731
Correspondence . Table. Characteristics of patients with, haematological malignancies and E. coli bacteraemia in 1991 Characteristics
E. coli susceptible to fluoroquinoloses
Number of patients Prior r^prr*fln^ffcm treatment Prior crproSoxacin exposure (days)
£. coli resistant to fluoroquinolones
6
6
2
4
4&7 each
median 35-5 range 10-77
co-trimoiazole: tetracyefine: Without any other
N. SOMOLINOS R. ARRANZ M. C. DEL REY M. L. JIMENEZ* Servicio de Microbiologia. Hospital de la Princesa. Diego de Leon 62. 28003 Madrid, Spain References Acar, J. F. & Francoual, S. (1990). The clinical problems of bacterial resistance to the new quinolonet. Journal of Antimicrobial Chemotherapy 26, Suppl. B, 207-13. EORTC International Antimicrobial Therapy Cooperative Group (1991). Prospective randomized evaluation of dprofloxacin versus piperadllin plus amikadn for empiric antibiotic therapy of febrile granulocytopenic cancer patients with rymphomas and solid tumors. Antimicrobial Agent* and Chemotherapy 35, 873-8. Diaz Mediavilla, J., Scaglione, C , Martinez, R., Vazquez, L., Figuera, A., Camara, R. el al. (1991). Estudk) prospectivo y ateatorizado de la eflcacia y tolerancia entre dprofloxacma y ceftaTirihna-amiVarinii para d tratamiento empirico de las infecdones en pscientes con hemopatias maKgnm y neutropenia grave. Revista Espakola de Quimioterapia 4, 37-42. Johnson, P. R. E , Uu Yin, J. A. & Tooth, J. A. (1990). High dose intravenous dprofloxacin in febrile neutropenic patients. Journal of Antimicrobial Chemotherapy 26, Supp/. F. 101-7. Wolfson, J. S. &. Hooper, D. C. (1989). Fhioroquinolone antimicrobial agents. Clinical Microbiological Reviews 2, 378-424. 'Corresponding author.
Human skin disposition of cefpodoxbne after oral administration of Its proxetfl ester
/ Antbnicrob Chemother 1992; 30: 731-733 Sir, Cefpodoxime proxctil (RU 51807), an orally active third generation cephalosporin, is the isopropoxy-carbonyloxyethyl ester of cefpodoxime. After oral administration, cefpodoxime proxetil is deesterified in the intestinal mucosa and absorbed into the bloodstream as cefpodoxime (RU 51763) (Hughes et al., 1989). The drug is resistant to various types of 0-lactamase and has good activity against Gram-positive and Gram-negative bacteria, particularly Streptococcus spp., Haemophitus influenzat, Neisseria gonorrhoeae, and Proteus mirabilis (Utsui, Inoue & Mitsuhashi, 1987; Wise et al., 1990). Because cefpodoxime proxetil has potential for the treatment of skin and soft tissue infections (Hoshino, Mogi & Takahashi, 1988), the aim of the present study was to investigate the distribution of the drug in human skin to assess if cefpodoxime achieves adequate therapeutic concentrations. Fourteen patients who were undergoing abdominal surgery were studied; all provided informed consent and the study was approved by the local Ethics Committee. Patients were given four oral doses of cefpodoxime proxetil 100 mg (expressed as cefpodoxime equivalents) at 12-h intervals and they had multiple skin and plasma samples taken between 30 min and 9 h after the last dose was administered. Normal skin was taken from the margins of the abdominal surgical wound.
Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on March 10, 2015
Prior therapy with other intibiotics Resistance to other antibiotics:
732
Correspondence
0-01 0
1
2 3 4 5 6 7 8 Time after lost dote (h)
9
Figure. Semilogarithmic plot of concentration w time of cefpodoxime io skin and plasma of surgical patients after the last of four oral doses of 100 mg bd (expressed as cefpodoxime equivalents) of cefpodoxime proxetil. Each point represents the mean vahie of 2-14 samples with S.E.M. shown by vertical bars. Where error bars are not visible, the S.E.M. was smaller than the symbol size. Chwrncwl structure of cefpodoxime acid form (RU 51763) is shown in the upper insert.
