Adam Witold Stadler
email: astadler@prz.edu.pl

Andrzej Kolek

Zbigniew Zawiślak

Krzysztof Mleczko

Malgorzata Jakubowska

Konrad Rafal Kielbasiński

Anna Mlożniak

Zbigniew Zawi Lak

Małgorzata Jakubowska

Konrad Rafał Kiełbasi Ski

Anna Mło Niak

Noise properties of Pb/Cd-free thick film resistors

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Thick film resistors (TFRs) gain a wide variety of applications. Developed by many years, they achieved high quality and are commonly used in both commercial and specialized electronics. Their main features are wide range of sheet resistances, high stability and low temperature coefficient of resistance (TCR). Even the noise figure, for long time considered as not satisfactory, now is suppressed to acceptable level. Materials used in cermet TFRs fabrication are RuO 2 and/or various ruthenates which are the ingredients of resistive pastes and Ag, Au, Pd and Pt which are contained in conductive pastes used for resistors terminations. Both resistive and conductive pastes are also made of various kinds of glasses that usually contain Pb. Manufacturers optimized their products in order to offer systems of compatible pastes that form well matching resistive-to-conductive film interfaces as well as low ohmic, high reliable joints with conventional Sn/Pb solders. The situation has changed only after RoHS directive was introduced. First, the restrictions for the use of Pb-containing solders forced the manufacturers to workout new conductive pastes able to form good joints with Pb/Cd-free solders. Second, lead has started being eliminated both from conductive and resistive inks [START_REF] Ruffi | Lead-free rutheniumbased thick-film resistors: a study of model systems[END_REF][START_REF] Jakubowska | Thick Film Materials -Achievements and Trends in Development[END_REF][START_REF] Prudenziati M Zanardi F Morten | Lead-free thick film resistors: an explorative investigation[END_REF][START_REF] Rane | Structural and electrical properties of perovskite ruthenate-based lead-free thick film resistors on alumina and[END_REF][START_REF] Maeder | Lead-free low-firing thick-film resistors based on bismuth glasses and ruthenium oxide[END_REF]. Consequently, recently new pastes have appeared on the market, which are not as well described and optimized as their Pb-containing antecedents.

This paper explores the field of cermet TFRs manufactured with the use of novel materials prepared to fulfill RoHS directive [START_REF] Jakubowska | Thick Film Materials -Achievements and Trends in Development[END_REF]. Several combinations of (i) resistive pastes made of RuO 2 or CaRuO 3 powder and glass of complex composition and (ii) conducting pastes based on Ag, Ag-Pd, or Ag-AgPt-Pd have been used to manufacture TFRs on alumina substrates in high-temperature process. We aim at the description and evaluation of the quality of the interface between resistive and conductive layers that form in these resistors. Our main experimental tool is the low-frequency noise spectroscopy (LFNS) which recently has been proved to be very efficient method for such research [START_REF] Kolek | Noise spectroscopy of thick resistive-conductive film interface[END_REF][START_REF] Kolek | Lowfrequency 1/f noise of RuO 2 -glass thick resistive films[END_REF][START_REF] Mleczko | Evaluation of conductive-to-resistive layers interaction in thick-film resistors Microel[END_REF][START_REF] Vandamme | Resistance noise measurement: A better diagnostic tool to detect stress and current induced degradation Microel[END_REF]. This method enables the estimation of the noise parameters which qualitatively describe the strength of interaction between resistive and conductive layers as well as estimation of the noise index of the resistive layer itself which is also important, as in general there is lack of studies on noise of Pb/Cd-free TFRs especially in a wide range of temperature.

Samples

Geometry

Samples are designed as multiterminal devices. Resistive layer of L = 15 mm length and w = 1 mm width is terminated by two opposite current contacts and has several lateral voltage probes evenly spaced along both its sides. The advantage of such geometry has been proved in many noise-oriented experiments [START_REF] Mleczko | Evaluation of conductive-to-resistive layers interaction in thick-film resistors Microel[END_REF][START_REF] Kolek | Noise and switching phenomena in thick-film resistors[END_REF][START_REF] Kolek | Spatial distribution of noise sources in thick-film resistors[END_REF][START_REF] Rhee | Contact noise in thick film resistors Solid[END_REF][START_REF] Masoero | An improved technique of measuring the contact noise in thick film resistors[END_REF]. The shape of sample TFR and contacts enumeration scheme are shown in the inset of figure 1.

Materials

The conducting constituent in resistive pastes is either RuO 2 or CaRuO 3 . The mean grain size of RuO 2 powder has been estimated as d ≈ 1 µm [START_REF] Kiełbasi | Vanadium Oxide as a Devitrification Exhibitor in Lead-free Glass for Environmental Friendly Thick Film Resistors Proc[END_REF]. The method of digital image processing and analysis was employed to obtain this value. For CaRuO 3 powder, the use of SEM allows the estimation of mean grain size of d ≈ 0.5 µm. RuO 2 /CaRuO 3 powders are mixed together with Pb/Cdfree glass and ethylocellulose based organic vehicle to give resistive pastes containing 35%/27% of conductive phase by volume. Two types of glass were used. Both of them contain SiO 2 , B 2 O 3 , Al 2 O 3 , V 2 O 5 , and metal oxides: either MgO, CaO, ZnO, Na 2 O, K 2 O (glass -R16) or BaO (glass -R10). Contacts to resistive films are made from Ag-based pastes. Namely, Ag, Ag-AgPt-Pd, and AgPd pastes were used as listed in table 1. All conductive and resistive pastes were developed as Pb/Cd-free materials according to RoHS directive [START_REF] Jakubowska | Electical properties of new leadfree thick film resistors[END_REF][START_REF] Kiełbasi | High ohm eco-friendly resistors in thick film technology[END_REF][START_REF] Jakubowska | Lead free thick film materials Monographies of Tele & Radio Research Institute[END_REF], and were produced in the Institute of Electronic Materials Technology (ITME), Warsaw, Poland. In table 1 samples used in this study, their description, details of fabrication and some features are collected.

Printing and firing

Resistive pastes were printed onto alumina substrates through 200 mesh screen. After drying in 120 °C for 15 min., films were fired in a tunnel furnace gaining the final thickness of ~20 µm (figure 1). The process of firing followed a suitable temperature profile with peak temperature at 850 °C lasting 10 minutes. Contacts to the films were made of conductive pastes in a very similar process. They were deposited onto substrates prior to resistive films printing.

Selection and entry tests

Several tens of resistors in 6 series have been manufactured. They were then aged in temperature 125 °C for 100 hours. The drift of the resistance of RuO 2 -based resistors was less than 0.1%, whereas for CaRuO 3 -based resistors it usually exceeded 1%. In fact, out of 3 series of CaRuO 3 based resistors, only those with AgPd contacts survived the ageing, maintaining reasonable long-term stability. Therefore, only samples from this CaRuO 3 -based series as well as samples from all 3 RuO 2 -based series were used in noise measurements. For each series, one pair of samples that match best their resistance at room temperature was selected for further studies. Total resistance between terminations 1 and 7 (R ≡ R 1-7 = V 1-7 /I, where I is biasing current and V 1-7 is the voltage between terminations 1-7) was used as a matching criterion. For all selected samples, voltage distribution along resistive layer was measured (figure 1) to evaluate size effect [START_REF] Mleczko | Evaluation of conductive-to-resistive layers interaction in thick-film resistors Microel[END_REF], and estimate sheet resistance R sq . Size effect was calculated as the ratio of average resistance per square, R 1-7 w/L, and "bulk" sheet resistance R sq = V 2- 6 w/(L 2-6 I), L 2-6 is the length of the sector 2-6 (i.e. the part of the main film that extend between contacts 2 and 6) and V 2-6 is the voltage across this sector. It stems from the data gathered in table 1 that for our Pb/Cd-free TFRs size effect is negligible. The thickness of resistive film in-between side probes was measured directly using Vistronik C1 meter. Average film thickness was then used to calculate film resistivity ρ.

