Comparison of Different Sources of Energy
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"5236",leadTitle:null,fullTitle:"High Energy and Short Pulse Lasers",title:"High Energy and Short Pulse Lasers",subtitle:null,reviewType:"peer-reviewed",abstract:"This book gives the readers an introduction to experimental and theoretical knowledge acquired by large-scale laser laboratories that are dealing with extra–high peak power and ultrashort laser pulses for research of terawatt (TW), petawatt (PW), or near-future exawatt (EW) laser interactions, for soft X-ray sources, for acceleration of particles, or for generation of hot dense thermal plasma for the laser fusion. 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Remote monitoring of the vital health information facilitates personal in-home care, reduces the cost and time of frequently going to the hospitals and minimizes the difficulties of monitoring the health of the elderly persons. Recent research on contemporary implantable and wearable sensors for monitoring various physiological parameters as well as improvement of wireless technology have led to the development of all-inclusive patient monitoring systems such as Wireless Body Area Network (WBAN) and Body Sensor Network (BSN). One of the integral parts of these networks is implantable sensor. Applications of implantable sensors include (but not limited to) monitoring of blood glucose level for diabetic patients, continuous in vivo monitoring of lactose in the bloodstream or tissues, pressure monitoring of blood vessels and electronic interfaces to monitor the nervous system. Monitoring of physiological parameters such as pH level in tissues, glucose and lactose in bloodstreams, heart rate and respiration rate not only improves the quality of life of the patients but also increases their lifespan. Even though astounding advancements have been made in medical electronics and instrumentation, invasive medical devices such as small lancets are still used to collect samples from human body for testing and diagnostic purposes. These devices increase the risk of infection in human body. For a diabetic patient the discrete measurements provided by the lancets are not sufficient for monitoring of blood glucose level. In order to get an idea of the blood glucose trend line, continuous monitoring of glucose level is highly desirable and minimally invasive implantable sensors are ideal fit for this application. The most important concern related to the use of implantable sensor is the health safety of the patients. The true success of an implant depends on the proper functioning of the sensor without having any adverse effect on the tissues surrounding the implant.
Recent developments in biomedical sensors and state-of-the-art CMOS technologies have led to the realization of minimally invasive implantable biomedical sensors for continuous monitoring of the patients. A continuous monitoring system allows the doctors to investigate the medical data of the patient online and thus provides savings in both time and money. The data acquired by the sensor from frequent monitoring also helps the hospital to efficiently record the medical history of a patient for future references. Figure 1 represents a detailed implantable sensor system with the combination of different biosensors and integrated circuits (ICs) which are designed to be implanted underneath the skin. Sub-micron CMOS technologies offer various advantages such as small form factor and reliable operation which make them very suitable for implantable medical applications. Biosensors on this platform include glucose, lactose, oxygen and pH sensors, etc. The state of the art research on implantable biosensor system focuses on its small form factor and light-weight for easy integration and biological safety [1]. Even though the development of deep sub-micron CMOS processes has significantly brought down the overall chip area, still the power unit such as lithium ion battery takes up a substantial area of the overall system. Therefore elimination of the battery as the power source can potentially reduce the system area significantly. Batteries also impose a potential risk of leakage which might result in serious health hazards to the patient and require periodic replacement. An eco-friendly solution of this potential problem involves the development of more efficient wireless powering methods or the design of low-power ICs. In contrast to a battery operated system, wireless powered system eliminates the hassle of frequent replacement of the power source and can be considered as a minimally invasive option with no risk of infection [1] [2]. Previously reported works present the use of inductive coupling (i.e. inductive link) [1] and optical coupling (i.e. solar cells) [2] as potential wireless powering approaches. A noninvasive, reliable, and efficient power supply along with a reliable data communication interface is a potentially important feature that an implantable sensor must possess.
A biosensor usually consists of an electrochemical sensor which generates an electrical signal that corresponds to the concentration of a particular electrolyte. Readout electronics such as potentiostats (amperometric or voltametric electrochemical sensors) help maintain a constant potential difference between two electrodes to facilitate the chemical reaction to take place and provide output in the form of a current (amperometric) or a voltage (voltametric) signal. A typical potentiostat consists of three electrodes: a working electrode (WE), a counter electrode (CE), and a reference electrode (RE). The potential difference between the working and the reference electrodes stimulates the chemical reaction and the counter electrode provides the corresponding output current signal, which is then delivered to the signal processing unit (SPU). The SPU modulates the data so that it can be transmitted outside of the body wirelessly to a receiver, which can be a smart phone or a similar electronic device. Peripheral ICs such as power supply units, sensor activation circuits etc. are also integrated together to realize this scheme on a system-on-a-chip (SoC) platform.
Implantable biosensor system (inside the dashed red rectangle) [3].
Even though the amplitude of the signal generated by the implantable biosensors depends on the concentration of various physiological parameters, nonetheless the signal needs to be amplified and converted to a digital signal for further processing. Low-voltage and low-power circuit design techniques are required to be employed in the design of the signal processing circuitry of the implantable devices for long-term reliable operations. Depending on the application the most appropriate circuit topology needs to be chosen to meet the design challenges. Various innovative low-power circuit design methodologies have appeared in literatures to meet the requirement of long term operations. Their working principles are discussed in the following sections.
From the perspective of a circuit designer, employing of short-channel transistors is an appealing and efficient method to reduce the SoC chip area. The added advantage of these transistors is that the power supply voltage also downscales proportionally with the reduction of the transistor channel length. Thus hot electron effect and time-dependent dielectric breakdown (TDDB) [4] do not deteriorate the robustness and reliability of the devices. However, the threshold voltage, VT of the MOSFET does not scale down as aggressively as the channel length or the power supply voltage [5], which puts a constraint on the number of transistors that can be cascaded in a given process. Some of the techniques for low-power circuit design include bulk-or body-driven technique, floating gate technique, subthreshold biasing scheme of the transistors etc. The following sections summarize various low-power circuit design techniques reported in literature.
The bulk (or body-)-driven scheme is a technique that allows circuit designers to implement ultra-low voltage and ultra-low power system. In the bulk-driven circuit design scheme, the bulk or the body terminal of a MOSFET is enabled as an AC input. The gate of the device is kept at a certain potential so that the transistor is ‘on’ during the entire operation. This technique eliminates the threshold voltage limitation mentioned earlier and helps achieve ultra-low supply voltage requirement while cascading a good number of transistors. Circuit designers have used this technique to design a low-voltage, low-power amplifier with a supply voltage of as low as 1 V [3]. A major drawback of this approach is the lower body transconductance (gmb). In addition, the bulk-driving voltage needs to be kept within a certain range so that the body diodes of the MOSFET are reverse-biased during the variation of the AC input signal of the body terminal. Therefore, this technique can only be applied to a limited number of applications [6].
Although the implementation of the floating gate technique is mostly seen in the integrated memory cell applications, it can also be used for designing low-power circuits for implantable sensors. Floating gate is the polysilicon gate of the MOSFET that is surrounded by silicon dioxide (SiO2). Once the charge has been deposited on the floating gate, it can be stored permanently. Therefore this technique is suitable for flash memory cells. The amount of this charge can be adjusted by an ultraviolet (UV) light or a large gate voltage. The stored charge on the floating gate can be used to reduce the threshold voltage of the transistor. Thus this technique helps reduce the DC supply voltage requirement as well as the total power consumption [7].
Another method that is being used to implement the low-power circuit is the subthreshold design technique. In subthreshold region (or weak inversion region) design, the gate-to-source voltage of the MOSFET is biased below the threshold voltage (VGS\n\t\t\t\t\t≤ VTH) of the transistors. This level of gate-to-source voltage can weakly invert the transistor channel underneath the gate. This process of inversion of the channel is also known as weak inversion. Previously it was assumed by the researchers that this condition put the MOSFET in to cut-off region and therefore no current flows through the device. Now, it is well known that there is actually a small current that flows through the channel of the MOSFET mostly due to the diffusion of electrons from the drain to the source. A common expression for this subthreshold current of a MOSFET is shown in equation 1:
Where ID0 is the current that flows when the gate-to-source voltage is equal to the threshold voltage, n is a technology specific slope parameter, and UT is thermal voltage (UT\n\t\t\t\t\t≈ kT/q ≈ 26 mV at room temperature where k is the Boltzmann constant, T is the temperature in Kelvin and q is the charge of an electron which is equal to 1.6×10-19 coulomb). The exponential relationship between the drain current and the gate-to-source voltage causes subthreshold biased circuits to be extremely sensitive to noise and matching. In comparison with the strong inversion circuit design technique that requires the gate-to-source voltage of the transistor to be much higher than the threshold voltage, this technique can achieve higher transconductance efficiency for the same level of current. Combined with rational circuit design and layout approach, this method can be used for implementing low-power analog circuits for implantable sensors.
For tether-less operation and to avoid skin infections, the data signal from the signal processor needs to be wirelessly transmitted to the outside environment. Several research works have been reported in recent years to meet the design requirements of wireless operation in biomedical applications. These systems should be miniaturized, light-weight, low-power and reliable for long term operation. The radiated power needs to be less than the limit set by FCC (Federal Communications Commission) for wireless telemetry. Wireless communication is one of the most prevailing means of data transmission for biomedical sensors. Wireless transmitters and receivers can be found everywhere from short-distance medical endoscopic applications [8] to long-distance cell phone communication. Technological advances in silicon manufacturing have made it possible to design low-power, low-cost integrated circuit for biomedical sensing application. Examples include electroencephalography (EEG), electrocardiography (ECG) and biometric information sensing for early detection of diseases such as tumor, cancer, and Alzheimer. Most of these applications require low data rates of a few Hz to a few kHz. ECG monitoring typically needs 12-bit resolution of ADC with 250 Hz data sampling rate for a transmission data rate of 3 kbps [9]. However the minimum energy per bit requirements for implantable sensor put a constraint on the transmitter power consumption to extend the battery life time. Since it would not be feasible to change the battery of the sensor often for an implantable sensor, low-power circuit design is an essential requirement. Considering most of the power harvesting techniques as well as battery storage capacities, a power budget of only 100 µW could be available for each sensor node [10]. Although one can relax the power constraints by larger battery/energy-harvester size, the importance of a low-power communication scheme cannot be overlooked for a compact design of the sensor node. Despite the urge for the design of a low-power low-data rate transceiver with traditional narrowband architecture, the best transceiver design in this domain for implantable sensors still consumes about 500 µW of power [11].
