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Temocillin

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Summary

Temocillin is a β-lactamase resistant penicillin marketed by Eumedica Pharmaceuticals as Negaban® primarily for the treatment of multiresistant Gram negative bacteria.

Pharmacology

Temocillin is a β-lactamase resistance penicillin. It is not active against Gram positive bacteria or bacteria with altered penicillin-binding proteins.

It is normally active against Branhamella catarrhalis, Brucella abortus, Burkholderia cepacia, Citrobacter species, Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Pasteurella multocida, Proteus mirabilis, Salmonella typhimurium and Yersinia enterocolitica. It is also active against some Enterobacter species, Morganella morganii and Serratia species. Temocillin has no useful activity against Gram positive organisms, Acinetobacter species or Pseudomonas aeruginosa.

Its primary use is against Enterobacteraceae producing extended spectrum β-lactamase or AmpC β-lactamase (Bonacorsi 1999).

Dosage

The most common dosage is 1g intravenously or intramuscularly every 12 hours. For severe infections, the dose is 2g intravenously every 12 hours. There are good theoretical reasons for giving Temocillin as a continuous intravenous infusion in severe disease: a single loading dose of 2g is given intravenously followed by a 4g infusion over 24 hours. Temocillin for intravenous injection is diluted in 20ml of sterile water; it is diluted in less than 2.7ml of sterile water when being prepared for intramuscular injection; the continuous infusion is diluted in 48ml of sterile water for ease of administration (1ml per half hour). To reduce pain, the intramuscular injection may be made up using sterile 1% lignocaine instead of sterile water.

Temocillin may be given to patient with impaired renal function. No adjustment needs to be made to the dose in mild to moderate renal impairment (creatinine clearance greater than 30ml/min). The manufacturer does not recommend using reduced doses, instead they recommend increasing the duration between doses. In severe renal impairment when it is 10 to 30, the dose is 1g in 24 hours; when less than 10, the dose is 1g every 48 hours. Temocillin is cleared by haemodialysis, which means that in dialysis patients, the dose should be given after dialysis.

There is no licensed oral preparation of Temocillin.

Undesirable effects

The undesirable effects of Temocillin are those of any β-lactam antibiotic. In particular, Temocillin has been associated with angioedema and anaphylaxis in penicillin allergic patients. As with any antibiotic, Temocillin has been associated with Clostridium difficile colitis. As with any other penicillin, convulsions can occur if very high doses are given.

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Bacterial surveillance cultures in a geriatric ward
From Age and Ageing, 5/1/93 by W. Michielsen

Introduction

It is well known that elderly people are more susceptible to infections as changes in their immune system and alterations of organs occur [1-5]. The risk increases with the presence of various disorders, especially in patients who are hospitalized in geriatric wards [6-9].

The risk of colonization with micro-organisms is increased in advanced age, but it is not clear that this colonization leads to infections [10-12]. Medical literature mainly of American origin has warned of the risk of colonization with Gram-negative rods and of subsequent infections with resistant strains in geriatric patients [13-18]. The aim of the present study was to examine the prevalence of oropharyngeal and urinary tract colonization in a Belgian geriatric ward and to compare the colonizing bacteria with the strains causing infections during the hospital stay.

Methods

In a prospective study, colonizing bacteria of the oropharynx and the urinary tract were identified as well as the bacteria responsible for pneumonia and urinary tract infections (UTI).

All patients admitted to our geriatric clinic during the period January June 1990 were included in this study.

During the study, 119 patients were followed, 56 men and 63 women. The youngest patient was 65 years old and the oldest 99; the average age was 81 years. As five patients had been hospitalized twice, the total number of cases studied amounted to 124. Sixty-seven patients (54%) were admitted from home, 15 (12%) from a nursing home, 32 (26%) were transferred from another department within the hospital, 10 (8%) from the Intensive Care Unit (ICU) .

The length of stay in hospital varied between 7 and 99 days, with an average of 29 days. During the hospitalization, 13 patients (11%) died. Fifty-nine patients (48%) went back home, 44 (35%) to a nursing home and 8 (6%) to another ward.