Noise measurements

Experimental setup

Low-frequency noise has been measured in dc bridge configuration (see figure 2). A selected pair of samples was placed in the bottom arms of the bridge and biased through load resistors of much larger resistance. Only the samples and the calibrated temperature sensor (Pt-100 RTD) were inserted into LN cryostat and subjected to cooling. The voltages from the bridge diagonal and sub-diagonals were conditioned in ac-coupled low-noise differential preamplifiers and low-pass filtered. Noise Signal Analyzer [START_REF] Stadler | Noise signal analyzer for multi-terminal devices[END_REF] was used to manage experiment and calculate power spectral densities (PSDs) of measured voltages. Additional equipment shown in figure 2 is involved to monitor actual temperature and record bias voltage and current. All is controlled via GPIB interface. Noise Signal Analyzer calculates the cross-power spectra of the voltages V X-Y acquired frombetween a certain pair of voltage probes and the voltage V 7-7 from-between the terminations No. 7. As the V 2-2 contains a part of V 7-7 , their cross-PSD refers to the fluctuations originated from these sectors of the resistors, which give contribution to both voltages. This is illustrated in figure 3a: PSD S 2-2 measured (for different bias, V ≡ V 1-7 = 7.8 V and V = 0) between the terminations No. 2 refers to the noise signal generated in (i) contact No. 1/main film interfaces, (ii) sectors 1-2 of the main resistive film, (iii) side legs No. 2 that include resistive film lead and contact No. 2. On the contrary cross-PSD of voltages V 2-2 and V 7-7 refers only to the signal generated in sectors 1-2 of the main film, so that S 2-2 > S 2-2,7-7 . As shown in figure 3a the difference is not much for biased samples as in this case the signal of component (ii) is much greater than the other two. However, the difference becomes quite large for V = 0, when all three components give signals of the same order.

In the experiment, noise generated in successive sectors of the resistor was of interest. Measurements have been made for sectors 1-7 (whole resistor), 1-6, 2-6, 3-5. Its power spectral density, S V was measured with the cross-correlation method as described above. Of them, only the sectors 2-6 and 3-5 have spectra that are free from noises generated in current and voltage contacts. Unlike these two, spectra acquired for sectors 1-7 include noise generated in both upper and lower current contacts, whereas spectra for sectors 1-6 contain noise generated only in lower current taps. 3a noise spectra were measured for non-zero bias voltages (S V ) as well as with no bias (background noise S V=0 ). Excess noise was then calculated as S Vex (f) = S V (f) -S V=0 (f). Examples of the measured spectra are shown in figure 3b: 1/f noise contributes most to non-equilibrium S V (f) dependence. Background noise in case of cross-correlation measurements is dominated mainly by thermal noise of the resistors. Only for the spectra measured for the whole resistor, it is described both by the source resistance and by the amplifier equivalent noise resistance, which is ≈ 1.1 kΩ. The spectrum S V=0 shown in figure 3b refers to this case. As shown, 1/f background noise dominates only below 10 Hz and is much lower than the noise of the biased samples.

V = 0 V S 2-2 ,7-7 S 2-2 S 2-2 , S 2-2,7-7 , V 2 /H z f, H z V = 7 . 8 V 1 /f (a )
All signals are sampled simultaneously and spectra are calculated in real time in a frequency range from 0.5 Hz to 5 kHz with 0.5 Hz resolution employing 2 19 point FFT. Only low-frequency part 0.5 -5000 Hz is recorded for further processing.

Low-frequency noise spectroscopy

Low-frequency noise spectroscopy was used in the investigations of e.g. semiconductor materials and devices [START_REF] Jones | Low-frequency noise spectroscopy[END_REF], UV detectors [START_REF] Wirko R Bielecki Z Wirko | Low-frequency noises as a tool for UV detector characterisation Opto-Electron[END_REF], gas sensors [START_REF] Seguin | Bases of Noise Spectroscopy for Enhancing Metallic Oxide Gas Sensors Selectivity Science and technology of chemiresistor gas sensors[END_REF] and TFRs [START_REF] Kolek | Noise spectroscopy of thick resistive-conductive film interface[END_REF][START_REF] Kolek | Lowfrequency 1/f noise of RuO 2 -glass thick resistive films[END_REF][START_REF] Mleczko | Evaluation of conductive-to-resistive layers interaction in thick-film resistors Microel[END_REF][START_REF] Kolek | Noise and switching phenomena in thick-film resistors[END_REF][START_REF] Kolek | Spatial distribution of noise sources in thick-film resistors[END_REF]. The method examines the evolution of low-frequency noise spectrum as a function of temperature. In our experiment, noise spectra were measured as a function of slowly ramping temperature in the range 77 -300 K. Noise data are presented in the form of noise maps i.e. 2D contour graphs of the product fS R (f ) versus frequency and reciprocal temperature [START_REF] Kolek | Lowfrequency 1/f noise of RuO 2 -glass thick resistive films[END_REF][START_REF] Kolek | Noise and switching phenomena in thick-film resistors[END_REF][START_REF] Kolek | Spatial distribution of noise sources in thick-film resistors[END_REF]. Sample noise maps are shown in figure 5. During these measurements, the resistance R of the samples was also recorded. R vs. T curves obtained in these experiments are shown in figure 4. Below 77 K, R(T) was measured in helium cryostat.

Results and discussion

Resistance fluctuations

The dependence of noise intensity on the excitation voltage (or current) is one of major tests for noise identification. Since noise spectra may include components like 1/f and/or Lorentzians, it is desirable to perform this test with respect to noise power in different frequency bands. Sample results are illustrated in figure 6 where the product fS Vex (f ) averaged in frequency bands (decades) is plotted versus the bias voltage. Lines, if drawn through the points, would have the slope of 2. Thus, all parts of the spectrum depend linearly on excitation voltage square, which is the sign that all components of the noise originate from resistance fluctuations (resistance noise) [START_REF] Hooge | Experimental studies on 1/f noise Rep[END_REF]. PSD of these fluctuations can be calculated as S R (f) = S Vex (f)/I 2 . This quantity is bias independent, and so the spectra S R (f ) are used in LFNS. Physical mechanisms that can lead to resistance fluctuations in TFRs were discussed in ref. [START_REF] Kolek | Lowfrequency 1/f noise of RuO 2 -glass thick resistive films[END_REF]. It stems from that discussion that fluctuating mobility is responsible for these fluctuations.

