In vitro antimicrobial susceptibility tests can play an essential role in clinical management of infectious diseases, and in vitro MIC break point is important in choice of antibiotic. Standarization of method for measuring MIC is necessary, if break points are to be fixed internationally. However, it is difficult to settle on uniform international break points, since standard doses of antibiotics and the preferred routes of administration differ in different parts of the world.
With respect to in vitro MIC break points, the NCCLS system is used in the U. S. A., and in Japan, Showa disc system and the NCCLS system are both used. In Europe 6 different systems are utilized (BSAC, DIN, SFM, SIR, NCCLS, and WRG). There is a certain degree of similarity between different concentration values used to define break points in these systems. In general, however, the BSAC and DIN systems recommend lower break points and the NCCLS and SFM systems higher break points. The MIC values of the break points, +++ and ++ categories of Showa 4 category classification system (+++, ++, +,-) used in Japan, are similar to those of the BSAC system.
Higher ratio of positive responses to bactericidal antibiotic therapies have been reported when ratios. of peak concentrations of drugs in plasma/in vitro MIC are increased, and maximum responses are obtained when the ratio reaches about 8 in cases with aminoglycosides and β-lactams. In neutropenic compromized patients, drug concentrations with ratios higher than 8 to 10 may be required to treat infections. Drug availabilities are different depending on drugs and sites of infections. Susceptibility patterns to antibiotics are also quite different with different organisms. From the evidence presented above, a multiple (at least 2, low and high) sensitivity MIC break point system appears to be more appropriate than a single sensitivity MIC break point system to cope with various infections.
Multiplicity of break points should depend on types of organisms, antibiotic availabilities at sites of infections, and specific factors in patients. Pharmacokinetic data on antibiotics must be more precisely taken into account with respect to the diversity of dosages, and especially effective antibiotic concentrations at sites of infections.

View full abstract

Antimicrobial activities of cefmetazole (CMZ) and cefotiam (CTM) in combination were studied against clinical isolates of Staphylococcus aureus (9 methicillin-susceptible strains and 47 methicillin-resistant strains) by the checkerboard MIC method and the disc diffusion test using Mueller-Hinton agar with or without addition of 4% NaCl.
MICs of CMZ and CTM individually against 9 methicillin-susceptible strains (MSSA) were 0.78-1.56μg/ml and 0.39-0.78μg/ml without 4% NaCl, and 1.56-3.13μg/ml and 0.78-1.56μg/m with 4% NaCl, respectively. In combination of CMZ and CTM, MICs of CMZ and CTM against these MSSA decreased to 0.20-0.39μg/ml and 0.20μg/ml without 4% NaCl, and 0.20-0.78μg/ml and 0.10-0.78μg/ml with 4% NaCl, respectively, showing minimum FIC indexes of 0.313 to 0.628. FIC indexes≤50.5 were observed against 7 out of 9 strains.
MICs of CMZ and CTM individually against 47 methicillin-resistant strains (MRSA) were 6.25-100μg/ml and 3.13-800μg/ml in the absence of 4% NaCl, and 6.25-100μg/ml and 50->800μg/ml in the presence of 4% NaCl, respectively. In combination of CMZ and CTM, MICs of these drugs against MRSA were reduced to 0.20-25μg/ml and 0.39-200μg/ml without 4% NaCl and 0.39-25μg/ml and 3.13-200μg/ml with 4% NaCl, respectively. The strains studied showed minimum FIC indexes of 0.02 to 0.5 either with 4% NaCl or not.
By the disc diffusion method, between CMZ disc and CTM disc a synergistic interaction against MRSA was well observed. In addition, discs containing both drugs showed a greater inhibitory zone than discs containing the equivalent amount of CMZ or CTM alone. These in vitro observations reported here suggest that the use of CMZ and CTM in combination is more effective than the use of these drugs individually for the treatment of MSSA and slight to moderate resistant MRSA infection. Prophylactic use of CMZ and CTM in combination for surgical infection would be also more effective than the use of these drugs individually.
The synergistic enhancement of antimicrobial activity of CMZ and CTM in combination was assessed using discs containing various amounts of these drugs at various ratios. In this investigation, discs containing CMZ/CTM (20μg/10μg) was selected. Using discs containing CMZ/CTM (20μg/10μg), disc inhibitory zone diameters against MSSA and MRSA were well correlated negatively with MICs of CMZ or CTM in combination. From inhibitory zone diameter obtained with such combination discs, MICs of CMZ or CTM in combination can be assessed.