In all patients, a smear from the oropharynx and a midstream urine sample

were taken on the day of admission and after 3 and 7 days and then once a week during the rest of the stay within the department.

The oropharyngeal swab was inoculated on tryptic soy agar with 5% sheep blood (BA) and on Sabouraud agar (SAB) (Becton Dickinson, Cockeysville, Maryland, 2103U USA). The two media allow detection of most of the non-fastidious aerobes and the yeasts. No enrichment broth for Gram-negatives was used, as inocula of [greater than or equal to] [10.sup.3] CFU are easily detected on solid media [19].

The urine sample was routinely processed for sediment and culture. The sample was inoculated with a 0.001 ml calibrated loop on to a BA and an eosine methylene blue agar (EMB) as selective medium for Gram-negatives [19].

Sputum was collected, if available, from patients presenting with signs of respiratory tract infection (RTI). The sputum was washed with sterile saline before Gram staining and inoculated on standard media (BA, chocolate agar, SAB, mannitol salt agar, EMB) [20].

Cultures from pharyngeal swabs and sputum samples were read semi-quantitatively (0, [+ or -], +, + +, + + +) and the results were categorized as routinely performed in: 1. Classical pathogens, e.g. pneumococci + + in a good sputum sample. 2. Normal oral flora: mixed culture of generally accepted oral micro-organisms, predominance of alpha haemolytic streptococci. 3. Colonization: small numbers of possible pathogens in a normal oral flora, e.g. Staphylococcus aureus + or yeasts + . 4. Uninterpretable without clinical context and other data: E. coli + + in a normal oral flora from a sputum with high numbers of squamous epithelial cells. Special attention was given to the presence of Enterobacteriaceae and non-fermenting Gram-negatives.

On urine samples, colony counts were performed and interpreted according Kass criteria ([10.sup.5] CFU/ ml) and modulations made by Stamm ([10.sup.4] CFU/ml-[10.sup.3] CFU/ml) [21].

The diagnosis of pneumonia and UTI was made by combining the clinical findings, clinical laboratory data (peripheral blood, urine), bacteriological data (cultures of urine, sputum, blood) and technical investigations such as radiography, ultrasonography and other imaging techniques [9, 13, 16].

Results

The colonizing bacteria found at admission are summarized in Table I. Colonization of the oropharynx was limited. Four patients harboured Gram-negatives, one patient a Staphylococcus aureus and nine patients yeasts in their throats. The colonization of the urinary tract was more marked. An asymptomatic bacteriuria was detected in 23 patients mainly with E. coli, Pseudomonas aeruginosa and Enterococci .

Fifty patients were admitted on clinical grounds for RTI (n = 28) or UTI (n = 22). UTI was bacteriologically documented in 90% (20/ 22) of the cases, whereas only 32% (9128) of the RTI were confirmed by culture. These results conform with the literature [9, 13].

The UTI were mainly caused by E. coli, as in general practice. The aetiological agents for RTI included the classical ones such as pneumococci, H. influenzae, Staphylococcus aureus and M. tuberculosis, but also, surprisingly, Enterobacteriaceae (43%) (Table II). Without invasive diagnostic techniques, these isolates are highly suspicious pathogens in the clinical context but cannot be absolutely incriminated. Table III shows the important colonization rate occurring during stay in the geriatric ward. In the oropharynx, yeasts and K. pneumoniae were frequent colonizers. E. coli, K. pneumoniae and Ps. aeruginosa predominated in colonization of the urinary tract.

Thirty-six patients (29%) developed a nosocomial respiratory (2 documented) or urinary tract (14 documented) infection (18 RTI, 18 UTI). The aetiological agents are listed in Table IV. Seventy-eight per cent of the UTI were bacteriologically documented and only 11% of the RTI. Although nosocomial in origin, the aetiological agents showed no major differences with those at admission. In five patients with UTI the infection was polymicrobic (TABLE IV)

The antibiotic sensitivity of the organisms isolated is summarized in Table V. Of the 14 Staphylococcus aureus isolates only one was methicillin resistant. Few resistant Ps. aeruginosa were detected. The intensive care unit of our hospital has a nosocomial problem with broad-spectrum beta-lactamase-producing strains, mainly K. pneumoniae. Of 95 Enterobacteriaceae isolated in the geriatric ward, 12 strains--11 K. pneumoniae and 1 E. coli--contained this beta-lactamase. Two patients were infected with these strains, ten were colonized. Four patients presented this strain on admission: three of them were transferred from the ICU, the fourth came from home but had been an inpatient at our hospital previously.