The first demonstration of a fully customized mixed-signal silicon chip that had most of the attributes required for a wearable or implantable BSN was described in [12]. The system blocks include low-power analog sensor interface for temperature and pH sensing, a data multiplexing and conversion module, a digital platform based around an 8-b microcontroller, data encoding for spread-spectrum wireless transmission, and an RF section requiring very few off-chip components as shown in Figure 2. A programmable direct-sequence spread-spectrum (DS-SS) transmitter is integrated into the SoC in order to improve the reliability of the wireless transmission [13]. The transmitter is comprised of a data encoder and an RF section. The minimum data rate from the encoder is approximately 3.67 kbps. The amplification stage of the RF section is designed to be a near-class-E RF power amplifier driven by the digital output of the encoder. The gain budget of the amplifier enables it to maintain high gain and linearity while limiting the total current. The on-chip RF section uses a relatively low frequency carrier for modulation. An 800µm × 300µm on-chip spiral inductor transmits the signal that is detectable at a range of 0.5 m in air using a Winradio receiver with a conventional whip antenna at a data rate of up to 5 kbps. Even though the on-chip inductor is less efficient than an external antenna, it demonstrates the feasibility of integrated antennas on silicon [14], [15]. A data-acquisition device detects the signal from the SoC.
Schematic diagram of the system-on-chip architecture for body sensor networks [12].
An integrated CMOS ultra-wideband, high duty cycled, non-coherent wireless telemetry transceiver for wearable and implantable medical sensor applications was reported in [16]. A prototype wireless capsule for endoscopy was designed using the proposed transceiver and it demonstrated in vivo image transmission of 640 × 480 resolution at a frame rate of 2.5 fps with 10 Mb/s data rate. This transceiver supports scalable data rate of up to 10 Mbps with energy efficiency of 0.35 nJ/bit and 6.2 nJ/bit for transmitter and receiver, respectively. The block diagram of the transmitter is shown in Figure 3. The transceiver uses On/Off keying (OOK) modulation scheme where a binary “1” is represented by a short pulse and binary “0” is represented by no pulse transmission. For improved performance of antennas with miniaturized size, UWB frequency band in 3–5 GHz is selected. The UWB pulse is generated by a fast on/off voltage-controlled oscillator (VCO) controlled by the TX data. A driving amplifier provides voltage amplification and isolation between the VCO and the antenna. Both the VCO and the driving amplifier consume power during pulse generation only. At the receiver end, the weak signal is first amplified by a variable gain low-noise amplifier (LNA) followed by a squarer performing the energy detection. A variable gain amplifier (VGA) amplifies the squarer output further and a slicer digitizes the final signal. The digital baseband provides synchronization, error correction coding, and interfaces with the external sensors. The transceiver chip consumes a die area of 3 mm × 4 mm when designed in a standard 0.18 µm CMOS process. The transmitter draws an average power of 0.35 mW with the energy per bit of 0.35 nJ/bit for up to 10 Mbps. The receiver average power consumption is as low as 6.1 mW with duty cycling under 1 Mbps data rate and with the energy efficiency maintained at 6.2 nJ/bit.
Block diagram of the ultra-wideband wireless telemetry transceiver [16].
Cleven et al. [17] presented a novel fully implantable wireless sensor system implanted into the femoral artery with computed tomography angiography intended for long-term monitoring of hypertension patients. The system was employed to measure intra-arterial pressure at a sampling rate of 30 Hz and an accuracy of ±1.0 mmHg over a range of 30–300 mmHg, and consumed up to 300μW power. The implant consists of two functional components: the pressure sensor tip and the transponder unit for communicating with the external readout station. Both the components are linked by a data cable. The full length of the sensor system is approximately 22 cm. The telemetric unit has a diameter of approximately 2 cm and a thickness of approximately 4 mm. The telemetry chip schematic including external components necessary for telemetric mode is presented in Figure 4. The analog output signal from the pressure sensor ASIC is digitized by the sensor readout block. At the same time, the bidirectional data pads provide the offset and the gain settings. The digital component of the chip, a state machine, provides the protocol for data transmission of the measured values. The HF front-end controls the telemetry components while generating the controlled supply voltage required for sensor readout. Using a transmission frequency of 133 kHz, the digitalized information is sent by telemetry to the receiver coil of the external readout electronics.
Schematics of transponder ASIC and external circuitry for long-term monitoring of hypertension patients [17].
A transcutaneous two-way communication and power system for wireless neural recording was reported in [18]. Figure 5(a) shows a schematic of the power and bidirectional data transfer system. Wireless powering and 1.25 Mbps forward data transmission (into the body) are achieved using a frequency-shift keying modulated class-E converter. The carrier frequency for reverse telemetry (out of the body) is generated using an integer-N phase-locked loop which provides the necessary wideband data link to support simultaneous reverse telemetry from multiple implanted devices on separate channels. The physical arrangement of the coils is illustrated in Figure 5(b). For the implanted device, coil 1 (L1) represents the external power coil, coil 2 (L2) is the implanted power coil, coil 3 (L3) is regarded as one of the external differential data coils, and coil 4 (L4) is the implanted data coil. A large AC current is generated in coil 1 using a class-E converter to transfer power to the implant. An AC current proportional to the coupling coefficient between the external and the implanted power coils is induced in coil 2. The resulting AC voltage is rectified and supplied to the application-specific integrated circuit (ASIC) to power it up. Frequency-Shift Keying (FSK) modulation of the 5 MHz power carrier at a data rate of 1.25 Mbps is performed to achieve forward data transfer and to send control data to the ASIC. The reference clock is multiplied up by an integer-N PLL in the ASIC circuitry to generate a reverse telemetry carrier between 50 and 100 MHz. The reverse telemetry uses either Amplitude-Shift Keying (ASK) or Binary-Phase-Shift Keying (BPSK) modulation scheme. To generate the reverse telemetry signal, the on-chip driver circuitry induces current in coil 4. Data is received by one of the two external differential data coils, coil 3. The purpose of a differential coil configuration is to cancel both the large power signal at its fundamental frequency and harmonics generated by the class-E converter that fall within the frequency range of the reverse telemetry.
(a) Schematic of bidirectional data transfer system for wireless neural recording, (b) Physical diagram of dual inductive link coils [18].
Cao et al. prototyped a device for gastroesophageal reflux disease (GERD) monitoring in [19]. The system consists of an implantable, battery-less and wireless transponder with integrated impedance and pH sensors and a wearable, external reader that wirelessly powers up the transponder and interprets the transponded radio-frequency signals. The total size of the transponder implant is 0.4 cm × 0.8 cm × 3.8 cm and it harvests radio frequency energy to operate dual-sensor and load-modulation circuitry. The system is designed in a way that it can store data in a memory card and/or transmit data to a base station wirelessly. Figure 6 shows the block diagram of the sensor system. The coil antennas and the tuning capacitors form the resonant circuits. Relaxation oscillators are used as the frequency converters in the transponder. The system is designed to operate at 1.34 MHz since the recommended maximum permissible exposure of magnetic fields is the highest in the frequency range of 1.34 MHz to 30 MHz [20]. A coil antenna is made using a 34-AWG magnet wire wound around the printed circuit board. The energy harvesting circuit consists of a series of diodes and capacitors (100 pF) in a voltage multiplier circuitry that builds up the DC voltage from the received RF signals [21], [22], [23]. To maintain a constant DC level of 2.5 V for biasing the circuits, a voltage regulator is used.
Block diagram of the gastroesophageal reflux disease (GERD) monitoring system [19].
Cheong et al. [24] presented an inductively powered implantable blood flow sensor microsystem with bidirectional telemetry. The microsystem is comprised of silicon nanowire (SiNW) sensors with tunable piezoresistivity, an ultra-low-power application-specific integrated circuit (ASIC), and two miniature coils that are coupled with a larger coil in an external monitoring unit to form a passive wireless link. The implantable microsystem operates at 13.56-MHz carrier frequency. It receives power and command from the external unit and backscatters digitized sensor readout through the coupling coils. Cheong et al. fabricated the ASIC in a standard 0.18-μm CMOS process and the chip occupied an active area of 1.5 × 1.78 mm2 while consuming only 21.6 μW of power. The overall system architecture consisting of an implantable wireless sensor microsystem and an external hand-held device is shown in Figure 7. The ASIC consists of a sensor interface circuit, an analog-to-digital converter (ADC), a digital baseband (DBB), a low-dropout (LDO) regulator, and front-end circuits for wireless powering and bidirectional telemetry. The external monitoring unit needs to be placed in close proximity to the implant microsystem to initiate the passive sensing operation. The RF power is transmitted by the external unit through the carrier at 13.56 MHz. The parallel resonant LC tanks and the rectifiers convert the received RF signal to a DC signal, and the LDO regulator powers the ASIC with regulated DC supply. Following the demodulation of the incoming modulated carrier, it is de-spread by the DBB to configure the system parameters such as integration time, amplifier gain, selection between two sensors, resonance tuning, and modulation index. At the same time, the clock is extracted from the incoming carrier and is provided to the DBB. Once the system parameters are set according to the received commands, the sensing operation ensues. A successive approximation register (SAR) ADC converts the analog voltage output from the sensor interface circuit into digital data. The digital data is spread and formatted by the DBB and is sent to the load modulator that backscatters the incoming RF carrier according to the sensor data bit stream from DBB.
Architecture of the implantable blood flow monitoring system [24].
The above discussion presents an overall picture of the recent evolution in wireless technology for implantable sensors for monitoring of various physiological parameters. The background information and the current trends for the design of a wireless transmitters and receivers are also discussed. For a low-power, non-invasive and unobtrusive performance of an implantable sensor, wireless power transfer is mandatory. In the following sections, a brief discussion on various wireless power transfer and energy scavenging techniques are presented in terms of application requirements, available resources and radiation constraints.
Previously, transcutaneous power cables were used in clinical implantable applications [25] at the expense of the introduction of a significant possibility for infection. Another alternative for power cables is an implanted battery. The use of batteries is usually intended to be avoided in implantable biomedical sensors as battery replacement is cumbersome and there is always a probability of leakage which can have serious health consequences. For this reason, various energy harvesting schemes and wireless powering techniques are employed in implantable sensors for battery-less operation. Energy harvested from body heat, breathing, arm motion, leg motion or from the motion of other body parts during walking or any other activity can be converted into a usable voltage to power up the sensor.