View full abstract

Against 200 strains of methicillin-resistant Staphylococcus aureus (MRSA) isolated from 1990 to 1991, minimum inhibitory concentrations (MICs) of a total of 15 antibacterial agents including arbekacin (ABK) were determined. In addition coagulase types of the tested strains were determined and classified according on their origins.
1. Among the coagulase types of 200 strains, type II were 63.5%, type IV 18.5%, type VII 11.0% and the other types 7.0%. Type II strains were prevailing among those isolated from the respiratory tract specimens and type IV among those from the surgical specimens. These results were in agreement with other recent reports including our previous ones.
2. The MIC₅₀ of methicillin, 6 cephalosporins (CEPs), imipenem, fosfomycin (FOM), gentamicin, tobramycin and clindamycin for 200 strains ranged from 50 to>100μg/ml. On the other hand, MIC₅₀ and MIC₉₀ of ABK, minocycline (MINO) and vancomycin (VCM) were 0.78 and 3.13μg/ml for ABK, 0.39 and 50μg/ml for MINO, and 0.78 and 1.56μg/ml for VCM.
3. The MIC₉₀ of ABK against coagulase type IV strains was rather high, 12.5μg/ml. However, the strains inhibited by 6.25 to 12.5μg/ml of ABK were isolated even in our studies performed in 1986, 1988 and 1989. Further studies are therefore required to confirm whether appearance of these strains used in the present study inhibited at relatively high concentrations of ABK is due to the use of ABK.
4. It is reported that, at present, most of the MRSAs spreading in Japan are acceleratedly aquiring resistance to many drugs, and especially, they are developing high resistance against β-lactams. ABK showed potent antibacterial activities even against these strains. Since ABK has been shown to display potent activities against MRSA in conbination with β-lactams or FOM, we believe ABK is one of the useful aminoglycoside antibiotics for the treatment of MRSA infections.

View full abstract

This study was aimed at determining whether the thrombin (TRB)-induced aggregation and intracellular free Ca²⁺ ([Ca²⁺]_i) mobilization of fura-2-loaded human platelets would be affected by aminoglycoside antibiotics (AGs), i. e., kanamycin (KM), gentamicin (GM) and fradiomycin (FRM) with 4, 5 and 6 amino groups in their molecules, respectively. We used pH-adjusted solution of AGs, since the TRB-induced aggregation and [Ca²⁺]_i mobilization are pH-dependent.
TRB (0.1U/ml) induced aggregation in the presence of 1mm external Ca²⁺ but did not in the absence of external Ca²⁺. The 3 AGs reduced the TRB-induced aggregation and the antiaggregating potencies were in the order FRM=GM>KM. TRB-induced [Ca²⁺]_i elevation in the presence of external Ca²⁺ was 3 times higher than in the absence of external Ca²⁺ and the 3 AGs concentration-dependently reduced the TRB-induced [Ca²⁺]_i elevation in the absence of external Ca²⁺ as well as in its presence, and the potency order was FRM>GM>KM. The IC₅₀ of GM or KM was higher in the absence of external Ca²⁺ than in its presence, while the IC₅₀ of FRM was scarcely affected by the deprivation of external Ca²⁺.
These results suggest that the reducing potency of the 3 AGs in the TRB-induced aggregation and Ca²⁺_i mobilization of human platelets is based on the number of amino groups. Furthermore, it is suggested that GM and KM predominantly reduce the Ca²⁺ influx rather than the intracellular Ca²⁺ release but FRM is equieffective in decreasing both of them.

