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Analytical and Bioanalytical Chemistry

, Volume 410, Issue 3, pp 773–790 | Cite as

Photonic monitoring of treatment during infection and sepsis: development of new detection strategies and potential clinical applications

  • Astrid Tannert
  • Anuradha Ramoji
  • Ute Neugebauer
  • Jürgen Popp
Review
Part of the following topical collections:
  1. ABCs 16th Anniversary

Abstract

Despite the strong decline in the infection-associated mortality since the development of the first antibiotics, infectious diseases are still a major cause of death in the world. With the rising number of antibiotic-resistant pathogens, the incidence of deaths caused by infections may increase strongly in the future. Survival rates in sepsis, which occurs when body response to infections becomes uncontrolled, are still very poor if an adequate therapy is not initiated immediately. Therefore, approaches to monitor the treatment efficacy are crucially needed to adapt therapeutic strategies according to the patient’s response. An increasing number of photonic technologies are being considered for diagnostic purpose and monitoring of therapeutic response; however many of these strategies have not been introduced into clinical routine, yet. Here, we review photonic strategies to monitor response to treatment in patients with infectious disease, sepsis, and septic shock. We also include some selected approaches for the development of new drugs in animal models as well as new monitoring strategies which might be applicable to evaluate treatment response in humans in the future.

Figure

Label-free probing of blood properties using photonics

Keywords

Treatment response Microcirculation imaging Therapeutic drug monitoring Indocyanine clearance Imaging infection Antibiotic susceptibility testing 

Introduction

Since the discovery of antibiotics early last century, the mortality due to infections, which were the leading cause of death in 1900, has been greatly reduced [1]. However, with about 26% of worldwide deaths, infectious diseases are still a major cause of mortality [2]. Moreover, the rising emergence of multidrug-resistant strains are an increasing problem, which is caused by the excessive use of antibiotics both in clinics and agriculture [1, 3]. For instance, methicillin-resistant Staphylococcus aureus (MRSA) possessing multidrug-resistance genotype against quinolones, macrolides, and sulfonamide are already the predominant strain of Staphylococcus aureus in hospitals and a major cause of mortality [4]. Also, in the community an increasing number of Gram-negative bacteria that possess an extended spectrum of \(\beta \)-lactamase are becoming untreatable [1]. Therefore, new drugs targeting bacterial infections are urgently needed. Sepsis is a life-threatening uncontrolled complication to infection leading to systemic response associated with organ dysfunction. Sepsis is commonly caused by invading bacteria or fungi and can occur as a complication of any infection or following surgical procedures or trauma. Mortality rates in sepsis are still very high ranging from 25–30% of septic patients and 40–50% of patients developing a septic shock [5]. Sepsis is more frequently found in older patients and patients with co-morbidities like cancer or immune suppression [6]. In sepsis, early effective antibiotic therapy essentially determines outcome. The increasing number of multidrug-resistant pathogens requires to calculate the risk from restricting the use of so-called reserve drugs versus the possibility to not adequately treat the patient who might be infected with multidrug-resistant organisms [5]. Therefore, monitoring methods for early detection of therapeutic efficacy are urgently needed. In addition, treatment of sepsis or septic shock aims at stabilizing hemodynamic parameters by volume resuscitation and the administration of vasoactive agents, however the most suitable type and optimal amount of these agents is still a matter of debate [6]. Monitoring the influence of treatment strategies on microcirculatory perfusion, which is now believed to critically influence the patient’s mortality [7, 8] is therefore important and might in the future lead to therapies adapted on the patient’s response and, thus, personalized medicine [9]. An emerging field in medicine is the so-called theranostics, which combines diagnostics and therapy to achieve personalized and efficiently tailored treatment of the patient. This includes diagnostics to stratify patients to select the appropriate therapy as well as monitoring efficacy of treatment for therapies that work but not for all patients. Photonic approaches are a growing field in medicine both for diagnosis and to monitor treatment responses. Many applications, especially in the field of oncology [10, 11, 12, 13], are now in use. One example of diagnostic evaluation mostly by imaging with direct targeting of the disease is found in photodynamic therapy (PDT). Theranostic molecules specifically target diseased areas and can be visualized for diagnosis as well as activated for therapy. Besides others, theranostic molecules have been mainly applied in oncology [14], in cardiovascular diseases [15], and are now also applied to infectious diseases [16].