There are several possible sources of energy for sensorsincluding kinetic and thermal energy harvesters such as piezoelectric and pyroelectric transducers, photovoltaic cells etc. A summary is provided in the following table highlighting their sizes, produced energy or power and respective applications [26].
\n\t\t\t\tMethod\n\t\t\t | \n\t\t\t\n\t\t\t\tDensity\n\t\t\t | \n\t\t\t\n\t\t\t\tAdvantage\n\t\t\t | \n\t\t\t\n\t\t\t\tDisadvantage\n\t\t\t | \n\t\t
\n\t\t\t\tPiezoelectric\n\t\t\t | \n\t\t\t200 μW/cm3\n\t\t\t | \n\t\t\tNo energy required from outside | \n\t\t\tDependent on movement | \n\t\t
\n\t\t\t\tThermoelectric\n\t\t\t | \n\t\t\t60 μW/ cm3\n\t\t\t | \n\t\t\tNo material to be replenished | \n\t\t\tLow efficiency less than 5% | \n\t\t
\n\t\t\t\tKinetic\n\t\t\t | \n\t\t\t4 μW/ cm3\n\t\t\t | \n\t\t\tNo material to be replenished | \n\t\t\tDependent on movement | \n\t\t
\n\t\t\t\tAmbient RF energy harvesting\n\t\t\t | \n\t\t\t*1 μW/cm2\n\t\t\t | \n\t\t\tHarvesting energy from ambient EM wave | \n\t\t\tDepends on EM wave availability | \n\t\t
\n\t\t\t\tVisible light\n\t\t\t | \n\t\t\t*100 mW/cm2\n\t\t\t | \n\t\t\tFree | \n\t\t\tNot available at night and in cloudy days. | \n\t\t
\n\t\t\t\tTemperature variation\n\t\t\t | \n\t\t\t10 μW/ cm3\n\t\t\t | \n\t\t\tNo material to be replenished | \n\t\t\tLow efficiency, Energy storage required | \n\t\t
\n\t\t\t\tAirflow\n\t\t\t | \n\t\t\t*1 μW/cm2\n\t\t\t | \n\t\t\tNo material to be replenished | \n\t\t\tImplantation is difficult | \n\t\t
\n\t\t\t\tHeel strike\n\t\t\t | \n\t\t\t*7 W/cm2\n\t\t\t | \n\t\t\tGood source of energy | \n\t\t\tDependent on movement. | \n\t\t
Comparison of Different Sources of Energy
* Energy Density per Unit Area
All the above methods presented in Table 1 have their benefits as well as disadvantages. The method which is free of most of these disadvantages is the wireless power transfer (WPT). WPT is clean, controllable, independent of patient’s movement, always available and more efficient than all the sources of energy that have been mentioned in Table 1. Although WPT has lower efficiency compared to the battery, it does not have the risk factors that are associated with a battery. Especially for sensors that come in direct contact with blood, any leakage can cause chemical burning, poisoning etc. and may eventually lead to death. A battery usually lasts for 5 to 7 years and then surgical procedure is required for its removal and replacement. On the other hand, WPT usually lasts for 15 to 20 years and consequently it is much cheaper than the batteries.
WPT is a technique for supplying energy from the source to the destination without any interconnecting wires. Nicola Tesla first demonstrated WPT using his resonant transformer called ‘Tesla coil’. In this design, resonant inductive coupling was used to excite the secondary side of a transformer. With the passage of time, many researchers came up with different applications for the use of WPT and now WPT is used when a wire interconnection is inconvenient, risky or impossible. WPT is now used in induction heating coils, wireless chargers for consumer electronics, biomedical implants, radio frequency identification (RFID), contact-less smart cards etc. Several types of wireless power transfer techniques have been briefly discussed in the following section.
There are two major methods for wireless power transfer – electromagnetic induction and electromagnetic radiation. Electromagnetic induction can be subdivided into three categories – electrodynamic, electrostatic and evanescent wave coupling. Electromagnetic radiation such as microwave power transfer and laser are also used for transferring power wirelessly. Figure 8 illustrates various types of wireless power transfer techniques.
Types of wireless power.
Electromagnetic Induction
By varying the magnetic field an electromotive force can be produced across a conductor. This is called electromagnetic induction. The three possible ways to achieve that are summarized below:
Inductive coupling: This is achieved via near field radiation which causes coupling of energy between two inductors (coils) and is also known as the electrodynamic or magnetic coupling.
Electrostatic or capacitive coupling: This is the propagation of electrical energy through a dielectric medium. High voltage and high frequency alternating current gives rise to the electrical field for this form of WPT. Unintended parasitic capacitance (e.g. capacitance between two adjoining wires or PCB traces) can cause noise and has to be taken into account for high frequency circuit design.
Evanescent wave coupling: In this process, an exponentially decaying electromagnetic field is used to transmit the electromagnetic waves from one medium to another.
Electromagnetic Radiation
After an electromagnetic radiation is emitted, it can be absorbed by some charged particles. This type of radiation can propagate through vacuum at the speed of light. It has a time varying electric field component as well as a magnetic field component, which oscillates perpendicularly to each other and perpendicularly to the direction of energy and wave propagation. Two ways in which wireless power transfer using electromagnetic radiation can be accomplished are:
Microwave power transmission: It is the transmission of energy using electromagnetic waves with wavelengths ranging from 30 cm down to 1 cm or equivalently a frequency range of 1 GHz to 30 GHz. It is used for directional power transmission to a remote destination.
Laser: In this technique electricity is first converted into a laser beam which is then directed towards a photovoltaic cell. The receiver is an array of photovoltaic cells designed to convert the light back to a usable electrical energy. This method is also known as optical coupling.
Since inductive link is the most commonly used wireless power transferring technique for biomedical sensors, it is discussed in more detail in the following section.
Basic inductive link caused by alternating electromagnetic field.
An inductive link comprises of a loosely coupled transformer consisting of a pair of coils as shown in Figure 9. An alternating source (AC) drives the primary coil and generates the desired electromagnetic field. A portion of the generated magnetic flux links the secondary coil and according to Faraday’s Law of electromagnetic induction, the temporal change of magnetic flux induces a voltage across the secondary coil. The voltage induced in the secondary coil is proportional to the rate of change of magnetic flux in the secondary coil and the number of turns in that coil.
Schematic of basic inductive link based on series parallel resonance.
Figure 10 illustrates a basic inductive link based on series-parallel resonance. The maximum value of the mutual inductance, M that can possibly be achieved between the two coils of inductance of L1 and L2 is (L1L2)1/2 and this occurs when all the flux generated in the primary coil links with all the turns in the secondary coil. The ratio of mutual inductance to its maximum value is called the coupling coefficient k, which is a dimensionless quantity ranging from 0 to 1 and can be determined using the following equation:
The performance of the inductive link is dependent on the link efficiency, which is defined as the ratio of the power delivered to the load to the power supplied to the primary coil. For a parallel resonant circuit, the link efficiency of the secondary side can be written as [46],
For a series resonant circuit, the link efficiency of the secondary side turns out to be,
In both Equation 3 and 4, Q1 is the quality factor of the primary coil, Q2 is the quality factor of the secondary coil, k is the coupling factor between the coils, α is a unit-less constant which is equal to ωC2RL, where ω is the angular frequency, C2 is the capacitance of the secondary coil and RL is the load resistance.
Inductive link is a common method for wireless powering of implantable biomedical electronics and data communication with the external world. WPT and data telemetry using inductive link have been demonstrated for various biomedical applications including visual prosthesis, cochlear implant, neuromuscular and nerve stimulator, cardiac pacemaker/defibrillator, deep-brain stimulator, brain machine interface, gastrointestinal microsystem and capsule endoscopy[27-37]. A summary of various inductive link wireless power transfer applications and their respective carrier frequencies is presented in Table 2:
\n\t\t\t\tReference\n\t\t\t | \n\t\t\t\n\t\t\t\tApplications\n\t\t\t | \n\t\t\t\n\t\t\t\tFrequency\n\t\t\t | \n\t\t\t\n\t\t\t\tInductor Type\n\t\t\t | \n\t\t
\n\t\t\t\t[28]\n\t\t\t | \n\t\t\tNeural prosthetic Implant | \n\t\t\t2-20 MHz | \n\t\t\tFerrite core | \n\t\t
\n\t\t\t\t[29]\n\t\t\t | \n\t\t\tCochlear Implant | \n\t\t\t-- | \n\t\t\t-- | \n\t\t
\n\t\t\t\t[37]\n\t\t\t | \n\t\t\tRetinal prosthesis | \n\t\t\t1 MHz | \n\t\t\tLitz wire | \n\t\t
\n\t\t\t\t[36]\n\t\t\t | \n\t\t\tBiomedical implant | \n\t\t\t5/10 MHz | \n\t\t\t-- | \n\t\t
\n\t\t\t\t[35]\n\t\t\t | \n\t\t\tNeural implant | \n\t\t\t4 MHz | \n\t\t\tCopper magnet wire | \n\t\t
\n\t\t\t\t[32]\n\t\t\t | \n\t\t\tEndoscope | \n\t\t\t1.055 MHz | \n\t\t\tLitz wire | \n\t\t
\n\t\t\t\t[33]\n\t\t\t | \n\t\t\tGastrointestinal microsystems | \n\t\t\t58.418 KHz | \n\t\t\tCopper wire | \n\t\t
\n\t\t\t\t[38]\n\t\t\t | \n\t\t\tNeural recording | \n\t\t\t4 MHz | \n\t\t\tLitz wire | \n\t\t
\n\t\t\t\t[39]\n\t\t\t | \n\t\t\tImplantable system | \n\t\t\t13.56 MHz | \n\t\t\tOn-chip | \n\t\t
\n\t\t\t\t[40]\n\t\t\t | \n\t\t\tNeural prosthesis | \n\t\t\t25 MHz | \n\t\t\tWire | \n\t\t
\n\t\t\t\t[41]\n\t\t\t | \n\t\t\tImplantable prosthesis | \n\t\t\t1 GHz | \n\t\t\tBond wire | \n\t\t
\n\t\t\t\t[42]\n\t\t\t | \n\t\t\tNeuroprosthetic implantable device | \n\t\t\t13.56 MHz | \n\t\t\tPCB | \n\t\t
\n\t\t\t\t[43]\n\t\t\t | \n\t\t\tNeural recording | \n\t\t\t2.64 MHz | \n\t\t\tOff-chip power, on-chip data | \n\t\t
\n\t\t\t\t[44]\n\t\t\t | \n\t\t\tNeural recording | \n\t\t\t<10 MHz | \n\t\t\tWire | \n\t\t
Wireless Power Transfer for Different Biomedical Implants
The design of an inductive link is required to meet the power requirement of any of the above mentioned applications. There are several parameters which play key roles in determining the performance of an inductive link. A qualitative analysis of these key factors is presented in the following section.