View full abstract

Eightysix patients with infections associated with hematological disorders were treated with sulbactam/cefoperazone (SBT/CPZ) and amikacin (AMK). Among 71 evaluable cases, 30 cases had acute non-lymphocytic leukemia, 3 acute lymphoblastic leukemia, 25 malignant lymphoma, and 7 myelodysplastic syndrome as underlying diseases. Excellent responses were obtained in 33 cases (46.5%) and good responses in 14 cases (19.7%), with an overall efficacy rate of 66.2%. The efficacy rate among cases with suspected sepsis was 72.5%. This treatment was also effective in 69.2% of cases in which neutrophil counts were less than 500/μl through the course of administration. The eradication rate was 83.3% among 6 strains in which Gram-negative rods were detected. Side effects were minimum; skin rash in 1 case, slight elevation of APTT in 3 and slight elevation of total bilirubin in 1. Thus, this combination antibacterial chemotherapy is an effective and safe regimen for the treatment of severe infections in patients with hematological disorders.

View full abstract

The clinical and bacteriological efficacy of imipenem/cilastatin (IPM/CS) was evaluated in 30 cases of serious infections associated with hematological malignancies.
1. Among 28 evaluable cases, excellent efficacy was obtained in 6 cases and good effectiveness in 10 cases, resulting in a high clinical efficacy rate (57.1%). The clinical effectiveness of IPM/CS was not dependent on neutrophil count in peripheral blood. A 53.8% efficacy rate was observed in 26 cases which had received pretreatment with other antibiotics.
2. Antibacterial activities of IPM/CS have so far been evaluated against organisms isolated in 20 of 28 cases: 2 strains of coagulase-negative Staphylococcus, 2 strains of methicillin-resistant Staphylococcus aureus, 2 strains of Enterococcus faecalis, 9 strains of Enterobacter cloacae, and 8 other strains.
3. Among 3 evaluable cases treated with IPM/CS alone, response was good in 1 case. Among 25 patients receiving IPM/CS in combination with an aminoglycoside or a penicillin, the efficacy rate was 60%.
4. Five patients had IPM/CS-related adverse events; nausea and vomiting in 2 cases, seizures in 1 case, small increases in GOT and GPT in 2 cases, and the appearance of casts in urine sediment in 1 case. These patients, however, tolerated the complete course of therapy with IPM/CS except the 2 cases with nausea and vomiting.
These results indicate that chemotherapy with IPM/CS is effective for the treatment of severe infectious diseases accompanied by hematological disorders.

View full abstract

In Japan, oral antimicrobial agents are prophylactically used with oxytocics after normal delivery to prevent puerperal infections. The present study was designed to investigate bacterial floras in the endometrial cavity immediately after normal delivery and the effect of prophylactic use of antimicrobial agents on those floras.
Sixty-six puerperae who underwent uneventful courses of pregnancy and delivery were subjected for this study.
Intrauterine contents were collected on the first day and the fifth day of the puerperium and submitted to microbiological examinations. Cefpodoxime proxetil (CPDX-PR) was orally given to the puerperae for prophylaxis for 5 days after the initial sampling.
On the puerperal first day, a total of 98 strains (71 strains of aerobic bacteria, 27 strains of anaerobic bacteria) was detected in the uteri of the 66 subjects. The incidences of aerobic Gram-positive cocci, aerobic Gram-negative bacilli and anaerobic bacteria were 59.2%, 12.2%, 27.6% of the 98 strains, respectively.
On the puerperal fifth day, a total of 82 strains (51 strains of aerobic bacteria and 31 strains of anaerobic bacteria) were detected in the uteri of the 66 subjects. The incidences of aerobic Gram-positive cocci, aerobic Gram-negative bacilli and anaerobic bacteria were 52.5%, 8.6% and 37.7% of 82 strains, respectively.

View full abstract