In this review we focus on the monitoring of therapeutic progress in infectious diseases and selected animal models of infection and sepsis, for the application of photonic technologies in the range of the visible and IR spectrum. We will introduce monitoring of therapeutic interventions on three selected organs/organ systems: the cardiovascular system, the liver, and the eye, and then focus on the detection of bacterial infections, their monitoring during therapeutic intervention and the selection and monitoring of antibiotic therapy in patient samples. For pure diagnostic applications, the reader is referred to several excellent reviews on this issue [17, 18]. However, a few methods with high potential for therapeutic monitoring are presented here. Further technologies using X-ray-emitting labels like positron emission tomography (PET), single-photon emission computed tomography (SPECT) etc., have their main application in oncological problems but are occasionally also used to monitor infections. Details on these techniques and their application to infectious disease are covered by a recent review [19].

Blood flow and tissue oxygen saturation measurements

During sepsis, the microvascular blood flow can be severely altered leading to reduced perfusion/shunting in some vessels while normal or even increased blood flow occurs in other vessels (excellently reviewed in [8] and [7]). In many cases, systemic hemodynamic- and oxygen-derived variables are in the normal range while microcirculation is disturbed, necessitating specialized techniques for monitoring possible damage and verifying changes in microcirculation under treatment strategies. Different photonic techniques are now available to directly or indirectly monitor microcirculation including measurement of sublingual, buccal, and subcutaneous CO2 levels, measuring the microcirculatory hemoglobin saturation by absorbance reflectance or near-infrared spectroscopy (NIRS), orthogonal polarization spectral (OPS) imaging and sidestream dark-field (SDF) imaging [7].

Direct monitoring of microcirculation by microvideoscopy

To directly image the perfused microvessels, a microscopic system has to be applied to the organ surface. Invasive intravital microscopy is largely limited to experimental animal models of sepsis. In humans, microvideoscopy is restricted to transillumination of thin areas like in nailfold videocapillaroscopy, which during sepsis is of limited use since shock is often associated with peripheral vasoconstriction. Another approach in clinical settings, allowing somewhat deeper tissue penetration, is the application of reflection from deep tissue layers for back-illumination of the investigated tissue. Therefore, the light reflected by superficial layers has to be discarded, which was first achieved by using polarized light with orthogonal detection in OPS imaging. Later developments (SDF imaging and incident darkfield (IDF) imaging) inspired by OPS imaging focused on an optimized geometry between excitation source and the detection path leading to even-clearer images [20, 21, 22]. These back-illumination methods will be discussed in more detail in the following sections. From these imaging techniques, the velocity of microcirculatory perfusion can be assessed semiquantitatively by estimating the flow in different areas (there are slightly different protocols for this estimation) by a trained investigator giving the so-called microvascular flow index (MFI) [23].