The factors that affect the performance of an inductive link wireless power transfer are as follows:
Diameter of coils: The diameters of the receiver and the transmitter coils are important parameters affecting the voltage gain of an inductive link [28]. Both the self inductance and the mutual inductance are proportional to the diameters of the coils. Therefore increasing the diameters boosts the link efficiency. In case of an implantable system, due to the constraint on the size of the implant there are more stringent limitations on the receiver coil size compared to those of the transmitter coil.
Number of turns: The number of turns is another important factor since the mutual inductance is proportional to the product of the number of turns in the transmitter and the receiver coils. Therefore increasing the number of turns will improve the performance.
Spacing and alignment: Spacing between the primary and the secondary coils and their alignment also significantly affect the coupling between them. Therefore the position of the implantable sensor in terms of the external wireless power transferring module is an important factor that needs to be taken in to account. Compared to an exact coaxial alignment, similar or even better performance can be achieved if the receiver coil is present within the circumference of the transmitter coil [28]. In case of implantable sensors, any movement of the patient can cause misalignment between the transmitter and the receiver which in turn can alter the mutual inductance and the link gain. Two types of misalignment that affect the link efficiency are lateral misalignment and angular misalignment [25] as illustrated in Figure 11. After a certain lateral or angular misalignment, the performance degradation of the wireless inductive link becomes proportional to the magnitude of the misalignment.
Indcutive coupling bewtween two coils with lateral misalignment and angular misalignment.
Quality Factor: Higher Quality factors (Q) of the primary and the secondary coils can significantly improve the link efficiency of an inductive link [27], [47]. Therefore designing coils with high Q values at the desired frequency of operation is required to achieve a satisfactory power transfer. Another disadvantage of low Q circuit is that it makes the output voltage susceptible to load changes [45].
Operating frequency: The maximum power allowed to penetrate through human tissue depends on the operating frequency. It also dictates the size of the coil, the mutual impedance and the voltage transfer ratio. Since the quality factor depends on the operating frequency, the efficiency and the bandwidth of the link are influenced as well. Thus, the frequency of operation plays an important role in the design of wireless power transfer.
Other relevant factors: The primary coil of an inductive link is usually driven by low-loss switching amplifiers. It is necessary to have a high driver efficiency to ensure satisfactory power transfer efficiency of an inductive link. With a tuned amplifier load, the drive transistor only draws current when there is no voltage across it [48], improving the overall system efficiency significantly in the process. Different topologies for the amplifier have been reported in literature: class-C [27], [48], class-D [45], [50], class-E [35], [37], [49] and class-CE [47]. Sokal et al. reported a class-E amplifier with a very high efficiency and insensitivity to small timing errors [51]. Variation in output impedance has a pronounced effect on class-E amplifiers. When the power demand of the implantable sensor or the coupling factor between the coils changes the equivalent load seen by the driver amplifier also varies. Lastly, as far as implantable biomedical applications are concerned, the overall system gain and the efficiency also depend on the physical configuration of the two coils and the surrounding materials.
There are some major challenges associated with the implementation of an efficient wireless power transfer system in implantable sensors. The next section summerizes the major limitations.
There are several factors that impose serious limitations on the widespread use of wireless energy transfer for implantable sensors. First of all, it is not often possible to scale the transmitter or the receiver down to a small enough size to make it suitable for its implementation in a miniaturized system. Secondly, the range of energy transfer has not yet been demonstrated to exceed a few meters, which poses a major challenge for its practical implementation. Ongoing research is focused on finding more compact solution for wireless energy transfer covering a greater range. Another problem with wireless energy transmission is that its typical efficiency varies between 45% and 80% falling short of a conventional battery or wire based technology. Future innovations resulting in the reduction in size as well as increase in efficiency and operating range will undoubtedly make wireless energy transfer suitable for plenty of new potential sensor applications.
While designing wireless power transfer system for biomedical applications, the associated health risks have to be taken into consideration. Since RF energy can quickly heat up the biological tissues due to the thermal effect, the exposure to very high levels of RF radiation can be harmful. Since attenuation increases with frequency, most of the existing work in Wireless Body Area Networks (WBAN) considers only the Medical Implant Communication System (MICS) band (402-405 MHz) or sub-gigahertz bands. Federal Communications Commission (FCC) regulates the time and the amount of exposure of the electromagnetic radiation to human tissues at various frequencies [52]. American National Standard Institute (ANSI) standard C95.1-1982 sets the electromagnetic field strength limits for frequencies between 300 kHz and 100 GHz [53], [54]. For frequencies below 300 MHz, the electric and the magnetic fields have to be accounted for separately. The ANSI standard C95.1-1991 sets the electric and the magnetic field strength limits for the general public for the frequency range of 3 kHz-300 GHz [55]. Table 3 illustrates the IEEE standard C95.1-1991.
\n\t\t\t\tFrequency Range (MHz)\n\t\t\t | \n\t\t\t\n\t\t\t\tElectric Field Strength, E (V/m)\n\t\t\t | \n\t\t\t\n\t\t\t\tMagnetic Field Strength, H (A/m)\n\t\t\t | \n\t\t\t\n\t\t\t\tPower Density, S (mW/cm2)\n\t\t\t | \n\t\t\tAveraging Time |E|2\n\t\t\t\t, |H|2 (minutes) | \n\t\t|
\n\t\t\t\tE-field\n\t\t\t | \n\t\t\t\n\t\t\t\tH-field\n\t\t\t | \n\t\t||||
\n\t\t\t\t0.003-0.1\n\t\t\t | \n\t\t\t614 | \n\t\t\t163 | \n\t\t\t100 | \n\t\t\t1E6 | \n\t\t\t6 | \n\t\t
\n\t\t\t\t0.1-3.0\n\t\t\t | \n\t\t\t614 | \n\t\t\t16.3/f | \n\t\t\t100 | \n\t\t\t10000/f2\n\t\t\t | \n\t\t\t6 | \n\t\t
\n\t\t\t\t3-30\n\t\t\t | \n\t\t\t1842/f | \n\t\t\t16.3/f | \n\t\t\t900/f2\n\t\t\t | \n\t\t\t10000/f2\n\t\t\t | \n\t\t\t6 | \n\t\t
\n\t\t\t\t30-100\n\t\t\t | \n\t\t\t61.4 | \n\t\t\t16.3/f | \n\t\t\t1 | \n\t\t\t10000/f2\n\t\t\t | \n\t\t\t6 | \n\t\t
\n\t\t\t\t100-300\n\t\t\t | \n\t\t\t61.4 | \n\t\t\t0.163 | \n\t\t\t1 | \n\t\t\t6 | \n\t\t|
\n\t\t\t\t300-3K\n\t\t\t | \n\t\t\t-- | \n\t\t\t-- | \n\t\t\tf/300 | \n\t\t\t6 | \n\t\t|
\n\t\t\t\t3K-15K\n\t\t\t | \n\t\t\t-- | \n\t\t\t-- | \n\t\t\t10 | \n\t\t\t6 | \n\t\t|
\n\t\t\t\t15K-300K\n\t\t\t | \n\t\t\t-- | \n\t\t\t-- | \n\t\t\t10 | \n\t\t\t616000/f1.2\n\t\t\t | \n\t\t
IEEE Standard C95.1-1991: Limit of Maximum Permissible Exposure at Controlled Environment on Human Body [55].
An important parameter that is used to measure the effect of radio frequency exposure on human is SAR (specific absorption rate). SAR is a quantity that is used to measure the amount of energy absorbed by a body which is exposed to radio frequency (RF) electromagnetic field. It is defined as the power absorbed per mass of the tissue with units of watts per kilogram (W/kg) or milliwatts per gram (mW/g) and can be expressed as,
Here σ is the electrical conductivity of the sample, E is the RMS electric field and
Since there is direct contact between the implanted device and biological tissue, a compatibility assessment of the sensors needs to be performed prior to being deployed inside the human body. This biocompatibility assessment is defined in [60] as, ‘‘the ability of a material to perform with an appropriate host response in a specific application’’. Some of the major characteristics of the bulk and surface materials which can possibly influence host response and some of the important characteristics of host responses are listed in [61]. The biocompatibility of an implantable sensor depends on parameters such as the part of the human body where the implant is deployed and the surface material of the sensor itself. Also the shape and size of the sensor also have to be optimum to make the sensor compatible with human body. Surface chemistry and composition of the outer material also need to be kept in mind so that it does not react with the tissue and blood that come in contact with the implant. Finally, sterility issues, contact duration and degradation of the material that surrounds the sensor need to be taken into account while designing a biocompatible implantable sensor [62–63]. Several protocols related to the biocompatibility issues that are scrutinized thoroughly before an implantable device could be used in the human body have been developed by the U.S. Food and Drug Administration (FDA). Materials appropriate for long-term reliable implantable devices according to [61] include a) titanium alloys for dental implants, femoral stems, pacemaker cans, heart valves, fracture plates, spinal cages, b) cobalt-chromium alloys for bearing surfaces, heart valves, stents, pacemaker leads, c) platinum group alloys for electrodes, d) nitinol for shape memory applications, e) stainless steel for stents and orthopedic implants, f) alumina for bearing surfaces, g) calcium phosphates for bioactive surfaces, h) polyurethane for pacemaker lead insulation, i) PMMA for bone cement, intraocular lenses, j) silicone for soft tissue augmentation, insulating leads, ophthalmological devices. On May 28, 2014 FDA approved the first implantable wireless device with wireless monitoring feature to measure pulmonary artery pressure for heart patients [64]. With the ongoing research on finding biocompatible materials it can be easily inferred that there will be numerous implantable devices in the global market in near future.
In summary, the chapter includes the discussion on various implantable sensors that are currently being used in biomedical applications. Various low-power low-voltage signal processing schemes to convert the signal from the sensors into usable data signal have been discussed as well. This is followed by an analysis of current state-of-the-art research on wireless telemetry for implantable sensors. Different power management schemes have been explored at the later part of the chapter. Finally, the chapter concludes with a brief discussion on biocompatible issues related to implantable sensors.