efficacy of antimicrobial agents are based on comparative in-vitro activities in relation to plasma concentrations; in addition to this, the determination of antimicrobial concentrations at the potential site of infection has provided information which may improve the accuracy of predictions of efficacy. The results presented herein show that plasma pharmacokinetic parameters of cefpodoxime are in agreement with previously published data (Borin et al., 1990). In this study, the C^ reached in normal skin after oral administration of cefpodoxime proxetil was lower than in plasma and skin penetration was estimated to be 20-8%. Skin levels were above the MIC for skin pathogens, such as Streptococcus pyogenes (MIC«« 001 mg/L), but not for Staphylococcus aweus whose MIC*, is approximately 2 mg/L (Utsui et al., 1987; Wise et al., 1990). A drug's aflSnity for lipids and binding to proteins and glycosaminoglycans play a role in regulating drug penetration into normal skin (Walter & Kurz, 1988); the low protein binding of cefpodoxime may account for the relatively low concentrations of the antibiotic in normal skin. Serum protein binding of cefpodoxime is low; the high blister fluid penetration of this cephem antibiotic (Borin et al., 1990) suggests that the free drug
Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on March 10, 2015
Sterile distilled water was added to plasma samples (1:1, v/v) and left overnight at 4°C. Samples were centrifuged (IS min at 12,000 g), the supcrnatanls collected and the pellet extracted twice with distilled water (1:4, v/v). The supematants were pooled and their volume reduced to 10% of the original by warming them at 55°C. Skin samples were briefly washed with phosphate buffered saline (pH 7-4) or trimmed to remove blood clots and coagulated tissue, homogenized in distilled water by pounding them with aluminum oxide (1:2, w/w) at 0°C, mixed overnight at 4°C and processed as plasma samples. Cefpodoxime concentration in sample extracts (SO uL) was measured using a microbiological plate assay in which the indicator strain (P. mirabilis ATCC 21100) was inoculated on to prepoured Petri dishes (95 mm diameter) of Antibiotic Medium No 1 (Oxoid Ltd., Basingstoke, UK), pH 6-5. Plates were incubated at 37°C for 18 h and each assay was done in triplicate. Standards were prepared by dissolving cefpodoxime sodium salt (RU 51746) in distilled water for skin samples and in pooled human plasma for plasma samples. The lower limit of sensitivity of the assay was 0-015 mg/L and the percentage recovery of the drug from pooled normal plasma and homogenized skin was 85 and 95% respectively. Peak concentration (C^J, time to achieve Cm ( 7 ^ , half-life (r l/2 ), elimination rate constant (KJ and the area under the concentration-time curve from time zero to infinity ( A U Q were calculated simulating a one-compartment open pharmacokinetic model with first order absorption (Hughes et al., 1989). Penetration of drug into skin was estimated as C nujt JC 11BI/-nM , ratios (Borin el al., 1990). Cefpodoxime concentration-time profiles in both plasma and skin are shown in the Figure. Skin levels of the drug were lower than those in plasma; average Cnm in plasma and skin were 2-07 mg/L and 043 mg/kg, respectively. Skin C m of cefpodoxime was delayed as compared with plasma C,^; Tamx in plasma and skin were 2 and 3 h, respectively. Penetration of cefpodoxime in skin was estimated to be 20-8% as determined with CautJCmMi/iBm ratios. The mean value of plasma AUC (12-09 m g h / L ) was higher than skin AUC (2-28 mg- h/kg). Other mean plasma pharmacokinetic parameters were: K^ 0-27 h"1 and Tin 2-66 h; the corresponding values for skin were as follows: It, 041 h"1 and T,n n 1-70 h. Established methods for predicting clinical
Correspondence
I. ZOLFmO* S. SENESr M. CAMPA'
A. Divrro*
F. MOSCA* P. FAVINI' M.DUCCP R. DANESI' M. DEL TACCA* 'Dipartimento di Biomtdietna Sperimentale, Infettiva e Pubblica, Via San Zeno 35, 56127 Pisa; *htituto di Chirurgia Generate e Vascolare, Via Paradise 2, 56124 Pisa; 'Islituto di Farmacologia Medica, Via Roma 55. Vntvtrsila di Pisa, 56126 Pisa; 'Rotasel Pharma. Viale Gran Sasso 18. 20131 Milmo, Italy Correspondence to: Dr Mario Del Tacca, Isthuto di Farmacologia Medica, Universita di Pita, Via Roma 55,1-56126 Pita, Italy.
