains of S. aureus. The MICs of vancomycin had a single peak at 0.5μg/ml, and those for ABK had double peaks at 0.5 and 4.0μg/ml. The effect of arbekacin in lowering the MIC of minocycline (MINO) was slight because of the low MIC of MINO. Effects on fosfomycin (FOM), ampicillin, clavulanic acid/ticarcillin, cefotiam, cefuzonam, flomoxef, and imipenem/cilastatin were strong; the peaks were lowered by 1/2^7-/2¹¹. When 1.0μg/ml ABK was present in the medium, the efficacy of FOM was increased enough that, by prediction from the pharmacokinetics of FOM (blood level when given at the usual dose), all but one (2%) of the 47 resistant strains would be eradicated clinically. If 2.0μg/ml ABK were in the medium, all strain would be eradicated, by our calculations.
We treated 11 infections and one colonization by resistant strains of S. aureus with ABK and evaluated the response in these cases of infection. Four infections were treated with FOM as well. The clinical efficacy was good in four infections (three patients), fair in four, and poor in three, for an efficacy rate of 36%. All presumed causative bacteria were eradicated in two (18%) of the 11 infections and S. aureus strains were eradicated in three (27%) of the 11 infections. No symptoms of side effects were reported, but blood urea nitrogen and creatinine rose in a 72-year-old woman with duodenal perforation and peritonitis. The MIC levels of ABK were satisfactory, but clinical efficacy for staphylococcal infections caused by resistant strains was unsatisfactory.

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From January 1991 to July 1993, 58 patients with MRSA infections in our clinic at Wakayama Medical College and six affiliated hospitals were administered with arbekacin (ABK).
The clinical results were as follows:
1. The clinical efficacy rates of ABK were 84% in pneumonia, 100% in both wound infections and hepatobiliary tract infections, and 85% in total. The bacteriological efficacy rate was 83%.
2. Regarding the administration route, the clinical efficacy rates were 60-79% by the intravenous treatment and inhalation therapy. Especially by the local administration with ABK, MRSA was eradicated in all cases.
3. The sufficient efficacy was obtained by the treatment of ABK alone (89%) and by the combined treatment with ABK (82%) and another antibiotics.
From these results, it is concluded that ABK is useful for the treatment of MRSA infections after gastrointestinal surgery.

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