In Figure 1 the susceptibility to ampicillin, co-trimoxazole, tobramycin, piperacillin, fluoroquinolones and temocillin of the colonizing and infecting Enterobacteriaceae, on admission, is tabulated. Sensitivity varied with the origin of the patient--ICU, other hospital department, nursing home or home [7, 15, 17]. Overall, ampicillin and co-trimoxazole had the lowest activity.

Comparison of the susceptibility of the Enterobacteriaceae isolated on admission from home or from a nursing home with the strains isolated on admission from another hospital department or during the stay in the geriatric ward, demonstrates the higher resistance of nosocomially acquired strains (Figure 2).

Discussion

In the literature many reports stress the higher risk for colonization with Gram-negative rods in elderly patients, particularly in the pharyngeal tract [5, 6, 15, 16]. Since colonizing bacteria can provoke infections, the presence and the resistance pattern of these Gram-negatives are strongly emphasized [17, 18].

Our data indicate that this colonization is commonly present on admission and continues to develop during hospital stay (Tables I and III). Colonization with typical hospital strains occurs mainly during hospital stay and is found on admission in patients transferred from other hospital departments, mainly ICU.

Yeasts were frequent colonizers (9 on admission, 12 during hospital stay) of the oropharynx. No clinical infection with yeasts was observed.

During follow-up, colonizing strains frequently disappeared or were replaced by other colonizing species [11, 13, 22]. The number of patients infected on admission as well as during their stay is impressive. UTIs are usually bacteriologically documentable and treatment can be guided or corrected by susceptibility testings. The number of resistant strains was limited (Table V) (18-23).

As expected, the number of documented RTI is low. Our 32% recovery rate on admission compares favourably with the 25% reported by others [9]. In six cases Enterobacteriaceae were isolated and considered to be significant. In nosocomial RTI our isolation rate is very low. Some of these primary nosocomial pneumonias are aspiration pneumonias with mixed oral flora. More invasive techniques could be considered for diagnosis but this could in turn increase the number of nosocomial pneumonias

With regard to nosocomial Gram-negative pneumonias our findings differ from reported data, which correspond more with what we have observed in the intensive care unit where patients are as aged as our patients, but often on mechanical ventilation [9, 17, 24]. Since Gram-negatives are non-fastidious, the culture techniques in use cannot be responsible for a loss of isolates and the differences must be considered as significant [19].

In our population a weak relationship exists between colonizing and infecting agents. In three of the 14 nosocomial UTI the colonizing micro-organism infected the patient. In RTI no relationship between colonizers and infection could be observed. From our data we conclude that the predictive value for infection of the colonization cultures is very small. Of the patients who remained without nosocomial infection 36% were colonized and colonization did not often cause infection [10, 11].

Enterobacteriaceae were not infrequently resistant to ampicillin and co-trimoxazole and blind use of these drugs may be unjustified [15, 23, 25]. Patients with previous hospitalization, particularly in the ICU, where there is currently an epidemic of infection with a broadspectrum beta-lactamase-producing organism, must be suspected of carrying more-resistant strains. Although these strains rarely cause infections, their importance for infection control measures and their influence on the antibiotic prescribing pattern must not be underestimated.

The surveillance of community-acquired and nosocomial infections together with the study of colonization rates in pharynx and urethra in our geriatric wards was instructive in their similarities and differences with published reports and their therapeutic consequences [26]. The importance of Gram-negative colonizers on subsequent infections may be overemphasized in the literature.