References Bonn, M. T , Hughe*, O. S., Spilkrt, C. R. & Patel, R. K. (1990). Pharmacokincticg of cefpodoxime in plasma and ikin blister fluid following oral dosing of cefpodoxime proxetil. Antimicrobial Agents and Chemotherapy 34, 1094-9. Hoshino, M., Mop, S. & Takahashi, H. (1988). fTin»?»i evaluation of CS-807 against skin and toft tinue infections. Chemotherapy (Tokyo) 36, Suppt. 1. 1074-8. Hughes, O. S., Heald, D. L., Barker, K. B., Patel, R. K., Spfflers, C. R., Watts, K. C. et al. (1989). The effect! of gastric pH and food on the pharmacokinetics of a new oral cephatosporin, cefpodoxime proxetiL Clinical Pharmacology and Therapeutics 46, 674~«5. Uttm, Y., Inoue, M. & Mittuhashi, S. (1987). In vitro and in vivo antibacterial activities of CS-807, a new oral cephalosporin. Antimicrobial Agents and Chemotherapy 31, 1085-92. Walter, K. & Kurz, H. (1988). Binding of drugs to human skin: influencing factors and the role of tissue tipids. Journal of Pharmacy and Pharmacology 40, 689-93.
Wise, R., Andrews, J. M., Ashby, J. P. & Thornber, D. (1990). The in-vitro activity of cefpodoxime-. a comparison with other oral cephalosporins. Journal of Antimicrobial Chemotherapy 25, 541-50.
The treatment of > large outbreak of scute bacterial gastroenteritis with dproOoxadn
/ Antimicrob Chemother 1992; 30: 733-735 Sir, The annual incidence of infective gastroenteritis is increasing in the UK. The reasons for this increase are not entirely clear but in the case of salmonella gastroenteritis this is probably influenced by the presence of salmonella in eggs and poultry. It can also be explained in part by improvement in surveillance and awareness by doctors and patients. Salmonella enteritidis has become the most common cause of salmonella gastroenteritis. An outbreak of gastroenteritis occurred following an evening meeting of the Chiltern Medical Society which included a buffet dinner. Of 120 people attending the meeting, 110 ate the supper. These included 48 doctors, 35 wives and husbands, 16 visitors, the speaker, his wife and nine caterers. All food consumed at the dinner was available and cultured the following day. S. enteritidis phage type 4 was isolated from the potato salad and food contaminated with mayonnaise which had been made with raw egg yolks. Of the 110 participants 104 ate the potato salad, 98 (94%), 51 women and 47 men, developed symptoms of acute gastroenteritis; four had mild symptoms; six were asymptomatic of whom four were later found to be faecal carriers. The symptoms included general discomfort, fever and vomiting on day 1, followed by headache, myalgia, rigors and diarrhoea; these started within 12 h of eating the meal in 8% and between 13-24 h in 69% (in the remaining patients symptoms occurred after 24 h). The range for women was slightly earlier than the men. Rigors suggesting bacteraemia were found in 38% of the participants. Most (54%) participants developed diarrhoea by the fifth day and 76% by the seventh day; somewhat surprisingly diarrhoea was delayed until after seven days in some (mainly women). In 78% there were greater than four motions per day and in 51% greater or equal to eight motions per day. Diarrhoea was more severe in women.
Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on March 10, 2015
is the driving force for passage into the interstitial fluid. Concentrations of cefpodoxime in excess of MIC*, for S. aweus are reached in skin blister fluid (Bonn el al., 1990) but not in normal skin. High drug levels in inflammatory tissues could be expected because of the alteration in vascular permeability and, therefore, the presence of inflammatory exudates with high protein concentrations. On the basis of the extent of cefpodoxime penetration into normal skin and skin blister fluid, and the good antimicrobial activity of the drug against skin pathogens, cefpodoxime could be of therapeutic value for the oral treatment of skin and soft tissue infections.