Thermally activated noise sources

The use of LFNS makes possible identification of thermally activated noise sources (TANSs) in the measured noise signal and estimation of their activation energy E a . On the maps like these in figure 5, TANSs appear as the streaks [START_REF] Kolek | Lowfrequency 1/f noise of RuO 2 -glass thick resistive films[END_REF][START_REF] Stadler | Thermally Activated Noise Sources in Thick Film Resistors of RuO 2 and Glass[END_REF] whereas smooth surface between the streaks refers to pure 1/f noise. The value of E a can be calculated from the slope of the streak [START_REF] Kolek | Noise spectroscopy of thick resistive-conductive film interface[END_REF][START_REF] Stadler | Thermally Activated Noise Sources in Thick Film Resistors of RuO 2 and Glass[END_REF]. Each value of the activation energy is associated with two-state system localized in grain boundaries and/or in the glass [START_REF] Kolek | Lowfrequency 1/f noise of RuO 2 -glass thick resistive films[END_REF]. Transitions in these systems are thermally activated. They couple to (modulate) the local resistances. Only those that modulate critical resistances in the percolation path [START_REF] Shklovskii | Electronic Properties of Doped Semiconductors[END_REF] contribute significantly to the overall resistance and can be detected in noise measurements. Therefore merely few activation energies are observed for individual samples. The discrete set of their values differs from sample to sample but all values of E a found in this work, fall into the range 0.083 -0.74 eV. These values are a bit lower than the value E a 1.15eV found in ref. [START_REF] Pellegrini B Saletti R Terreni | 1/f noise in thick-film resistors as an effect of tunnel and thermally activated emissions, from measures versus frequency and temperature[END_REF], but fit well within the range of activation energies found in refs. [START_REF] Kolek | Lowfrequency 1/f noise of RuO 2 -glass thick resistive films[END_REF][START_REF] Kolek | Noise and switching phenomena in thick-film resistors[END_REF][START_REF] Kolek | Change of Coupling Mechanism in the Low-Frequency Noise of RuO 2 -Glass Films[END_REF] for Pb-containing TFRs. For definiteness, one should note, however, that in ref. [START_REF] Pellegrini B Saletti R Terreni | 1/f noise in thick-film resistors as an effect of tunnel and thermally activated emissions, from measures versus frequency and temperature[END_REF] measurements cover temperature range up to 800 K, where different TANSs are active.

Apart from detection of TANSs and their activation energies, noise maps give more informative view on fluctuating phenomena that take place in TFRs. Noise maps shown in figure 5 refer to different sector of the same resistor. The map of figure 5a refers to resistance fluctuations measured for sectors 1-7 whereas the map of figure 5b refers to internal sector 3-5. Data on both maps were gathered simultaneously. As different streaks appear on figures 5a and 5b it is obvious that intensity and number of TANSs vary from sector to sector. In other words, TANSs (and the corresponding twostate systems) are randomly distributed inside the resistor. experiments. Another interesting phenomenon observed on the noise maps is spectra switching. It vertically "cuts" the maps and divides the streaks into separate pieces (see figure 7). Physically it means that in a certain temperature TANS is accidentally turned on/off in a sharp manner. Possible reasons for this process were discussed in refs. [START_REF] Mleczko | Evaluation of conductive-to-resistive layers interaction in thick-film resistors Microel[END_REF][START_REF] Kolek | Noise and switching phenomena in thick-film resistors[END_REF] and involve dynamic current redistribution due to stress relaxation, and/or interacting fluctuators. Briefly, when current is redistributed (topology of percolation cluster changes) certain TANSs become more distant from the percolation network, so they no longer can modulate critical resistances in this network and no longer can be observed as the fluctuations at the overall resistance. In our experiments spectra switching has not been observed for RuO 2 -based TFRs. For CaRuO 3 -based TFRs series, switching of the spectra was observed in temperature range 150 -160 K. It is interested that in different cooling-heating cycles the switching of the spectra always took place in the same temperature range. As shown in figure 7, in different experiments TANS of different activation energy and intensity appears. This means that process of switching can turn on/off TANS also in time scale that exceeds single experiment; that is, it is nonstationary in this time scale.

Noise scaling and decomposition

The intensity of all noise sources localized in a resistor's sector is given by the power of its resistance fluctuations <δR 2 >. Exemplary plots of <δR 2 > versus temperature are shown in figure 8. As noise maps are sample-dependent, so are the plots <δR 2 >(T). That is why the plots for RuO 2 based TFRs in figure 8 are different: different contacts are hardly responsible for these differences. For CaRuO 3 -based sample the number of TANSs, and intensity of the noise they generate, increase in the sector close to the upper (No. 7) resistor termination. For the remaining samples the density of TANS in a resistor volume is more or less homogeneous. To prove it the integral measure of noise [START_REF] Mleczko | Evaluation of conductive-to-resistive layers interaction in thick-film resistors Microel[END_REF]:

- ≡ 2 1 ) , ( 1
1 2 T T f f R u l dfdT T f S T T s , (1)
was scaled versus sector size. The integration in equation ( 1) should be over the surface as broad as possible. However, the measurement conditions describe the frequency and temperature limits of the integral: the frequency band 10 -100 Hz, has been chosen in order to omit (i) distortion of the spectra in low-frequency limit caused by temperature drift, (ii) overlapping 1/f resistance noise by thermal noise in high-frequency limit [START_REF] Mleczko | Evaluation of conductive-to-resistive layers interaction in thick-film resistors Microel[END_REF]. Temperature range 77 -300 K was used due to the cryostat capabilities. Plotting the integral s versus the sector size enables decomposition of the measured noise into bulk and contact components. The approach is illustrated in figure 9 where the plots for the samples P-202 Sz R-16-65 RuO 2 and P-202 Sz R-10-73,5 CaRuO 3 are shown. The points referred to the internal sectors of the resistor very tightly follow straight lines that start at the plot origin. Such linear increase of noise intensity is expected for spatially uncorrelated noise sources. The slope of the line gives bulk noise per square s sq that can be used to calculate dimension-independent bulk noise intensity C bulk ≡ s sq /R sq 2 ×Ω sq , where Ω sq is the square volume. Parameter C bulk occurred to be very helpful when comparing noise properties of different materials [START_REF] Mleczko | Evaluation of conductive-to-resistive layers interaction in thick-film resistors Microel[END_REF][START_REF] Kolek | Noise characteristics of resistors buried in lowtemperature co-fired ceramics[END_REF][START_REF] Vandamme | The 1/f noise versus sheet resistance in poly-Si is similar to poly-SiGe resistors and Au-layers[END_REF].

The noise generated in the interfaces of both current contacts can be evaluated as a difference between noise intensity measured for whole resistor, s 1-7 , and extrapolated bulk noise s bulk = L/w×s sq . Namely 2s int = s 1-7 -s bulk . The "quality" of the interface is described by contact-geometry-independent parameter, C int ≡ ws int /s sq [START_REF] Mleczko | Evaluation of conductive-to-resistive layers interaction in thick-film resistors Microel[END_REF]. Numerically, its value is the length of hypothetical resistive film, which would have the noise intensity equal the intensity of the interface noise. Parameters C bulk and C int have been calculated and are collected in table 2.