Orthogonal polarization spectral (OPS) imaging

OPS imaging was the first method introduced to achieve back-illumination from deeper tissue layers using scattered light while directly reflected light from the surface is omitted. To achieve this, linearly polarized light is used for excitation of the tissue, while images are acquired through a polarizer that is oriented orthogonally to the illuminating plane. Thereby, directly reflected light, which maintains its polarization, is omitted from detection while scattered light with deep tissue penetration is used for absorbance imaging by illuminating the microvessels from the back (see Fig. 1a). By choosing a wavelength where both oxygenized and de-oxygenized hemoglobin absorb (548 nm), the hemoglobin in the red blood cells (RBC) can be detected and thereby perfused vessels can be visualized [24]. OPS is easily implemented for sublingual measurements in patients, internal organs are only accessible in perioperative use [25]. Monitoring of vessel perfusion by OPS in septic patients indicates a reduced density of vessels and a smaller proportion of perfused small but not large vessels compared to a non-septic control groups (both healthy and from the ICU) [26]. Patients with septic shock and treated with high doses of vasoactive agents and additionally topical treated with acetylcholine were monitored by OPS imaging, showing an increase in the number of perfused vessels upon treatment [26]. The effect of administration of recombinant human activated protein C (Drotrecogin alfa activated) to patients with sepsis was investigated using OPS and an improvement of the microcirculation was observed, which was not present in the control group [27].
Fig. 1

Schematic representation of the light path in OPS and SDF imaging. a In OPS imaging, reflected light maintaining its polarization is filtered by a polarizer, while deep tissue scattered light is used for back-illumination of blood vessels. b In SDF imaging, a light guide is surrounded by green light-emitting diodes (530 nm) and optically isolated from the collection core. The light is scattered by leukocytes and absorbed by hemoglobin of the red blood cells

Sidestream darkfield (SDF) imaging and incident dark field (IDF) imaging

SDF imaging is a specialized darkfield illumination technique that was inspired by OPS imaging. Like in OPS imaging, green light, which is absorbed by deoxy- and oxyhemoglobin, is used for back-illuminating microvessels [7, 28]. Therefore, a light guide is surrounded by 530-nm light emitting diodes (LEDs), which are optically isolated from the core, allowing deep tissue illumination while avoiding surface reflections (see Fig. 1b). By using pulsed illumination in synchrony with the CCD frame rate, stroboscopic images with decreased smearing of moving objects can be obtained [28]. SDF imaging was applied to monitor changes in microvascular flow (besides other parameters) in patients with septic shock after administration of noradrenaline to stepwise increase the mean arterial pressure (MAP) to values of up to 90 mmHg, however no changes in microvascular flow were detectable in this study [29]. In an ovine model of septic shock, SDF was applied to study the effect of tetrahydrobiopterin on microcirculation showing an improvement upon treatment [30]. Recently, the Cytocam device (by Braedius Medical), which is based on IDF imaging [31] was introduced [32, 33] to yield a further improvement compared to available SDF imaging devices in that it can use very short camera-synchronized excitation pulses and comes with a automated bedside analysis software omitting the need of successive semiquantitative offline analysis.

Laser speckle contrast imaging

The laser speckle contrast imaging (LASCI) technique is relatively new in the field of biology and medicine although the concept was first introduced in the late 1980s. This method is used for visualization of tissue blood perfusion in microcirculation. When a coherent light scatters from an object, light is backscattered. This backscattered light forms interference pattern called speckle pattern. If the object is static, then the speckle pattern is stationary, movement of the object causes a phase shift in the scattered light, thus, changes in the interference pattern produce temporal fluctuations in the speckle pattern. A high-end CCD camera with high resolution and speed capability is employed to record the speckle pattern [34]. A recent improvement in LASCI is the introduction of a webcam in combination with low-cost lenses and a laser pointer as illumination source for recording speckle images in order to make it inexpensive [35]. Application of LASCI was mainly limited to animal models, but recently has found its place in clinical studies. Speckle pattern imaging was applied during neurosurgery for real-time assessment of blood flow, for hemodynamics during stroke, brain activation, [36], tissue perfusion [37] and hepatic microcirculation dysfunction during sepsis [38, 39].