733
Correspondence . Table. Characteristics of patients with, haematological malignancies and E. coli bacteraemia in 1991 Characteristics
E. coli susceptible to fluoroquinoloses
Number of patients Prior r^prr*fln^ffcm treatment Prior crproSoxacin exposure (days)
£. coli resistant to fluoroquinolones
6
6
2
4
4&7 each
median 35-5 range 10-77
co-trimoiazole: tetracyefine: Without any other
N. SOMOLINOS R. ARRANZ M. C. DEL REY M. L. JIMENEZ* Servicio de Microbiologia. Hospital de la Princesa. Diego de Leon 62. 28003 Madrid, Spain References Acar, J. F. & Francoual, S. (1990). The clinical problems of bacterial resistance to the new quinolonet. Journal of Antimicrobial Chemotherapy 26, Suppl. B, 207-13. EORTC International Antimicrobial Therapy Cooperative Group (1991). Prospective randomized evaluation of dprofloxacin versus piperadllin plus amikadn for empiric antibiotic therapy of febrile granulocytopenic cancer patients with rymphomas and solid tumors. Antimicrobial Agent* and Chemotherapy 35, 873-8. Diaz Mediavilla, J., Scaglione, C , Martinez, R., Vazquez, L., Figuera, A., Camara, R. el al. (1991). Estudk) prospectivo y ateatorizado de la eflcacia y tolerancia entre dprofloxacma y ceftaTirihna-amiVarinii para d tratamiento empirico de las infecdones en pscientes con hemopatias maKgnm y neutropenia grave. Revista Espakola de Quimioterapia 4, 37-42. Johnson, P. R. E , Uu Yin, J. A. & Tooth, J. A. (1990). High dose intravenous dprofloxacin in febrile neutropenic patients. Journal of Antimicrobial Chemotherapy 26, Supp/. F. 101-7. Wolfson, J. S. &. Hooper, D. C. (1989). Fhioroquinolone antimicrobial agents. Clinical Microbiological Reviews 2, 378-424. 'Corresponding author.
Human skin disposition of cefpodoxbne after oral administration of Its proxetfl ester
/ Antbnicrob Chemother 1992; 30: 731-733 Sir, Cefpodoxime proxctil (RU 51807), an orally active third generation cephalosporin, is the isopropoxy-carbonyloxyethyl ester of cefpodoxime. After oral administration, cefpodoxime proxetil is deesterified in the intestinal mucosa and absorbed into the bloodstream as cefpodoxime (RU 51763) (Hughes et al., 1989). The drug is resistant to various types of 0-lactamase and has good activity against Gram-positive and Gram-negative bacteria, particularly Streptococcus spp., Haemophitus influenzat, Neisseria gonorrhoeae, and Proteus mirabilis (Utsui, Inoue & Mitsuhashi, 1987; Wise et al., 1990). Because cefpodoxime proxetil has potential for the treatment of skin and soft tissue infections (Hoshino, Mogi & Takahashi, 1988), the aim of the present study was to investigate the distribution of the drug in human skin to assess if cefpodoxime achieves adequate therapeutic concentrations. Fourteen patients who were undergoing abdominal surgery were studied; all provided informed consent and the study was approved by the local Ethics Committee. Patients were given four oral doses of cefpodoxime proxetil 100 mg (expressed as cefpodoxime equivalents) at 12-h intervals and they had multiple skin and plasma samples taken between 30 min and 9 h after the last dose was administered. Normal skin was taken from the margins of the abdominal surgical wound.
Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on March 10, 2015
Prior therapy with other intibiotics Resistance to other antibiotics:
732
Correspondence
0-01 0
1
2 3 4 5 6 7 8 Time after lost dote (h)
9
Figure. Semilogarithmic plot of concentration w time of cefpodoxime io skin and plasma of surgical patients after the last of four oral doses of 100 mg bd (expressed as cefpodoxime equivalents) of cefpodoxime proxetil. Each point represents the mean vahie of 2-14 samples with S.E.M. shown by vertical bars. Where error bars are not visible, the S.E.M. was smaller than the symbol size. Chwrncwl structure of cefpodoxime acid form (RU 51763) is shown in the upper insert.