Due to the non-stationary behavior observed for CaRuO 3 -based samples, numerical values of integral s obtained for this resistor in different experiments are different. This explains scattering in the values of s observed for this sample in figure 9. The scattering is the largest for the value of s 1-7 what means that most non-stationary switchings occur in the interfaces. For other samples, the values of s are not scattered. As they were obtained for different bias voltages this is in line with the conclusion that stationary resistance fluctuations are the origin of the noise. [START_REF] Vandamme | Criteria of Low-Noise Thick-Film Resistors ElectroComp[END_REF][START_REF] Wolf | Comment on the dependence of R and current noise on grain size in thick film resistors-TFR's Active and Passsive[END_REF] and verified experimentally [START_REF] Vandamme | Criteria of Low-Noise Thick-Film Resistors ElectroComp[END_REF][START_REF] Müller | Dependence of the Sheet Resistivity and Current Noise Behaviour of the Grain Size and Volume Fraction of Conducting Material in Thick-Film Resistors Experiments Active and Passive[END_REF], that bulk noise of TFRs is proportional to resistivity ρ, C bulk = K'ρ, when resistivity is changed by the content of conductive constituent of the resistive paste. As in this study, samples with different RuO 2 /CaRuO 3 content are not available we refer to our previous work of ref. [START_REF] Mleczko | Evaluation of conductive-to-resistive layers interaction in thick-film resistors Microel[END_REF] in order to compare bulk noise of Pb/Cd-free compositions with its Pb-containing antecedents. In figure 10, data for TFRs studied in ref. [START_REF] Mleczko | Evaluation of conductive-to-resistive layers interaction in thick-film resistors Microel[END_REF] have been plotted together with the current data, all as C bulk vs. resistivity. One can see that noise of CaRuO 3 films is the largest also when compared to non Pb/Cd-free TFRs. Note, however, that resistivity of these films is relatively high. Regarding Pb/Cd-free RuO 2 -based resistive films, experimental points in figure 10 lie on the line with K' = 2×10 -9 µm 2 /Ω which is almost an order of magnitude larger than the value K' = 4×10 -10 µm 2 /Ω found in ref. [START_REF] Mleczko | Evaluation of conductive-to-resistive layers interaction in thick-film resistors Microel[END_REF] for Pb-containing RuO 2 films. The question appears for the reason of such large discrepancy. In our opinion the reason for this is the difference in RuO 2 grain size in resistive films studied in ref. [START_REF] Mleczko | Evaluation of conductive-to-resistive layers interaction in thick-film resistors Microel[END_REF] where d ≈ 10 nm and in this work, where d ≈ 1 µm. Although there are only few studies concerning the influence of grain size on noise of TFR [START_REF] Vandamme | Criteria of Low-Noise Thick-Film Resistors ElectroComp[END_REF][START_REF] Wolf | Comment on the dependence of R and current noise on grain size in thick film resistors-TFR's Active and Passsive[END_REF][START_REF] Müller | Dependence of the Sheet Resistivity and Current Noise Behaviour of the Grain Size and Volume Fraction of Conducting Material in Thick-Film Resistors Experiments Active and Passive[END_REF][START_REF] Rao | Studies on electrical properties of polymer thick film resistors[END_REF][START_REF] Tamborin M Piccinini | Piezoresistive properties of RuO 2based thick-film resistors: the effect of RuO 2 grain size[END_REF], it has been rather argued that increase in the grain size results in both larger resistivity [START_REF] Müller | Dependence of the Sheet Resistivity and Current Noise Behaviour of the Grain Size and Volume Fraction of Conducting Material in Thick-Film Resistors Experiments Active and Passive[END_REF][START_REF] Rao | Studies on electrical properties of polymer thick film resistors[END_REF][START_REF] Tamborin M Piccinini | Piezoresistive properties of RuO 2based thick-film resistors: the effect of RuO 2 grain size[END_REF] and bulk noise.

From theoretical point of view the relations ρ ~d, C bulk ~d3 , and thus C bulk ~ρ3 are expected when ρ is driven solely by the grain size of the conductive powder [START_REF] Wolf | Comment on the dependence of R and current noise on grain size in thick film resistors-TFR's Active and Passsive[END_REF][START_REF] Müller | Dependence of the Sheet Resistivity and Current Noise Behaviour of the Grain Size and Volume Fraction of Conducting Material in Thick-Film Resistors Experiments Active and Passive[END_REF]. Experimentally, the increase of sheet resistance with conductive constituent grain size was observed, e.g. in refs. [START_REF] Vandamme | Criteria of Low-Noise Thick-Film Resistors ElectroComp[END_REF][START_REF] Wolf | Comment on the dependence of R and current noise on grain size in thick film resistors-TFR's Active and Passsive[END_REF][START_REF] Müller | Dependence of the Sheet Resistivity and Current Noise Behaviour of the Grain Size and Volume Fraction of Conducting Material in Thick-Film Resistors Experiments Active and Passive[END_REF][START_REF] Rao | Studies on electrical properties of polymer thick film resistors[END_REF][START_REF] Tamborin M Piccinini | Piezoresistive properties of RuO 2based thick-film resistors: the effect of RuO 2 grain size[END_REF]. Much less frequent are noise versus grain size measurements. For Bi 2 Ru 2 O 7 -based films the relation C bulk Rsq 2.4 was found in ref. [START_REF] Müller | Dependence of the Sheet Resistivity and Current Noise Behaviour of the Grain Size and Volume Fraction of Conducting Material in Thick-Film Resistors Experiments Active and Passive[END_REF]. In refs [START_REF] Tamborin M Piccinini | Piezoresistive properties of RuO 2based thick-film resistors: the effect of RuO 2 grain size[END_REF] and [START_REF] Inokuma | Conductive and Insulative Particle Size Effects on the Electrical Properties of RuO 2 Thick-Film Resistors[END_REF] increase of the noise intensity with increasing grain size was observed for RuO 2 -based TFRs. Obviously, our data are not rich enough to definitely and quantitatively verify the hypothesis, but it seems that increase in the value of C bulk observed for our Pb/Cd-free RuO 2 films is caused by the increase of conductive constituent grain size rather than by Pbremove.

Interface noise

Parameter C int can be used to evaluate the usefulness of various combinations of resistive and conductive pastes in forming well-behaved resistive/conductive films interfaces. Relatively large value of C int indicates that the contact significantly contributes to the noise of the resistor, degrading performance characteristics of the device. Analyzing the values of C int gathered in table 2, one can conclude that Pb/Cd-free RuO 2 films form well-behaved contacts made of various Ag-based conductive pastes. On the other hand, the interface of CaRuO 3 -based sample is poor: CaRuO 3 films should not be terminated with AgPd contacts.

Summary

LFNS technique has been applied to study noise properties and evaluate systems of materials to be used in RoHS compliant TFRs technology. Four samples made of different combinations of Pb/Cdfree resistive and conductive pastes have been examined in temperature range 77 -300 K. Two basic components of low-frequency noise have been detected. Namely 1/f noise and TANSs, each of them is resistance noise. In every sample, several TANSs have been observed. Their activation energies seem to be resistor rather than material specific. It has occurred that TANSs are non-uniformly distributed in the resistor volume.

Pb/Cd-free RuO 2 -based resistive pastes form well-behaved interfaces with various Ag-based conductive pastes. On the contrary, CaRuO 3 -based paste forms bad contacts with AgPd terminations because density of TANSs increases in the interface area. This knowledge will certainly be helpful in further optimization of materials systems used in the fabrication of Pb/Cd-free low-noise, stable and reliable TFRs. It could have been gained in spite that in all our samples the size effect, estimated from ordinary resistance measurements (table 1), was negligible. We came to these conclusions due to the advantages of the research method we used. The information about the quality of resistive-toconductive layers interface occurred to be stored in the values of noise parameter C int .

Noise intensity of new-resistive layers has been described by another noise parameter, C bulk . Its values have been calculated and compared with those available in the literature [START_REF] Mleczko | Evaluation of conductive-to-resistive layers interaction in thick-film resistors Microel[END_REF]. Pb/Cd-free layers occurred to be noisier than their Pb-containing counterparts, however the remove of Pb and Cd from resistive composition is hardly responsible for the increase of the noise. Although for CaRuO 3 layers noise data are not available at all, in case of RuO 2 layers noise increases most likely due to larger grain size of RuO 2 powder used to prepare resistive pastes.