Escherichia coli strains compose, physiologically part of the microflora of the gastrointestinal tract [1, 2, 3, 4]. Belonging to the Enterobacteriaceae family, fermentative, non-sporulated and facultative anaerobic commensals, they are mainly from the large intestine [5, 6].
Despite being commensal microorganisms, they are the Gram-negatives which are most often a cause of human infections, having pathogenic strains that cause a wide variety of intestinal or extra-intestinal infections, such as urinary tract, intra-abdominal and soft tissue, sepsis, neonatal meningitis, gastrointestinal infection, and pneumonia, often leading to bacteremia [3, 7]. Although Gram-positive microorganisms have been increasing as a cause of sepsis due to the instrumentation of medical care—understood as the use of invasive devices or tools for the treatment or diagnosis of patients, and to infections associated with health care—E. coli continues to be an important and perhaps the most frequent cause of threatening infections in our environment [8, 9].
They are classified as Gram-negative bacteria and divided into 3 main groups: commensal lines, intestinal pathogenic lines (enteric or diarrhea) and extra-intestinal pathogenic lines [10].
Furthermore, Gram-negative bacteria produce large molecules consisting of a lipid and a polysaccharide, known as lipopolysaccharides (LPS), lipoglycans and endotoxin, which increases their pathogenicity in relation to Gram-positive bacteria [11].
E. coli is one of the most commonly isolated bacteria in the bloodstream (responsible for approximately 20% of all clinically significant isolates) and is the Gram-negative organism most frequently isolated in adult patients with bacteremia [12]. In the United States of America, E. coli sepsis was associated with approximately 40,000 deaths in 2001, a number that corresponds to 17% of all cases of sepsis [13].
Studies have shown an increasing incidence of E. coli early-onset sepsis in all age groups, overruling group B Streptoccocus for the last 10 years. Beyond that, E. coli resistant strains also increased equally in all age groups, with high resistance rates to first line antibiotics available (ampicillin and gentamicin).
Very low birth weight newborns remained the group with higher incidence (10.4 cases per 1000 live births) and mortality (35.3%). Systematic use of PCR increased E. coli early-onset sepsis diagnosis, mainly in the term newborn group. There was also an increase in resistant E. coli strains causing early-onset sepsis, with especially high resistance to ampicillin and gentamicin (92.8 and 28.6%, respectively) [14].
Several hospital-based studies have suggested that a number of comorbid illnesses, including diabetes, malignancy, chronic lung disease, cirrhosis and heart disease, may increase the risk of E. coli bacteremia. Previous researches have also identified age (very young and very elder), hospital acquisition, comorbid illnesses, presence of shock, non-urinary focus, and antimicrobial resistance in conjunction with inadequate treatment as being associated with higher rates of death [15, 16, 17].
Dialysis, solid organ transplantation and neoplastic disease were important risk factors for acquiring E. coli bacteraemia. Ciprofloxacin resistance and non-urinary focus were independently associated with an increased risk of death [18]. For males, urinary catheterization and incontinence were associated as risk factors to Escherichia coli bloodstream, and for females, cancer, renal failure, heart disease and urinary incontinence were risk factors reported [19]. Several risk factors which have significantly mortality due to E. coli bacteremia are age, severe sepsis or shock, non-urinary origin, Charlson index, inadequate empirical treatment (Table 1).
Mortality risk factor | P | OR (95% CI) |
---|---|---|
Age | 0.03 | 1.04 (1–1.08) |
Severe sepsis or shock | <0.0001 | 14.64 (6.14–30.86) |
Non-urinary origin | 0.013 | 2.78 (1.24–6.2) |
Charlson index | 0.006 | 1.31 (1.08–1.59) |
Inadequate empirical treatment | 0.006 | 2.98 (1.25–7.11) |
Results of multivariate analyses examining risk factors for mortality associated with bacteraemia due to E. coli [15].
The human gastrointestinal tract is normally inhabited by Escherichia coli, which is why they are the bacterial species most commonly found in the isolation of fecal culture [20, 21]. By the time the strains acquire additional genetic material, they can become pathogenic and circulate widely throughout the body. Pathological clones are divided into two major groups: intestinal (among the most virulent enteric pathogens) and extraintestinal (less present, but not less dangerous) [22, 23].
Typical enteropathogenic Escherichia coli (tEPEC) contains a virulence plasmid (pEAF) that encodes the bundle-forming pilus (BFP), the primary factor for colonization [24, 25]. In addition, EPEC carries the crossomic island of locus for enterocyte effacement, which features the eae gene, which is the encoder of a colonization factor in the outer membrane protein called intimin [26, 27]. Only the E. coli strain that has pEAF and the eae gene can be considered tEPEC, one that has only the eae gene and is called atypical EPEC (aETEC) [28].
The small intestine is the most likely place for EPEC infection to occur. For the onset of diseases, tEPEC obeys the following steps:
Initial localized adhesion of organisms to enterocyte via BFP.
Induction of signal transduction in the enterocyte by secretion of protein toxins.
Development of intimin-mediated intimate adhesion to the enterocyte.
Around 20 protein toxins are injected directly into the target epithelial cell, made, together with the intimin, by the chromosomal island LEE and expressed by both tEPEC and aEPEC [29]. The complex nanomachine called type III secretion injector is the one that injects protein toxins. It is assumed that some modifications happen to the epithelial stem cells, which is physiologically absorbent, and through a pathological process, it becomes a secretory dynamo [30].
What is believed is that type III ejection toxins are responsible for binding to protein elements of the cell’s signal transduction apparatus. This event is accompanied by the mobilization of calcium from the intracellular compartment, activation of protein kinase C, kinase light chain myosin and induction of protein phosphorylation by tyrosine. The rearrangement of cytoskeletal proteins is induced by effectors, which results in the classic lesion "attaching and erasing," changes in the secretion of water and electrolytes and increased permeability of the tight intestinal junctions [31].
Enterotoxigenic Escherichia coli (ETEC) consists of ingestion of bacteria, intestinal colonization and production of virulence factors. Colonizing fimbriae (CFs) must be expressed by ETEC to allow the consolidation of the bacteria in the intestine [32].
After colonization, ETEC produces two classes of secretory toxins encoded by plasmids: heat-labile toxin (LT) and heat-stable toxin (ST). To be classified as ETEC, E. coli must contain one or both classes of toxins [33, 34].
LT toxin is related to Vibrio cholera toxins in terms of structure, function and mechanism. It works by stimulating adenylate cyclase and increasing adenosine intracellular cyclic monophosphate (AMP), a fact that stimulates chloride secretion from intestinal crypt cells and inhibits the absorption of sodium chloride at the ends of the villi. After that, the water secretion is free in the intestinal lumen, clinically developing watery diarrhea [35].
STa toxin, the only ST variant that causes disease in humans, activates cyclic GMP of enterocytes, leading to increased chloride secretion and decreased sodium chloride absorption. As a final result, the secretion of free water in the intestinal lumen clinically appears as watery diarrhea [36].
Among the pathotypes that cause the most severe conditions, the strains classified as enterohemorrhagic (EHEC) stand out, which are the most common to cause disease in developed countries [29].
They are bacteria responsible for food infections and represent a risk to the health of the population, so they must be monitored frequently. Thus, good hygiene practices, as well as the use of quality tools, are extremely important to help reduce the risk of cross-contamination and human infection.
EHEC has the ability to attach itself to the host and to produce shiga-toxins, which gives the strain pathogenicity. The toxins produced by EHEC cause damage to the mucosa of the large intestine, where they are absorbed by reaching the bloodstream, which makes it possible to affect other organs, such as the kidneys [37]. An average of 5–10% of patients confirmed with EHEC infection develop potentially fatal complications, such as hemolytic uremic syndrome (HUS), which leads to sudden renal failure and hemolytic anemia [38].
Outbreaks are related to the ingestion of contaminated food and water, causing watery diarrhea and hemorrhagic colitis to those infected. The disease has a sudden onset with severe abdominal cramps and watery diarrhea that progresses to bloody, on average after 24 hours, lasting between 1 to 8 days.
The treatment consists of supportive therapy for fluid replacement, since the use of antibiotics is not indicated, as there is no proven efficacy. In fact, it could increase the risk of developing HUS, since the death of the bacteria would increase the release of toxins, predisposing to the syndrome [39].
Enteroinvasive E. coli (EIEC) is very close to Shigella and develops a colitis similar to shigellosis. The intestinal cell is invaded by the EIEC which multiplies intracellularly and reaches the adjacent intestinal cells [40].
To differentiate Shigella from EIEC it is necessary to analyze the strains, those from EIEC ferment glucose and xylose, this differentiates them. Nucleic acid tests, including multiplexed panels, are used to detect organisms [41].
Diffusely adherent E. coli is associated with diarrhea, which is characterized as watery and can become persistent in children between 1 and 5 years of age, occurring more frequently in developing and developed countries. In addition, this bacterium is also related to urinary tract infections and complications during the pregnancy period.
The pattern of diffuse adhesion in HEp-2 or HeLa cells is a characteristic that differentiates this pathotype from the others, although DAEC strains are quite heterogeneous. This adhesion is mediated by fimbrial and afimbrial adhesins, which can cause damage to microvilli due to the disorganization of the cytoskeleton. However, some strains produce an adhesin involved in diffuse adhesion (AIDA-I), instead of encoding the diffuse adhesion pattern, which is why they are called atypical DAEC [42].
In addition, DAEC can also provide a pro-inflammatory effect [43].
The type of E. coli responsible for the invasion, colonization and induction of diseases in body sites outside the gastrointestinal tract is the extraintestinal pathogenic Escherichia coli (ExPEC). It is noteworthy that diseases caused by ExPEC range from urinary tract infections, neonatal meningitis, sepsis, pneumonia, surgical site infections to infections in other extraintestinal sites, representing a burden in terms of medical costs and lost productivity [44].
Thereto, the ExPEC strains were isolated from food products, in particular raw meat and poultry, indicating that these organisms potentially represent a new class of foodborne pathogens [45].