References

[1.] Yoshikawa TT. Aging and infectious diseases: state of the art. Gerontology 1984;30:275-8. [2.] Saltzman R, Peterson PK. Immunodeficiency of the elderly. Rev Infect Dis 1987;9:1127-39. [3.] Finkelstein MS. Unusual features of infection in the aging. Geriatrics 1982;37:65-78. [4.] Cunha BA, Gingrich D, Rosenbaum GS. Pneumonia syndromes: a clinical approach in the elderly. Geriatrics 1990;45:49-55. [5.] Verghese A, Berk SL. Bacterial pneumonia in the elderly. Medicine 1983;62:271-85. [6.] Schneider EL. Infectious diseases in the elderly. Ann Intern Med 1983;98:395-400. [7.] Zilkoski MW, Smucker DR, Mayhew HE. Urinary tract infections in elderly patients. Postgrad Med 1988;84:191 206. [8.] Marrie TJ, Durant H, Yates L. Community-acquired pneumonia requiring hospitalization: 5-year prospective study. Rev Infect Dis 1989;11:586 9. [9.] Niederman MS, Fein AM. Pneumonia in the elderly. Geriatr Clin North Am 1986;2:241-68. [10.] Ortqvist A, Hammers-Berggren S, Kalin M. Respiratory tract colonization and incidence of secondary infection during hospital treatment of community-acquired pneumonia. Eur F Clin Microbiol Infect Dis 1990;9:725-31. [11.] Sveinbjornsdottir S, Gudmundsson S, Briem H. Oropharyngeal colonization in the elderly. Eur F Clin Microbiol Infect Dis 1991;10:959-63. [12.] Holmberg H. Aetiology of community-acquired pneumonia in hospital treated patients. Scand F Infect Dis 1987;19:491-501. [13.] Mulholland SG. Urinary tract infection. Clin Geriatr Med 1990;6:43-53. [14.] Rosenthal S, Tager IB. Prevalence of Gram-negative rods in the normal pharyngeal flora. Ann Intern Med 1975;83:355-7. [15.] Raju L, Khan F. Pneumonia in the elderly: a review. Geriatrics 1988;43:51-62. [16.] Horton JM, Pankey GA. Pneumonia in the elderly: a growing problem demanding special handling. Postgrad Med 1982;71:114-23. [17.] Roselle GA. Nosocomial and nursing home-acquired pneumonia: recent therapeutic advances. Postgrad Med 1987;81:131-6. [18.] Gaynes RP, Weinstein RA, Chamberlin W, et al. Antibiotic-resistant flora in nursing home patients admitted to hospital. Arch Intern Med 1985;145:1804-7. [19.] Balows A, Hausler WJ jr, Herrmann KL, Isenberg HD, Shadomy HJ, eds. Manual of clinical microbiology. 5th edn. Washington, DC: ASM, 1991. [20.] Cumitech 7. Laboratory diagnosis of lower respiratory tract infections, Washington, DC: ASM, 1978 Sep. [21.] Kunin CM, ed. Detection, prevention and management of urinary tract infections. 4th edn. Philadelphia: Lea & Febiger, 1987. [22.] Nordenstam G, Sundh V, Lincoln K, et al. Bacteriuria in representative population samples of persons aged 72-79 years. Am F Epidemiol 1989;130:1176 86. [23.] Bendall MJ, Ebrahim S, Finch RG, et al. Bacterial resistance to trimethoprim in geriatric medical wards. Gerontology 1989;35:121-6. [24.] Garb JL, Brown RB, Garb JR, et al. Differences in etiology of pneumonias in nursing home and community patients. F AMA 1978;240:2169-72. [25.] Heikkila E, Sundstrom L, Huovinen P. Trimethoprim resistance in Escherichia coli isolates from a geriatric unit. Antimicrob Agents Chemother 1990;34:2013-15. [26.] Haley RW, Culver DH, White JW, et al. The efficacy of infection surveillance and control programs in preventing nosocomial infections in US hospitals. Am F Epidemiol 1985;121:182-205.

Authors' addresses

W. Michielsen(*), D. Vandevondele, M. Afschrift Department of Geriatrics and Gerontology,

G. Verschraegen, G. Claeys Department of Microbiology,

University Hospital, De Pintelaan 185, 9000 Gent Belgium

COPYRIGHT 1993 Oxford University Press
COPYRIGHT 2004 Gale Group

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