efficacy of antimicrobial agents are based on comparative in-vitro activities in relation to plasma concentrations; in addition to this, the determination of antimicrobial concentrations at the potential site of infection has provided information which may improve the accuracy of predictions of efficacy. The results presented herein show that plasma pharmacokinetic parameters of cefpodoxime are in agreement with previously published data (Borin et al., 1990). In this study, the C^ reached in normal skin after oral administration of cefpodoxime proxetil was lower than in plasma and skin penetration was estimated to be 20-8%. Skin levels were above the MIC for skin pathogens, such as Streptococcus pyogenes (MIC«« 001 mg/L), but not for Staphylococcus aweus whose MIC*, is approximately 2 mg/L (Utsui et al., 1987; Wise et al., 1990). A drug's aflSnity for lipids and binding to proteins and glycosaminoglycans play a role in regulating drug penetration into normal skin (Walter & Kurz, 1988); the low protein binding of cefpodoxime may account for the relatively low concentrations of the antibiotic in normal skin. Serum protein binding of cefpodoxime is low; the high blister fluid penetration of this cephem antibiotic (Borin et al., 1990) suggests that the free drug
Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on March 10, 2015
Sterile distilled water was added to plasma samples (1:1, v/v) and left overnight at 4°C. Samples were centrifuged (IS min at 12,000 g), the supcrnatanls collected and the pellet extracted twice with distilled water (1:4, v/v). The supematants were pooled and their volume reduced to 10% of the original by warming them at 55°C. Skin samples were briefly washed with phosphate buffered saline (pH 7-4) or trimmed to remove blood clots and coagulated tissue, homogenized in distilled water by pounding them with aluminum oxide (1:2, w/w) at 0°C, mixed overnight at 4°C and processed as plasma samples. Cefpodoxime concentration in sample extracts (SO uL) was measured using a microbiological plate assay in which the indicator strain (P. mirabilis ATCC 21100) was inoculated on to prepoured Petri dishes (95 mm diameter) of Antibiotic Medium No 1 (Oxoid Ltd., Basingstoke, UK), pH 6-5. Plates were incubated at 37°C for 18 h and each assay was done in triplicate. Standards were prepared by dissolving cefpodoxime sodium salt (RU 51746) in distilled water for skin samples and in pooled human plasma for plasma samples. The lower limit of sensitivity of the assay was 0-015 mg/L and the percentage recovery of the drug from pooled normal plasma and homogenized skin was 85 and 95% respectively. Peak concentration (C^J, time to achieve Cm ( 7 ^ , half-life (r l/2 ), elimination rate constant (KJ and the area under the concentration-time curve from time zero to infinity ( A U Q were calculated simulating a one-compartment open pharmacokinetic model with first order absorption (Hughes et al., 1989). Penetration of drug into skin was estimated as C nujt JC 11BI/-nM , ratios (Borin el al., 1990). Cefpodoxime concentration-time profiles in both plasma and skin are shown in the Figure. Skin levels of the drug were lower than those in plasma; average Cnm in plasma and skin were 2-07 mg/L and 043 mg/kg, respectively. Skin C m of cefpodoxime was delayed as compared with plasma C,^; Tamx in plasma and skin were 2 and 3 h, respectively. Penetration of cefpodoxime in skin was estimated to be 20-8% as determined with CautJCmMi/iBm ratios. The mean value of plasma AUC (12-09 m g h / L ) was higher than skin AUC (2-28 mg- h/kg). Other mean plasma pharmacokinetic parameters were: K^ 0-27 h"1 and Tin 2-66 h; the corresponding values for skin were as follows: It, 041 h"1 and T,n n 1-70 h. Established methods for predicting clinical
Correspondence
I. ZOLFmO* S. SENESr M. CAMPA'
A. Divrro*
F. MOSCA* P. FAVINI' M.DUCCP R. DANESI' M. DEL TACCA* 'Dipartimento di Biomtdietna Sperimentale, Infettiva e Pubblica, Via San Zeno 35, 56127 Pisa; *htituto di Chirurgia Generate e Vascolare, Via Paradise 2, 56124 Pisa; 'Islituto di Farmacologia Medica, Via Roma 55. Vntvtrsila di Pisa, 56126 Pisa; 'Rotasel Pharma. Viale Gran Sasso 18. 20131 Milmo, Italy Correspondence to: Dr Mario Del Tacca, Isthuto di Farmacologia Medica, Universita di Pita, Via Roma 55,1-56126 Pita, Italy.