The values of parameters C int and/or C bulk contribute to noise index of a resistor -an important parameter for its applications and valuable indicator of its reliability, long-term drift and lifetime [START_REF] Rocak | Lowfrequency noise of thick-film resistors as quality and reliability indicator[END_REF] and efficient tool in failure prediction of electron devices and circuits [START_REF] Jevti | Noise as a diagnostic and prediction tool in reliability physics[END_REF][START_REF] Jevti | Thick-film qulity indictor based on noise index measurements Microelecron[END_REF][START_REF] Jevti | Evaluation of thick-film resistor structural parameters based on noise index measurements Microelecron[END_REF].

The region of low temperatures explored in the paper is of special interest as since 1970's TFRs enter the field of cryogenics, where they are used as temperature sensors [START_REF] Willekers | Thick film thermometers with predictable R-T characteristics and very low magnetoresistance below 1[END_REF][START_REF]Designe of RuO 2 -based thermometers for the millikelvin temperature range[END_REF][START_REF] Goodrich | Magnetoresistance below 1 K and temperature cycling of ruthenium oxide-bismuth ruthenate cryogenic thermometers[END_REF][START_REF] Watanabe | Magnetoresistance of RuO 2 -based resistance thermometers below 0[END_REF][START_REF] Ptak | Noise resolution of RuO 2 -based resistance thermometers[END_REF]. They exhibit large sensitivity to temperature changes due to the resistance sharply increasing below several K. Physical reasons for this increase is unknown. Thermally activated tunneling [START_REF] Pike | Electrical properties and conduction mechanisms of Ru-based thick-film (cermet) resistors[END_REF], fluctuation induced tunneling [START_REF] Sheng | Fluctuation-Induced Tunneling Conduction in Carbon-Polyvinylchloride Composites[END_REF][START_REF] Flachbart | RuO 2based Low Temperature Sensors with[END_REF], conduction in a narrow band [START_REF] Hill | Electrical transport in thick film resistors Electrocomp[END_REF], variable range hopping (VRH) [START_REF] Prudenziati | On the temperature coefficient of resistivity in thick-film resistors and the percolationf model[END_REF][START_REF] Affronte | Low temperature electronic transport in RuO 2 -based cermet resistors[END_REF], space charge limited transport [START_REF] Vest | Conduction mechanisms in thick film microcircuits[END_REF], emissions over graded barriers [START_REF] Flachbart | RuO 2based Low Temperature Sensors with[END_REF], and weak localization [START_REF] Affronte | Magnetoresistance of RuO 2based thick film resistors[END_REF], are considered as transport mechanisms -none is able to fully explain the feature. Our present results add the contribution to the practical aspect of the field: Pb/Cd-free compositions can be used as thermo-sensing layers in cryogenic RTD's. From figure 4 one can deduce that below 10 K these compositions maintain high sensitivity to temperature changes.

Figure 1 .

 1 Layer thickness and voltage distribution V(x) measured along resistive layer of the sample P-202 Sz R-16-65 RuO 2 . Solid line drawn through V(x) data demonstrates that size effect is very small. The inset shows sample's shape and contacts numbering scheme.

Figure 2 .

 2 Figure 2. Measurement setup for low-frequency noise spectroscopy.Noise Signal Analyzer calculates the cross-power spectra of the voltages V X-Y acquired frombetween a certain pair of voltage probes and the voltage V 7-7 from-between the terminations No. 7. As the V 2-2 contains a part of V 7-7 , their cross-PSD refers to the fluctuations originated from these sectors of the resistors, which give contribution to both voltages. This is illustrated in figure3a: PSD S 2-2 measured (for different bias, V ≡ V 1-7 = 7.8 V and V = 0) between the terminations No. 2 refers to the noise signal generated in (i) contact No. 1/main film interfaces, (ii) sectors 1-2 of the main resistive film, (iii) side legs No. 2 that include resistive film lead and contact No. 2. On the contrary cross-PSD of voltages V 2-2 and V 7-7 refers only to the signal generated in sectors 1-2 of the main film, so that S 2-2 > S 2-2,7-7 . As shown in figure3athe difference is not much for biased samples as in this case the signal of component (ii) is much greater than the other two. However, the difference becomes quite large for V = 0, when all three components give signals of the same order.In the experiment, noise generated in successive sectors of the resistor was of interest. Measurements have been made for sectors 1-7 (whole resistor), 1-6, 2-6, 3-5. Its power spectral density, S V was measured with the cross-correlation method as described above. Of them, only the sectors 2-6 and 3-5 have spectra that are free from noises generated in current and voltage contacts. Unlike these two, spectra acquired for sectors 1-7 include noise generated in both upper and lower current contacts, whereas spectra for sectors 1-6 contain noise generated only in lower current taps.

Figure 3 .

 3 Figure 3. (a) PSD of voltage fluctuations measured directly at contacts 2-2 and cross-PSD measured for voltages V 2-2 and V 7-7 . Both were measured with bias (V = 7.8 V) and with no bias (V = 0) (b) Noise spectra measured at room temperature (symbols). Solid line shows background noise for the sample P-121 Sz R-16-65 RuO 2 . In (a) and (b) dashed line shows the spectrum of pure 1/f noise. As shown in figure3anoise spectra were measured for non-zero bias voltages (S V ) as well as with no bias (background noise S V=0 ). Excess noise was then calculated as S Vex (f) = S V (f) -S V=0 (f). Examples of the measured spectra are shown in figure3b:1/f noise contributes most to non-equilibrium S V (f) dependence. Background noise in case of cross-correlation measurements is dominated mainly by thermal noise of the resistors. Only for the spectra measured for the whole resistor, it is described both by the source resistance and by the amplifier equivalent noise resistance, which is ≈ 1.1 kΩ. The spectrum S V=0 shown in figure3brefers to this case. As shown, 1/f background noise dominates only below 10 Hz and is much lower than the noise of the biased samples.All signals are sampled simultaneously and spectra are calculated in real time in a frequency range from 0.5 Hz to 5 kHz with 0.5 Hz resolution employing 219 point FFT. Only low-frequency part 0.5 -5000 Hz is recorded for further processing.

2 Figure 4 .

 24 Figure 4. Resistance R vs. temperature. In the range 77 -300 K, resistances and noise spectra were measured simultaneously.

Figure 5 .

 5 Figure 5. 2D filled contour graphs of the product fS R (f ) versus frequency and reciprocal temperature (noise maps) measured for the sample P-202 Sz R-16-65 RuO 2 . Maps were made of the spectra measured for sectors 1-7 (a) and 3-5 (b).

Figure 6 .

 6 Figure 6. The product fS Vex (f ) averaged < > over frequency decades versus the bias voltage. Solid line indicates proportionality to V 2 . The measurements were performed at room temperature for sample P-121 Sz R-16-65 RuO 2 .

Figure 7 .

 7 Figure 7. Noise maps for sample P-202 Sz R-10-73,5 CaRuO 3 , measured for sector 1-7 in two differentexperiments. Another interesting phenomenon observed on the noise maps is spectra switching. It vertically "cuts" the maps and divides the streaks into separate pieces (see figure7). Physically it means that in a certain temperature TANS is accidentally turned on/off in a sharp manner. Possible reasons for this process were discussed in refs.[START_REF] Mleczko | Evaluation of conductive-to-resistive layers interaction in thick-film resistors Microel[END_REF][START_REF] Kolek | Noise and switching phenomena in thick-film resistors[END_REF] and involve dynamic current redistribution due to stress relaxation, and/or interacting fluctuators. Briefly, when current is redistributed (topology of percolation cluster changes) certain TANSs become more distant from the percolation network, so they no longer can modulate critical resistances in this network and no longer can be observed as the fluctuations at the overall resistance. In our experiments spectra switching has not been observed for RuO 2 -based TFRs. For CaRuO 3 -based TFRs series, switching of the spectra was observed in temperature range 150 -160 K. It is interested that in different cooling-heating cycles the switching of the spectra always took place in the same temperature range. As shown in figure7, in different experiments TANS of different activation energy and intensity appears. This means that process of switching can turn on/off TANS also in time scale that exceeds single experiment; that is, it is nonstationary in this time scale.