Almost 25% of sepsis cases originate from the urogenital tract. [46, 47, 48]. Considering this percentage, the most common pathogen that causes urinary tract infection (and, consequently, urosepsis) is Escherichia coli (50%) [49]. It is known that this condition is better managed with an interprofessional team of health professionals—a nephrologist, infectious disease expert, urologist, intensivist, a nurse and a pharmacist [50, 51]. The outcomes after urosepsis depend on the cause and severity of the infection, and if the patient has a complicating factor in the urinary tract that is identified and warrants treatment, it should be performed as soon as possible. As an example, the literature reveals Foley catheter placement to relieve urinary retention or stent placement to bypass an obstructing ureteral calculus causing urosepsis. Moreover, the prognosis also depends on the type of bacteria, antimicrobial resistance, and patient comorbidity.
In addition to early antibiotics, there are some important parts of the management of sepsis. Initial fluid resuscitation with crystalloid is still recommended at a minimum of 30 mL/kg. Consider early administration of vasopressor support to maintain a mean arterial pressure greater than 65 mm Hg. The first choice for vasopressor support in sepsis is norepinephrine (with epinephrine and vasopressin 2 and 3). Tight glucose control is also recommended, with corticosteroids and blood products being more controversial in the literature [52].
Although Escherichia coli is one of the most-studied microorganisms worldwide, its characteristics are constantly changing. Elseways, one important global problem is the increase of antimicrobial resistance shown by bacteria, being considered as “threatens the achievements of modern medicine” [53, 54].
E. coli resistant strains increased equally in all age groups, with high resistance rates to our first line antibiotics (ampicillin and gentamicin), with relevant highlight in neonatal E. coli isolates from invasive infection [55]. Table 2 shows the temporal trends for antibiotic resistance to E. coli.
Agent or phenotype [n (%)] | 1997 n = 58 | 1998 n = 49 | 1999 n = 52 | 2000 n = 83 | 2001 n = 86 | 2002 n = 70 | 2003 n = 87 | 2004 n = 122 | 2005 (January–June) n = 56 | Total n = 663 | P |
---|---|---|---|---|---|---|---|---|---|---|---|
Ampicillin | 27 (46.6) | 24 (49) | 24 (46.2) | 50 (60.2) | 54 (62.8) | 46 (65.7) | 55 (63.2) | 70 (57.9) | 35 (62.5) | 385 (58.2) | 0.02 |
Trimethoprim/sulfamethoxazole | 14 (24.1) | 11 (22.4) | 13 (25.0) | 28 (33.7) | 21 (24.4) | 28 (40) | 32 (36.8) | 41 (33.6) | 20 (35.7) | 208 (31.4) | 0.02 |
Ciprofloxacin | 9 (15.5) | 7 (14.3) | 10 (19.2) | 7 (8.4) | 14 (16.3) | 16 (22.9) | 22 (25.3) | 27 (22.1) | 13 (23.2) | 125 (18.9) | 0.02 |
Amoxicillin/clavulanate | 9 (15.5) | 4 (8.2) | 9 (17.3) | 16 (19.3) | 8 (9.3) | 7 (10) | 11 (12.6) | 15 (12.3) | 20 (35.7) | 99 (14.9) | 0.1 |
Gentamicin | 4 (6.9) | 6 (12.2) | 5 (9.6) | 5 (6.0) | 8 (9.3) | 6 (8.6) | 7 (8.0) | 8 (6.6) | 8 (14.3) | 57 (8.6) | 0.8 |
Piperacillin/tazobactam | 1 (1.7) | 4 (8.2) | 1 (1.9) | 8 (9.6) | 6 (7.0) | 4 (5.7) | 5 (5.7) | 2 (1.6) | 2 (3.6) | 33 (5) | 0.4 |
Cefotaxime | 11 | 2 (4.1) | 0 | 2 (2.4) | 3 (3.5) | 5 (7.1) | 3 (3.4) | 12 (9.8) | 4 (7.1) | 31 (4.7) | 0.001 |
ESBL production | 0 | 0 | 0 | 2 (2.4) | 3 (3.5) | 3 (4.3) | 2 (2.3) | 9 (7.4) | 3 (5.4) | 22 (3.3) | 0.002 |
MDR | 4 (6.9) | 4 (8.2) | 5 (9.6) | 9 (10.8) | 9 (10.5) | 12 (17.1) | 15 (17.2) | 17 (13.9) | 12 (21.4) | 87 (13.1) | 0.006 |
Number, yearly percentages, and P values for temporal trend of non-susceptible cases of E. coli bacteraemia.
The sepsis’ diagnosis confirmation is done from the evaluation of the clinical status of the patient, analyzing some criteria. For adult patients, it is confirmed or a diagnosis of sepsis is made when two criteria are present: hyperthermia>38.3 °C or hypothermia <36°C, tachycardia>90 bpm, leukocytosis (>12,000 μL-1) or leukopenia (<4000 μL-1) or >10% bands, acutely altered mental status, tachypnea > 20 bpm, hyperglycemia (>120 mg/dl) in the absence of diabetes [56].
Collect a careful history from patient, addressing information such as previous illnesses, surgeries, how long ago the symptoms started, if there are comorbidities, if it have traveled to a place recently and other details, added to a complete physical examination, which provides very relevant information and leads to a line of rationality, it is extremely important to start the development of a preliminary differential diagnosis of the patient’s complaints.
All this information collected is recorded and saved in medical records, more recently, electronics, which are more organized, more readable and allows a better comparison, in relation to written records [57].
Some of the most frequent reasons that lead patients to go to a medical consultation are dyspnea, cough with or without hemoptysis and chest pain, as these symptoms can be indications of serious illnesses, it shows the importance of asking questions and exams in a way attentive and careful [58].
Ventilator-associated pneumonia (VAP) is the most common fatal hospital infection [59]. One of the bacteria most involved in the clinical picture in question is Enterobacteriaceae Escherichia coli [60, 61] and there is little awareness when it comes to the pathophysiology of E. coli pneumonia.
Studies show that these E. coli pathogenic islands (PAIs) are involved differently in the pathogenicity of the lung compared to those present in urinary tract and bloodstream infections [62]. In addition, research on mice has also shown that these isolated strains are highly virulent extra-intestinal pathogens that express virulence factors, representing potential targets for new therapy. A French national study also demonstrated that, despite the genomic and phylogenetic characteristics of E. coli pneumonia isolates from critically ill patients, they belong to the same extra-intestinal pathogen as E. coli, they have specific distinct characteristics when lungs [63].
E. coli meningitis is rare in adult forms of the disease [64, 65, 66], but it is a frequent pathogen in the pediatric field [67]. Despite its rarity, it has a serious clinical course [64, 65, 66]. It is usually diagnosed based on clinical signs and cerebrospinal fluid (CSF) analysis.
Due to the severity of the disease, early diagnosis, adequate antibiotic treatment and hemodynamic control are essential [68].
E. coli meningitis follows a high degree of bacteraemia and invasion of the blood–brain barrier. With mortality rates ranging from 15 to 40%, Meningitis due to this bacterium leaves approximately 50% of survivors with some type of neurological sequelae [69, 70, 71, 72, 73, 74, 75, 76, 77, 78].
Although the process is unknown, it is known that, for the onset of the disease, it is necessary to have an invasion of the blood–brain barrier by E. coli, which requires specific microbial and host factors such as specific signaling molecules for microbes and hosts. Thus, blocking these microbial and host factors that contribute to the invasion of the blood–brain barrier by E. coli is effective in preventing the penetration of E. coli into the brain.
With the complete discovery of this mechanism, it is likely that new targets for the prevention and therapy of Escherichia coli meningitis will be achieved [79].
Regarding treatment, it is currently known only that antimicrobial chemotherapy has limited efficacy [79, 80, 81].
Intra-abdominal infections (IAI) are invasive and bacterial multiplications in the hollow organ walls and beyond. Usually, it is located in the abdominal cavity, in the retroperitoneum and in the abdominal organs, being a common complication in the post-surgical period [82]. In addition, they have a wide variety of pathological conditions, from appendicitis to fecal peritonitis, which makes IAI generally have a poor prognosis (especially in high-risk patients) and is an important cause of morbidity [83]. Mostly, the most common source of this infection is the appendix, followed by gastroduodenal perforations. The Gram-negative bacteria E. coli is the most common causative agent of IAI. Therefore, it is important to know that they have great sensitivity to imipenem, meropenem, mainly, and to amoxi-clavulanate, amikacin and piperacillin-tazobactam, next [84, 85]. However, amici-clavulanate is prescribed as a first-line drug in developing countries, due to cost factors [86].
Although E. coli strains have been isolated as part of the normal beneficial flora of the intestine, some strains have developed pathogenic mechanisms to cause disease in humans and animals. One of these strains capable of causing diseases is enteric Escherichia coli (E. coli), comprising important pathogens, since they cause significant morbidity and mortality worldwide. Traditionally enteric E. coli was divided into 6 pathotypes, however two other divisions were proposed by several studies (as mentioned individually in topic 4) [87].
Although there are many etiological agents responsible for diarrhea, pathogenic E. coli is a major contributor. On the other hand, the onset and complications of enteric E. coli vary significantly, despite there are many common features in the pathogenic process of colonizing the intestinal mucosa and the onset of disease [88].
Outbreaks are common all over the world, with fatal consequences mainly in children under 5 years of age living in underdeveloped countries, where diarrheal diseases can lead to death more frequently [89].
The transmission of enteric E. coli is also a public health concern, related to the development of countries, since its transmission is through contaminated water and food. Thus, the seriousness in relation to the microorganism can be exemplified by national and international surveillance programs, created by developed countries that aim to constantly monitor outbreaks [90]. In developing countries ETEC, EPEC and EAEC are considered to be the main causes of childhood diarrhea, and when left untreated, they have potentially fatal consequences. However. in developed countries, these infections are mild and self-limiting, with EHEC and, more recently, EAEC and STEAEC being the main E. coli pathotypes associated with food poisoning outbreaks [91, 92].
Among the most common types of bacterial infections that occur both in the community and in hospitals, urinary tract infections (UTI) stand out. Urinary tract infections can be associated with the hospital (HAUTIs) and the community (CAUTIs). In the case of CAUTIs, it is known whether women are the predominant group of patients.
Although the UTI is multifactorial, the main bacteria related to the diagnosis is E. coli, predominant in both community and nosocomial UTIs [93].
Co-trimoxazole (trimethoprim/sulfamethoxazole), nitrofurantoin, ciprofloxacin and ampicillin are the antibiotics commonly recommended for the treatment of UTIs. However, there is an overall increase in antibiotic resistance among pathogens in the urinary tract, which is a limitation on treatment options [94, 95].