References Bonn, M. T , Hughe*, O. S., Spilkrt, C. R. & Patel, R. K. (1990). Pharmacokincticg of cefpodoxime in plasma and ikin blister fluid following oral dosing of cefpodoxime proxetil. Antimicrobial Agents and Chemotherapy 34, 1094-9. Hoshino, M., Mop, S. & Takahashi, H. (1988). fTin»?»i evaluation of CS-807 against skin and toft tinue infections. Chemotherapy (Tokyo) 36, Suppt. 1. 1074-8. Hughes, O. S., Heald, D. L., Barker, K. B., Patel, R. K., Spfflers, C. R., Watts, K. C. et al. (1989). The effect! of gastric pH and food on the pharmacokinetics of a new oral cephatosporin, cefpodoxime proxetiL Clinical Pharmacology and Therapeutics 46, 674~«5. Uttm, Y., Inoue, M. & Mittuhashi, S. (1987). In vitro and in vivo antibacterial activities of CS-807, a new oral cephalosporin. Antimicrobial Agents and Chemotherapy 31, 1085-92. Walter, K. & Kurz, H. (1988). Binding of drugs to human skin: influencing factors and the role of tissue tipids. Journal of Pharmacy and Pharmacology 40, 689-93.
Wise, R., Andrews, J. M., Ashby, J. P. & Thornber, D. (1990). The in-vitro activity of cefpodoxime-. a comparison with other oral cephalosporins. Journal of Antimicrobial Chemotherapy 25, 541-50.
The treatment of > large outbreak of scute bacterial gastroenteritis with dproOoxadn
/ Antimicrob Chemother 1992; 30: 733-735 Sir, The annual incidence of infective gastroenteritis is increasing in the UK. The reasons for this increase are not entirely clear but in the case of salmonella gastroenteritis this is probably influenced by the presence of salmonella in eggs and poultry. It can also be explained in part by improvement in surveillance and awareness by doctors and patients. Salmonella enteritidis has become the most common cause of salmonella gastroenteritis. An outbreak of gastroenteritis occurred following an evening meeting of the Chiltern Medical Society which included a buffet dinner. Of 120 people attending the meeting, 110 ate the supper. These included 48 doctors, 35 wives and husbands, 16 visitors, the speaker, his wife and nine caterers. All food consumed at the dinner was available and cultured the following day. S. enteritidis phage type 4 was isolated from the potato salad and food contaminated with mayonnaise which had been made with raw egg yolks. Of the 110 participants 104 ate the potato salad, 98 (94%), 51 women and 47 men, developed symptoms of acute gastroenteritis; four had mild symptoms; six were asymptomatic of whom four were later found to be faecal carriers. The symptoms included general discomfort, fever and vomiting on day 1, followed by headache, myalgia, rigors and diarrhoea; these started within 12 h of eating the meal in 8% and between 13-24 h in 69% (in the remaining patients symptoms occurred after 24 h). The range for women was slightly earlier than the men. Rigors suggesting bacteraemia were found in 38% of the participants. Most (54%) participants developed diarrhoea by the fifth day and 76% by the seventh day; somewhat surprisingly diarrhoea was delayed until after seven days in some (mainly women). In 78% there were greater than four motions per day and in 51% greater or equal to eight motions per day. Diarrhoea was more severe in women.
Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on March 10, 2015
is the driving force for passage into the interstitial fluid. Concentrations of cefpodoxime in excess of MIC*, for S. aweus are reached in skin blister fluid (Bonn el al., 1990) but not in normal skin. High drug levels in inflammatory tissues could be expected because of the alteration in vascular permeability and, therefore, the presence of inflammatory exudates with high protein concentrations. On the basis of the extent of cefpodoxime penetration into normal skin and skin blister fluid, and the good antimicrobial activity of the drug against skin pathogens, cefpodoxime could be of therapeutic value for the oral treatment of skin and soft tissue infections.
733