Figure 8 .

 8 Figure 8. The power of resistance fluctuations <δR 2 > in band 10 -100 Hz vs. temperature for different sectors of the samples. All three graphs for RuO 2 -based TFRs have identical vertical scale. CaRuO 3 -based TFR has the values of <δR 2 > larger by three orders of magnitude.

Figure 9 .

 9 Figure 9. The integral s vs. sector size (expressed in the number of squares in the sector). Different symbols refer to different measurements (cool-warm cycles) with different bias voltages. Sectors are labelled near RuO 2 series.

Figure 10 .

 10 Figure 10. Comparison of the bulk noise of various TFRs. Lines are the plots of relation C bulk = K'ρ with different values of the coefficient K'.

Figure 1 FigureFigure 8 Figure 9 Figure 10

 18910 Figure 1 (figure1.eps)

Table 1 . Samples labeling and details.

 1

	sample	Resistive paste	contacts		thickness, µm	R sq , k	,	cm	size effect
		Conducting	glass	Conductive	Paste
		constituent		constituent
	P-121 Sz R-16-65 RuO 2	RuO 2 -35%	R-16	Ag	P-121	21.2	4.29	9.09	1.028
	P-511 Sz R-16-65 RuO 2	RuO 2 -35%	R-16	Ag-AgPt-Pd P-511	20.4	4.28	8.77	1.028

Table 2 .

 2 Noise parameters of Pb/Cd-free TFRs.

	sample	P-121 Sz R-16-65 RuO2	P-511 Sz R-16-65 RuO2	P-202 Sz R-16-65 RuO2	P-202 Sz R-10-73,5 CaRuO3
	C bulk ×10 24 , m 3 198	190	215	8571
	C int , mm	0.56	0.77	0.25	3.92
	4.4. Noise of resistive films
	It has been shown by means of theoretical considerations

Confidential: not for distribution. Submitted to IOP Publishing for peer review 5 May 2010

Acknowledgments

The work has been supported by the Polish Ministry of Science and Higher Education through grant no N N515 341836 .


Giovanni Secondo

Francesca Vassallo

Nicola Solari

Luciano Moresco

Pierluigi Percivale

Lucia Zappi

Ferdinando Cafiero

Andrea De Maria
email: de-maria@unige.it

S S Infettivologia

Empirical first-line treatment with tigecycline for febrile episodes following abdominal surgery in cancer patients

Keywords:

No study so far has evaluated the performance of tigecycline (TIG) when administered as empirical first-line treatment in a homogeneous population of surgical cancer patients with a febrile episode. An observational review of the data records of 24 sequential patients receiving TIG for a febrile episode following a major abdominal procedure in a single cancer institute was performed. Large bowel surgery represented 68% of all procedures, followed by gastric surgery (16%) and urinary-gynaecologic-biliary surgery (16%). Complications following surgery were observed in 68% of febrile episodes, with peritonitis and sepsis accounting for 59% and 24% of complications, respectively.

Eight patients needed repeat surgery for source control. The mean duration of TIG treatment was 8 days. Causative pathogens were detected in 16 episodes (64%), and a total of 44 microorganisms were recovered (29% Escherichia coli, 9% Enterococcus faecalis and 9% coagulase-negative staphylococci). TIG was effective in 12 episodes (48%). The success rate was 67% when infectious episodes sustained by intrinsically resistant bacteria and fungi were excluded. Treatment failure was associated with the presence of complications and with microbiologically documented infection. TIG may be useful as a first-line treatment option in cancer patients requiring antibiotic treatment following surgery when complications are not present or suspected on clinical grounds and when local microbial epidemiology shows a low incidence of primary resistant bacteria.

A c c e p t e d M a n u s c r i p t

Introduction

Cancer patients may be prone to nosocomial infections as a consequence of chemotherapy or other procedures [START_REF] Guinan | Management of health-care-associated infections in the oncology patient[END_REF]. Patients affected by solid tumours may also present with post-surgical complications, including peritonitis and sepsis [START_REF] Solomkin | Guidelines for selection of anti-infective agents for complicated intra-abdominal infections[END_REF]. Intraabdominal infections (IAIs) remain one of the major challenges facing surgeons and internists because of their associated high rates of morbidity and mortality. Appropriate empirical antibiotic therapy and local nosocomial resistance patterns play a fundamental role in IAIs to improve clinical success rates, reduce length of stay and decrease overall hospitalisation costs [START_REF] Cattan | Cost of care for inpatients with community-acquired intra-abdominal infections[END_REF][START_REF] Sturkenboom | Inappropriate initial treatment of secondary intra-abdominal infections leads to increased risk of clinical failure and costs[END_REF]. Inadequate control of infection, owing to either incomplete drainage or incomplete management of enteric perforation, represents an independent risk factor for treatment failure [START_REF] Wacha | Risk factors associated with intraabdominal infections: a prospective multicenter study. Peritonitis Study Group[END_REF]. Tigecycline (TIG) is a glycylcycline antimicrobial with a broad spectrum of in vitro activity whose use is currently approved for the treatment of complicated IAIs (cIAIs) and complicated skin and skin-structure infections. Empirical therapy with TIG for patients with secondary or tertiary peritonitis would be appropriate as long as Pseudomonas aeruginosa or Proteus spp. were not a concern owing to its lack of in vitro activity against these isolates [START_REF] Frampton | discussion 2636-7[END_REF]. In surgical patients with cancer, for example, risk of infection with P. aeruginosa or Proteus spp. is associated with additional factors, including mechanical ventilation, prolonged hospital stay or previous exposure to antimicrobial agents [START_REF] Furtado | Imipenem-resistant Pseudomonas aeruginosa infection at a medical-surgical intensive care unit: risk factors and mortality[END_REF].

Based on the above considerations, it could be suggested that empirical therapy with TIG in surgical cancer patients might be appropriate if local bacterial epidemiology is compatible with its use and when used upfront at the time of first presentation of abdominal infection. These conditions would minimise the chance of P. aeruginosa infection for patients with no previous prolonged antibiotic use.

A c c e p t e d M a n u s c r i p t

In addition, in this context there are no studies focusing on patients with solid tumours and febrile episodes following major abdominal procedures.

Here, we studied the clinical performance of TIG in infections associated with abdominal surgery in cancer patients when used upfront as first-line empirical treatment for febrile episodes immediately after surgery.

Patients and methods

In this retrospective study, sequential patients with solid tumours who had been treated with TIG for >48 h following febrile episodes occurring after major abdominal procedures Data on TIG use, including dose, duration and adverse events, were also collected.

Outcome was recorded as response or failure to respond.

All causative microorganisms were identified using routine microbiological methods.

Susceptibility testing was performed by the agar dilution method. Disk susceptibility testing was performed and interpreted according to guidelines published by the Clinical and Laboratory Standards Institute (CLSI) [START_REF]Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically[END_REF].

Definitions

'Response' to treatment was defined as complete resolution of clinical signs and symptoms without therapeutic adjustments.

'Failure' was defined as no significant change in or progression of clinical signs and symptoms during TIG administration, or required change of antimicrobial therapy (e.g. for patients with infections due to organisms resistant to or known not to respond to TIG).