Since the evidence suggests a significant relationship between the extensive use of antibiotics and antimicrobial resistance, it is necessary to prescribe and use antibiotics in order to reduce their complications and costs [96].
For this reason, in order to guide the selection of empirical therapy, surveillance of antibiotic resistance is crucial for determining the pattern of antimicrobial resistance [97].
It aims to check the presence of fungi and bacteria in the urine, being carried out from a urine sample, which was placed in Petri dishes. The urine culture is placed in an incubator (1–2 days) and if there is any microorganism in the tested material, colonies grow and are visible on the plate. When the result is positive for some bacteria, a test antibiogram is performed, which determines the type of antibiotic needed to act against the pathogen [98].
The culture of urine is important precisely because it allows the precise recognition of the bacteria and, consequently, the best antibiotic to be used [99].
As urine culture is most frequently requested when UTI is suspected, the most common bacteria found are Escherichia coli (between 47.5% and 56.4% of all urine culture) [100, 101].
Blood culture is part of the routine assessment of patients with suspected bloodstream infection, and is crucial to guide therapeutic intervention. The ideal method for collecting blood culture is venepuncture, since it increases diagnostic yield, and has lower rates of contamination, according to some studies [102].
Since the timing of blood culture collection does not influence the detection of clinically relevant microorganisms, most authorities recommend collecting several sets simultaneously or for a short period of time, with the exception of patients with endovascular infection who need documented continuous bacteremia [103, 104].
Two to four sets of blood samples should be collected, whenever possible, at independent locations [103, 104, 105, 106]. For adults, the volume required for the examination varies between 40 and 160 mL of blood, and for babies and children, the volume is age-based and does not exceed 1% of the patient’s total blood volume [103, 107].
The importance of blood culture, as well as urine, is related to the determination of the bacteria and the antibiogram, which directs the treatment to the best antibiotic to be used [108].
In some cases, it is possible to suspect a complicated urinary tract infection/urosepsis without being serious urological abnormalities. In such cases, there are some screening options that can be performed to assist in the management of the patient. Thus, simple abdominal radiography, intravenous urography, ultrasound, computed tomography and magnetic resonance imaging are cited [109].
The anatomical identification of most areas of infection has become common with the development of high resolution cross-sectional images, which allow visualization of bacterial and viral metabolism, early diagnosis and treatment. Thus, the cross-sectional image was included as part of the routine investigation of unidentified infection sites and sources of sepsis. The trend is that the use of these images will become increasingly widespread and become part of standard clinical care in the near future [110].
When abdominal sepsis is suspected, ultrasound is a valuable tool. As it is a portable scanning technique, it is ideal for clinically unstable patients who cannot be transported to an examination room [110].
Ideal for the diagnosis of liver sepsis and gallbladder, ultrasound identifies and indicates the presence and location of intra-abdominal fluids (subphrenic space, in pericological calculations or pelvis) [110, 111, 112, 113]. Intrahepatic fluids are also well visualized, and can even be drained percutaneously with ultrasound guidance [110].
The main obstacle for ultrasound responses is air interference, highlighted in loop regions of the intestine with intraluminal gas, since the USG image is darkened and makes it difficult to visualize interloop abscesses or peri-pancreatic collections. The intestine in patients with disease due to sepsis or recent intra-abdominal surgery is also capable of compromising the quality of the ultrasound [114].
The availability of CT scanners with multiple detectors allows rapid acquisition of images, making this method the most common in the diagnosis and detection of intra-abdominal abscesses [114, 115]. It is an interesting option especially for sick patients who have difficulty holding their breath, obese or with abdominal or chest bandages.
In addition, CT is essential in the diagnosis of interloop and retroperitoneal pathologies (including retroperitoneal abscesses or pancreatitis or intra-biliary stones), in addition to being highly sensitive in the detection of chest pathologies (pneumonia, pleural effusion and localized collections) [113, 115, 116, 117]. For intra-abdominal fluids and abscesses, CT showed a sensitivity of 90–100%, while ultrasound showed sensitivity between 80% and 85% [115, 118, 119].
Due to the contemporary contrast protocols available, it is possible to identify by CT even small infected collections [110].
With the development of hybrid cameras, the combination of PET and magnetic resonance imaging was introduced, which despite having interesting advantages and clinical applications, is still such an expensive tool.
The simultaneous acquisition of PET and magnetic resonance imaging can provide quantitative molecular functional information about the inflammatory lesion and precise location, in addition to anatomical changes with movement correction, improving the differential diagnosis and guiding anti-inflammatory treatment strategies.
Since MRI cannot visualize all parts of the body at once, the new hybrid technique may require collaboration between radiologists and nuclear medicine doctors to interpret the image and can be more expensive than PET/CT (capital and operational costs).
The functional image of inflammation and infection was mainly restricted to the flat image and SPECT, however, with the increasing development of PET radiopharmaceuticals, the detection and quantification of specific aspects of inflammatory processes became more sensitive. Precisely for this reason, there is an interesting potential in the application of hybrid whole body PET/MRI in the context of the investigation of infectious and inflammatory diseases [120].
Imaging technique that uses biological radionuclides to track hidden infections and improve the specificity of the infection diagnosis that allows the detection of early pathophysiological changes even when there are no apparent anatomical changes. When compared to ex vivo techniques (blood culture), in vivo biological screening is preferred since it is accurate, does not require a sterile environment and does not expose the health team to the risk of contamination by blood-borne pathogens.
This type of tool is used mainly in patients suspected of infection or abscess, but who have had negative results for the cross-sectional image. Thus, the use of marked leukocyte traffic allows a response to hidden sites, based on the recognition of white blood cells marked with radionuclides. The marked leukocytes travel to the infection sites and allow noninvasive images in areas of hidden infection, such as osteomyelitis, orthopedic prosthesis, endocarditis or inflammation and intestinal disease [110].
Adequate organ perfusion must be ensured. Hypotension should be managed initially with intravenous fluid administration and the goal should be maintenance of pulmonary capillary wedge pressure at 12–16 mm Hg or central venous pressure at 8–12 cm H2O. Urine output rate should be kept at greater than 0.5 mL/kg/hr. A mean arterial blood pressure of greater than 65 mmHg (systolic blood pressure greater than 90 mmHg) and a cardiac index of greater than or equal to 4 L/min/m2 should be maintained. Vasopressor therapy should be initiated in the event of failure to achieve these goals with iv fluids alone. These include dopamine, dobutamine and norepinephrine [109].
Ventilatory support should be provided for patients with progressive hypoxemia, hypercapnia, altered sensorium or respiratory muscle fatigue. A study of “early goal directed therapy” (EGDT) found that prompt resuscitation to maintain SvO2 > 70% was associated with improved survival in patients of severe sepsis [121]. In this study, failure to maintain saturation after fluids and vasopressors was followed by erythrocyte infusion to raise hematocrit to 30%. Patients requiring mechanical ventilation should be adequately sedated and stress ulcer prophylaxis should be administered.
Blood glucose levels should be maintained at less than 150 mg/dL during initial few days of severe sepsis and normoglycemic range could be targeted later. Frequent blood glucose monitoring should be done to avoid hypoglycemia in patients on intensive insulin therapy. Multi-organ dysfunction, if any should be managed. Disseminated intravascular coagulation, if accompanied by major bleeding, should be treated with fresh-frozen plasma and platelet transfusion. Hypercatabolic individuals with acute renal failure benefit substantially from hemodialysis or hemofiltration. Prophylaxis for deep vein thrombosis and nutritional supplementation should be undertaken [109].
Considering the limited knowledge about the combination of antibiotics, the susceptibility of these pathogens to drugs and the lack of evidence to support the routine use of combined antimicrobial therapy, the decision regarding the ideal therapy is the responsibility of medical professionals [122]. Regarding the most appropriate approach, it is prioritized in the literature that the optimization of antimicrobial therapy includes adaptation of the appropriate antibiotics in terms of class, dose, frequency, route and duration [123].
The combination of different antibiotics has been widely used by large centers when it comes to invasive infections by multi-resistant Gram-negative bacteria [122].
The various positive and negative aspects of combination therapy are depicted in Table 3.
Positive aspects of combination therapy for treatment | Negative aspects of combination therapy for treatment |
---|---|
1. Greater probability of choosing an effective agent and well-founded theoretical reasons to support its use 2. Considering the increase in mortality related to the delay in the establishment of treatment and delays in appropriate and effective antimicrobial treatment, it is prudent to initiate empirical broad-spectrum antimicrobial treatment in the first suspected infection in critically ill patients 3. Indicated for patients with compromised immune systems, previous ICU admissions or who have recently received broad-spectrum antibiotics [124] | 1. Increased toxicity in treatment by combining antibiotics (nephrotoxicity and ototoxicity). In such cases, it is suggested to discontinue the old therapy and introduce a new one, based on the clinical evolution of the patient and the results of the culture and susceptibility profile 2. This type of therapy has not been shown to be effective by clinical data (meta-analyses performed with the evaluation of randomized clinical trials demonstrate that there was no difference in clinical results between the two strategies for definitive treatment of Gram-negative bacteria infections) [124] |
Comparison of positive and negative aspects of combination therapy.
Antibiotics such as colistin are the last resort to deal with infections by carbapenem-resistant Enterobacteriaceae (CREB), and when the pathogen does not respond to colistin, therapeutic options are severely restricted. Thus, it becomes necessary to restore the sensitivity of the pathogen to the drug [125].
The combination of colistin + salicylate + potent efflux pump inhibitor (BC1) has been documented with highly positive results, providing a connection between colistin and the efflux pump inhibitor (BC1), which prevents extrusion of colistin [126].
The reduction in affinity between the drug and Gram-negative bacteria is due to the modification of lipid A, linked to the appearance of the gene that confers resistance to bacteria, which is present in animals that receive colistin and are part of human food. Despite this, there is still no complete explanation of the mutation and resistance of Gram-negative bacteria (especially Enterobacteriaceae) in patients who received administered colistin [127].
Due to the increased resistance of bacteria to cephalosporin (and aminopenicillins), the use of narrow-spectrum β-lactamases, especially carbapenems, has increased considerably, being the only β-lactamase antibiotics with proven effectiveness in serious infections due to ESBL-producing bacteria [128, 129, 130].