'Complicated infections' were considered as those observed in patients developing postsurgical infectious syndromes including peritonitis and sepsis, or those who needed repeat surgery or invasive procedures for source control (bowel perforation, intestinal occlusion, abdominal abscess, enteric fistula). Patient with a diagnosis of both peritonitis and sepsis were included in the peritonitis group only.

A c c e p t e d M a n u s c r i p t

Treatment was defined as empirical when TIG was prescribed for signs of infection without prior identification of a responsible pathogen or even a specific localised source of infection.

Neutropenia was defined as an absolute neutrophil count of <500 cells/L of blood.

Statistical analysis

Categorical variables were compared using the  2 test. All tests were two-sided, at a significance level of P = 0.05. The Mann-Whitney U-test was used to compare continuous variables.

Results

Patient characteristics

Within the observation period, 25 febrile episodes meeting the inclusion criteria were identified in 24 patients (13 male and 11 female). Median patient age was 68 years (range 42-87 years). Patient demographics and clinical characteristics are shown in Table 1.

Based on the type of surgical procedure and on the risk of surgical contamination, it was decided to consider separately episodes occurring in patients with gastric surgery (4 patients), urinary-gynaecologic-biliary surgery (4 patients) and large bowel surgery (17 patients).

A c c e p t e d M a n u s c r i p t

Seventeen febrile episodes (68%) were sustained by complicated infections, the majority (12 patients) following large bowel surgery. None of the patients had neutropenia immediately before infection or surgery.

Although clinical severity scores [e.g. Acute Physiology and Chronic Health Evaluation (APACHE) score] were not calculated, disease severity in this patient series is relevant and suggested by the presence of advanced malignancy before surgery in 42% of the patients (Table 1) and by the high incidence of complications following surgery (68%), with a high rate of peritonitis and sepsis representing 59% and 24% of complicated febrile episodes, respectively. This compares with only a 20% rate of peritonitis in non-neoplastic patients in other studies [START_REF] Babinchak | The efficacy and safety of tigecycline for the treatment of complicated intra-abdominal infections: analysis of pooled clinical trial data[END_REF] and represents a four-fold higher rate.

Tigecycline use

TIG was given alone as empirical therapy for febrile episodes following surgery in the 25 episodes of infection surveyed. It was administered according to the recommended dosing schedule: an initial dose of 100 mg intravenous (i.v.) followed by 50 mg i.v. every 12 h. The mean duration of TIG treatment was 8 days (range 4-12 days).

In 12 episodes (48%), TIG was replaced by a different regimen owing to either clinical failure or according to antibacterial sensitivity. These regimens consisted of: (i) a broadspectrum -lactam with anti-P. aeruginosa activity + anti-Gram-positive agent or No other adverse events possibly associated with TIG administration, including nausea, emesis or diarrhoea, were recorded.

Microbiology

Microbiologically documented infections were observed in 16 febrile episodes (64%), in 11 (69%) of which more than one organism was isolated. In 9 episodes (36%) multiple site cultures yielded no growth of microorganisms.

A total of 44 microorganisms were cultured from blood, urine, surgical wound and drainages. Escherichia coli (29%), coagulase-negative staphylococci (CoNS) (9%) and Enterococcus spp. (9%) were the most common organisms. Proteus mirabilis or P. aeruginosa were isolated from two (8%) and three (12%) febrile episodes, respectively. In one episode both bacteria were present. Candida spp. was isolated during three febrile episodes (12%). Serratia spp., Klebsiella spp. and S. aureus were recovered in two febrile episodes each, whilst Streptococcus anginosus, Acinetobacter spp. and Bacteroides fragilis were identified in one febrile episode each.

Of the 44 microorganisms isolated, 24 (55%) were isolated in 10 febrile episodes with peritonitis (4 with concomitant bloodstream infection), whilst 12 bacteria (27%) were isolated during 8 febrile episodes with sepsis. Six isolates (14%) were derived from urine in five febrile episodes, eight isolates (18%) were from surgical wound specimens during 5

A c c e p t e d M a n u s c r i p t febrile episodes, and 24 isolates (55%) were derived from 10 peritoneal specimens yielded during 10 febrile episodes.

Analysis of in vitro susceptibility to selected antimicrobial agents with typical activity against the isolated microorganisms is shown in Table 2. Among the Gram-negative isolates, extended-spectrum -lactamase production was limited (10%), with fluoroquinolone resistance of in six isolates (21%) (Table 2). Forty-five percent of Grampositive isolates were meticillin resistant but retained sensitivity to glycopeptides and linezolid (not shown).

To provide a quantitative estimate of overall antibiotic resistance, for each microorganism the number of antibiotic agents for which in vitro resistance was observed was evaluated. Indeed, resistance to three or more antibiotics was observed in only 9% of Gram-positive and 6% of Gram-negative isolates, with in vitro susceptibility to all but one antibiotic agent in 73% and 83%, respectively.

Clinical outcome

Among patients with clinical success, TIG resulted in rapid defervescence (median time to defervescence 1.8 days, range 0-6 days).

A significant correlation was observed between febrile episodes accompanying complicated surgery and microbiologically documented infections (P < 0.05) (Table 3).

Overall, when used as single-antibiotic empirical treatment, TIG was effective 48% of times 12 febrile episodes (48%). Improved outcome rates (67%) were observed when A c c e p t e d M a n u s c r i p t episodes due to microorganisms not susceptible to TIG (i.e. P. mirabilis, P. aeruginosa or fungi) were not considered.

Absence of infectious complications after surgery, as defined herein, and lack of microbiologically documented infections were predictive of good outcome (P < 0.05;  2 test). A trend towards higher TIG efficacy was observed when surgical procedures involving the large bowel were excluded (Table 3).

All patients with persistent fever after 7 days of TIG therapy responded to second-line therapy with clinical cure. None of the patients died within 30 days from the beginning of antibiotic treatment.

No associations were observed between the clinical outcome on TIG treatment when accounting for baseline CRP, fibrinogen serum concentrations or neutrophil count.

Discussion

Cancer patients with complicated infections following abdominal surgery represent one of the worst clinical scenarios that is useful for testing the efficacy of empirical antimicrobial therapy. This was reflected in this study by an apparently low overall clinical response rate of 48%, which was however improved to 67% when febrile episodes sustained by microorganisms not susceptible to TIG (e.g. P. aeruginosa, Proteus spp. and Candida spp.) were excluded.

These rates differ from previous work [START_REF] Babinchak | The efficacy and safety of tigecycline for the treatment of complicated intra-abdominal infections: analysis of pooled clinical trial data[END_REF][START_REF] Swoboda | Tigecycline for the treatment of patients with severe sepsis or septic shock: a drug use evaluation in a surgical intensive care unit[END_REF], however relevant differences in the selection of patients, surgical procedures and treatment protocols underlie and explain this apparent A c c e p t e d M a n u s c r i p t discrepancy. In the pooled analysis of two phase III double-blind trials of TIG versus imipenem/cilastatin in patients with cIAI, systemic malignancy within the prior 6 months or metastatic malignancy to the abdomen within the prior 6 months represented patient exclusion criteria [START_REF] Babinchak | The efficacy and safety of tigecycline for the treatment of complicated intra-abdominal infections: analysis of pooled clinical trial data[END_REF]. In an analysis of TIG use in a surgical Intensive Care Unit, only 35 patients had cancer. IAIs accounted for 50% of cases and none of the patients received TIG as empirical monotherapy as other antibiotics were always associated with TIG [START_REF] Swoboda | Tigecycline for the treatment of patients with severe sepsis or septic shock: a drug use evaluation in a surgical intensive care unit[END_REF].

In a study of 110 febrile cancer patients with clinical response rates comparable with the present work (overall 64%; 79% in patients with bloodstream infection, 51% in patients with pneumonia) [START_REF] Chemaly | Tigecycline use in cancer patients with serious infections: a report on 110 cases from a single institution[END_REF], none of the 46 patients with solid tumours underwent surgical procedures and only 9 (8%) of the 110 patients had a cIAI. In addition, treatment protocols differed, as TIG was given as empirical treatment in only 56 patients (51%), with most patients (97%) concomitantly also receiving other antibiotics [START_REF] Chemaly | Tigecycline use in cancer patients with serious infections: a report on 110 cases from a single institution[END_REF].

The present evaluation therefore has the advantage of reporting a homogeneous group of sequential patients following cancer surgery requiring abdominal procedures. Another possible merit is the possibility of evaluating responses to treatment that are accounted for only by TIG, as other antibiotics were not associated (or switched to) as long as response to first-line treatment was observed. Significantly higher success rates were observed when peritonitis or sepsis were absent (87%). Patients with such complications had polymicrobial or resistant microbial infections that were more likely to lead to failure of TIG monotherapy and thus a switch to a different antibiotic regimen.

A c c e p t e d M a n u s c r i p t

One limitation of the present study is represented by the lack of a control group of patients treated with a different single-agent regimen (e.g. meropenem, piperacillin/tazobactam) to provide an estimate of true comparative efficacy. All patients failing TIG were 'rescued' and cured with a different regimen. The potency or effectiveness of the antibiotic regimen is, however, not a likely issue, as all these 'switch to' regimens included two or more antimicrobial agents and could therefore not be directly compared with a TIG-only regimen.

A high incidence of Gram-negative infections was observed (68%), with E. coli (29%) as the prevalent isolate, followed by enterococci (9%) and CoNS (9%). This reflects the origin of infections and is in line with the results from surveillance studies designed to monitor longitudinally the in vitro antimicrobial susceptibility of aerobic and facultatively anaerobic Gram-negative bacilli isolated exclusively from intra-abdominal sites or from sepsis syndromes of abdominal origin [START_REF] Hawser | In vitro susceptibilities of aerobic and facultative anaerobic Gram-negative bacilli from patients with intra-abdominal infections worldwide from 2005-2007: results from the SMART study[END_REF]. Other studies reported less frequent recovery of E. coli and higher frequencies of Enterococcus spp. from cases of post-operative peritonitis [START_REF] Seguin | Factors associated with multidrug-resistant bacteria in secondary peritonitis: impact on antibiotic therapy[END_REF], possibly due to prior antimicrobial use. Recovery of P. aeruginosa or Proteus spp. in these patients at a rate of 16% is in line with other studies of a similar setting [START_REF] Montravers | Clinical and microbiological profiles of community-acquired and nosocomial intra-abdominal infections: results of the French prospective, observational EBIIA study[END_REF][START_REF] Nicoletti | CIGAR (Gruppo Cooperativo Infezioni Gravi ed Antibiotico Resistenza). Bacterial isolates from severe infections and their antibiotic susceptibility patterns in Italy: a nationwide study in the hospital settings[END_REF] and, as expected, affected treatment outcome (i.e. failure). Also the low incidence of episodes with Candida spp. (12%) or multidrug-resistant bacterial infections detected here is in agreement with the timing of infection (i.e. early after surgery) and with the absence of prior prolonged antibiotic use. In this regard, use of TIG later after surgery/hospitalisation, and possibly after failure of empirical treatment with different first-line antibiotic regimens, could bear increased risks of failure due to the possibility of selection of emerging P. aeruginosa or Proteus spp. and of fungi that may determine febrile episodes.

A c c e p t e d M a n u s c r i p t

In conclusion, cancer patients undergoing abdominal surgery may be good candidates for early empirical monotherapy with TIG when complications (peritonitis, large bowel perforations) are not present or suspected on clinical grounds and when local microbial epidemiology confirms a low incidence of primary resistant bacteria. Under these conditions and in these patients, TIG represents a suitable alternative regimen to those currently used, thus widening the initial antimicrobial choice. Edited Table 3

A

  c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t ABSTRACT Cancer patients with complicated infections following abdominal surgery represent one of the worst clinical scenarios that is useful for testing the efficacy of empirical antimicrobial therapy.

between

  May 2008 and July 2009 at a single institution (Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy) were considered. Antimicrobial prophylaxis for the prevention of surgical-site infection was administrated according to current guidelines approved by Istituto Nazionale per la Ricerca sul Cancro. Data were derived from clinical records. Patient inclusion criteria were: established cancer diagnosis; abdominal surgery; febrile episode (≥37.7 C for ≥6 h) within 72 h after abdominal surgery; and TIG administration within 48 h from onset of a febrile episode. An exclusion criterion was >36-48 h of treatment with other antibiotics. The following data were collected: demographics (age, sex); hospital ward (High Care, Surgery or Medical Oncology); cancer type and staging; type of surgery; post-surgical complications; use of chemotherapy within 8 weeks before surgery; prior use of antibacterials; microbiological and antibacterial sensitivity data of isolates from blood, A c c e p t e d M a n u s c r i p t drainage or urine; markers of tissue inflammation and infection [including total leukocyte count and C-reactive protein (CRP)]; and duration of fever.

  carbapenem + antifungal agent (fluconazole) (5 patients); (ii) a broad-spectrum -lactam with anti-P. aeruginosa activity + anti-Gram-positive agent or carbapenem + antianaerobic antimicrobial agent (metronidazole or clindamycin) (4 cases); and other antimicrobial combinations (3 patients).

A

  c c e p t e d M a n u s c r i p t TIG was discontinued in one patient due to increasing liver enzyme serum concentrations.

Table 3

 3 Clinical response rates in patents treated with tigecycline

	Characteristic	Clinical response	Characteristic	Clinical response	P-
		(%)		(%)	value
	Male	57	Female	36	N/S
	Age 65 years	64	Age >65 years	36	N/S
	Large bowel cancer	40	Other tumours	60	N/S
	Metastatic disease	45	No metastatic disease	50	N/S
	Chemotherapy within 2 months	75	Chemotherapy beyond 2 months	38	N/S
	Colorectal surgery	35	Other abdominal surgery	75	N/S
	Presence of complications	29	Absence of complications	87	<0.05
	TIG start in ICU	25	TIG started outside ICU	59	N/S
	Sepsis	50	Peritonitis	30	N/S
	Monobacterial infection	33	Polybacterial infection	30	N/S
	Microbiologically documented	35	No microbiologically documented	77	<0.05
	infection		infection
	N/S, not significant; TIG, tigecycline; ICU, Intensive Care Unit.

Acknowledgments

The authors are grateful for patient support and clinical assistance to Emanuele Malfatto, MD, and Eva Schenone, MD (Clinica Malattie Infettive, University of Genoa, Genoa, Italy) and to Roberto Rezzo, MD, Paolo Meszaros, MD, and Sergio Bertoglio, MD (Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy) and for microbiological assistance with clinical isolates to M.P. Molinari and M. Mussap (Laboratorio Centrali, Azienda Ospedale San Martino, Genoa, Italy). Thanks to Ms Mattea Roccatagliata for secretarial assistance.

Funding

This work was supported in part by grants from Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR) to ADM.

Competing interests

None declared.

Ethical approval

Patient treatment was performed according to clinical guidelines for surgical patients. Use of TIG was according to its registered use.