With the discovery of E. coli isolates capable of producing new b-lactamases, a new strain of E. coli was found capable of resisting the action of carbapenems, mediated by plasmids.
These enzymes are able to confer resistance to drugs of the class b-lactamases, and in relation to E. coli specifically, the main types of enzymes are CMY, CTX-M and NDM of b-lactamase [131].
Tigecycline is a new expanded-spectrum antimicrobial agent in the glycylcycline class. Developed with the objective of overcoming the most common processes of bacterial resistance, the drug has emerged as a great therapeutic option in the treatment of serious infections, which endanger the patient’s life, and which no longer respond to traditional antibiotics. The use of tigecycline is mainly interesting for the initial therapy of major infections, and is largely effective in the action against multi-resistant Gram-negative bacteria [132].
Aminoglycosides are natural or semi-synthetic drugs obtained from actinomycetes, used as an antibiotic since the beginning of bacterial treatment. As it was replaced in the 1980s by cephalosporins, carbapenems and fluoroquinolones, aminoglycosides had little use.
With the increase in the number of cases of multidrug-resistant bacteria, aminoglycosides were again considered for their ability to synergize with a variety of other classes of antibacterials, improving the safety and effectiveness of the class through optimized dosing regimens, being broad-spectrum and quickly bactericidal.
Enzymatic modification by acetylation of an amino group, impaired uptake and phosphorylation of aminoglycosides are the most commonly reported processes that confer resistance to bacteria in relation to aminoglycosides [133].
Fosfomycin is an antibiotic from the 1969s, prescribed mainly in its oral form for the treatment of uncomplicated urinary tract infections (UTI), and considered as an option in the treatment of bacteria with advanced resistance, causing serious infections [134].
For E. coli NDM-producing strains, fosfomycin, colistin and tigecycline are more effective than other antibiotics [135].
The best pharmacological approach to E. coli infections resistant to carbapenems is still an obstacle to be overcome, since patients infected with this type of bacteria have more limited clinical results and when compared to patients infected with bacteria susceptible to drugs [136].
The duration of treatment for infection caused by Escherichia coli varies in the literature, but most patients require treatment for about 14–21 days [109]. For E. coli perinephric abscesses or prostatitis, it is recommended that the minimum antibiotic use time should be 6 weeks, intra-abdominal infections 14–21 days, and pneumonia 14 days (Table 4) [137].
Condition | General | Perinephric abscesses | Prostatitis | Intra-abdominal infections | Pneumonia |
---|---|---|---|---|---|
Duration | 14–21 days | 42 days | 42 days | 14–21 days | 14 days |
Recommended duration of antibiotic therapy depending upon the type of infection.
In general, infectious diseases occur more frequently and cause greater concern when dealing with diabetic patients. This occurs because the environment offered by the organism is rich in glucose, which favors immune dysfunction, including decreasing the antibacterial activity of the urine and its motility [138].
Moreover, when comparing E. coli isolated in the urine of diabetics and non-diabetics, the same virulence factors and the same resistance to antimicrobials are found, inferring that there is no difference in the causative bacteria. This way, what makes the prevalence of urinary infections to be higher in diabetic patients is the greater adhesion of E. coli bacteria to diabetic uroepithelial cells, the reduction of urinary cytokine secretion and the number of leukocytes [139].
Hence, to treat the disease, the most commonly prescribed antimicrobials are used—amoxicillin, nitrofurantoin, trimethoprim/sulfamethoxazole (TMP/SMX) and ciprofloxacin. It is understood that the same treatment choice used by nondiabetic patients can be made, depending only on the local resistance patterns of the commonly found uropathogens [140, 141].
Generally, most uropathogens have a high resistance to TMP/SMX, in addition, this antimicrobial can cause hypoglycemia, which makes it not a good first choice of treatment for this portion of patients [142].
As for the treatment, it is recommended to consider the urinary tract infection complicated, it is advisable to keep the treatment for a period of 7 to 14 days [143].
Acute pyelonephritis is an infection located in the upper urinary tract, which accommodates either parenchyma and renal pelvis, with Escherichia coli being the most common etiological agent [144, 145].
Approximately 250,000 cases of this disease are reported each year, with more than 100,000 eventually requiring hospitalization [146].
In order to confirm the diagnosis of the disease, the patient’s urine culture is performed before the start of antibiotic therapy [147]. In addition, it is recommended to perform a microbial susceptibility test in order to select the most appropriate antimicrobial regimen [148, 149].
If the diagnosis is uncertain or the patient is immunocompromised and suspected of having a hematogenic infection, blood culture analysis is requested [150, 151].
In the last few decades, there has been an increasing rate of resistance of E. coli bacteria to beta-lactam antibiotics of extended spectrum [152]. Thus, for patients with mild and uncomplicated acute pyelonephritis, fluoroquinolone is a good choice for initial outpatient antibiotic therapy, if the drug resistance rate is 10% or less in the community [153].
On the other hand, in cases of complicated infections, sepsis or failed outpatient treatment, hospital treatment is best indicated [154]. After antibiotic therapy, urine culture should be performed again after 1–2 weeks to conclude whether the treatment was successful or not [155].
Emphysematous pyelonephritis (EPN) is a severe necrotizing infection of the renal parenchyma and its surrounding tissues—resulting in the presence of gas in the renal parenchyma, collecting system or perinephric tissue—and is caused in 70% of cases by Escherichia coli (isolated in cultures of urine or pus from patients with the condition) [156].
The clinical evolution of EPN when not recognized and treated immediately can be serious and pose a risk to the patient’s life. Another fact that should be mentioned is that up to 95% of the cases of EPN are underlyingly associated with uncontrolled diabetes mellitus [157, 158].
In addition to the risk of developing EPN primarily, the risk of developing secondary to an obstruction of the urinary tract is considerably relevant, about 25–40% can be considered as positive findings in EPN [159, 160].
The combination of percutaneous drainage (PCD) and medical management (MM) revealed a significant reduction in mortality rates [161, 162]. Thus, it is recommended that PCD be performed in patients with localized areas of gas and the presence of functional renal tissue. Another approach that can be used in association with treatment is emergency nephrectomy, classified as simple, radical or laparoscopic [163].
Being caused by kidney stones, structural abnormality, history of urological surgery, trauma or any other cause of obstruction, renal abscess can also be related to pathogens [164]. The predominant organisms causing renal abscesses are Gram-negative organisms, and the most common is Escherichia coli [165, 166, 167].
Among the various intra-abdominal abscesses, renal abscess is a rare entity, especially in children and accounts for a number of cases of “missed diagnoses” [166, 168].
With regard to the symptoms of pediatric patients, the presentation of fever, flank pain, with or without a palpable mass, has been established in the literature; increased leukocyte count and increased erythrocyte sedimentation rate [169].
Early diagnosis is a key factor in the management of these patients, which can be aided by Ultrasound (USG). Drainage of pus and appropriate antibiotic therapy is the gold standard for treatment, being able to treat a great amount of cases. Thereby, the most successful combination of antibiotics was ceftriaxone, being associated with amikacin. Cases that cannot be resolved by the conventional approach can be treated with surgery, such as nephrectomy. Thus, complications such as extension of the peritoneal cavity, skin or chest can be avoided [166, 167].
Perinephric abscess results from perirenal fatty necrosis, usually a complication of urological infection (more than 75%) [170]. Most of these abscesses have Escherichia coli as the main responsible, about 51.4% [171]. Perinephric abscess, when more diffuse, is capable of affecting the renal capsule and also Gerota’s fascia [170]. Since the condition has an insidious onset of nonspecific protein symptoms, it is necessary for a clinical physician to maintain a high level of attention to avoid possible delay in diagnosis, since perinephric abscesses are associated with significant morbidity and mortality [172].
Renal papillary necrosis (NPN) is a condition defined as ischemic necrobiosis of the papilla in the kidney medulla. Among several etiological factors important for the involvement of papillary necrosis, pyelonephritis due to bacterial uropathogens such as E. coli is one of those mentioned in the literature [173].
In order to improve the prognosis of the disease and reduce morbidity, the ideal is that the diagnosis of the disease is as early as possible. In this sense, it is clear that the radiological image is able to offer an early diagnosis and guidance in relation to the immediate treatment of papillary necrosis, thus minimizing the decline in renal function [174].
Failure to respond to standard therapy for acute bacterial prostatitis can lead to complications, such as prostate abscess or fistula [175].
Acute bacterial prostatitis is a common and clinically important genitourinary disorder that has a higher incidence in patients with diabetes, cirrhosis and suppressed immune system. Usually caused by an ascending infection, it can also be triggered by organisms that cause other common genitourinary infections that may also be responsible for acute bacterial prostatitis. Being introduced during transrectal prostate biopsy, the clinical presentation ranges from mild symptoms of the lower urinary tract to total sepsis, and Escherichia coli is one of the main bacteria related to the clinical picture.
Regarding the therapeutic approach, oral or intravenous antibiotics are most effective in curing the infection. In this sense, the progression to chronic bacterial prostatitis is uncommon. It should be noted that special attention is needed in relation to immunosuppressed patients, whereas bacterial prostatitis in these patients may be caused by atypical infecting organisms and, therefore, may require additional therapies [176].
It is already known that iron is an essential micronutrient for most bacteria and hosts, in this thought line, it is also known that there are relatively rare classical siderophilic pathogens that cause an increase in hepcidin in the body, responsible for the sequestration of iron for macrophages and enterocytes and, consequently hypoferremia [177, 178, 179, 180]. So, current studies investigate if this mechanism used by the body against rare siderophilic bacteria, it also works for a wider set of bacteria. Results of these studies are shown to be positive, by demonstrating that excess iron allows rapid bacterial replication and spread, which means a susceptibility to infection caused by E. coli and that hepcidin is essential to protect against infections caused by Escherichia coli. [181, 182]. Thus, the use of hepcidin agonists promises to be an effective early intervention in patients with infections and dysregulated iron metabolism to avoid complications.
With regard to urinary tract infection, an effective preventive measure is the characterization and correction of the underlying genitourinary abnormalities that promote the infection. Another alternative mentioned in the literature is the future development of catheters whose material limits the growth of biofilm [109].
Early symptom recognition, followed by appropriate investigations, accurate diagnosis and early goal-directed therapy, is essential to improve results. Patient management includes an interprofessional team approach, with microbiologists, radiologists, surgeons and intensive care physicians [109].
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