Laser Doppler flowmetry

Laser Doppler flowmetry (LDF), also known as fluxmetry, is another imaging technique being widely used for monitoring microcirculation. In LDF, two monochromatic laser beams with wavelength in the visible spectrum, collimated and coherent, interact with each other with the point of intersection being the fluid under investigation. At the cross section, the lasers interfere and generate straight fringes. The fluid particles at the interface interact with the fringes and reflect light, which is then received by the collection optics. The frequency of intensity fluctuations of reflected light is equivalent to the Doppler shift of the incident and scattered light. LDF has been used to measure microcirculatory blood flow to assess the effect of sodium nitroprusside on splanchnic microcirculation [40] or esmolol on gut [41] in a porcine model of septic shock. LDF in combination with intravital fluorescence microscopy was used to evaluate the effect of dopexamine on intestinal microvascular blood flow and leukocyte-venular endothelium interaction in a sepsis rat model [42]. LDF has been used in a clinical study to show improved macrovascular (arterial flow response) and microvascular for cutaneous blood flow in response to activated protein C treatment in patients suffering from sepsis and septic shock [43]. Similarly, many other studies used LDF and have shown effects of various drugs on microcirculations [44, 45, 46].

Indirect monitoring of microcirculation by near-infrared spectroscopy (NIRS)

Microcirculatory malfunctions lead to local changes in tissue oxygen saturation (StO2), which can be monitored non-invasively using near-infrared spectroscopy (NIRS) by determining the ratio of oxygenated-to-deoxygenated hemoglobin in blood vessels. Tissue up to 15 mm below a sensor placed on the skin can be illuminated by different wavelengths between 700 and 1000 nm, where hemoglobin absorbance changes according to the degree of oxygenation. The reflectance signal is then used to calculate the mean percentage of oxygen saturation [47]. Additionally, also the hemoglobin concentration (tissue hemoglobin index) can be estimated [47]. Static measurements of StO2 are simple but correlate only poorly with severity of sepsis, since they give an estimate of oxygen saturation in all vessels and no information about relative blood flow and vessel dynamics. In many studies, dynamic measurements were found more meaningful. They are performed using a vascular occlusion test (VOT) that may yield information about oxygen consumption (slope of fall) and vascular responsiveness (slope of recovery). Here, a correlation between recovery slope and sequential organ failure assessment (SOFA) score and mortality has been established [47, 48]. One study including 49 patients found no correlation of static StO2 measured at hospital arrival (which was lower than in healthy controls) and outcome. Dynamic monitoring, the StO2 in the first hours of treatment, however, revealed a correlation between poor improvement of StO2 and mortality rate [49].

NIRS was also used to monitor brain tissue oxygenation (BtO2) in patients with septic shock. The results were very inconclusive regarding correlation with other parameters like heart rate, mean arterial pressure (MAP), systolic and diastolic blood pressure. However, patients developing a delirium showed significantly reduced BtO2 levels [50].

The influence of several drugs on the progress of both static and dynamic StO2 during the treatment of acute sepsis and septic shock conditions has been evaluated using NIRS in a number of studies. The changes in tissue oxygenation in septic shock patients with life-threatening hypotension, which were treated with norepinephrine (NE) to increase their MAP to at least 65 mm Hg, were determined as a baseline and after a VOT. The influence of treatment of septic shock patients with the vasopressive agent NE on patients outcome showed inconclusive results in several previous studies. NE increased the recovery slope after performing a VOT in the majority of the investigated patients indicating that NE improves rather than worsens tissue oxygenation in severely hypotensive septic shock [51]. In contrast, stepwise-increase of MAP above 65 mmHG to values up to 85 mmHg did not improve sublingual microcirculation measured by sidestream darkfield (SDF) imaging [52]. Treatment of septic patients with recombinant activated protein C, which has a number of beneficial functions in inflammatory response, coagulation, leukocyte, and endothelial properties, was monitored using NIRS in combination with a VOT at different time points during and after administration of the drug. Whereas the static parameters (baseline tissue oxygenation) appeared unchanged during treatment, there was an improvement during and after drug administration of both oxygen consumption and vascular responsiveness following a VOT, which was not detected in the untreated control group, indicating improved microvascular reperfusion after ischemia, which correlated well with an improved SOFA score in these patients [53].

Reflectance spectrophotometry

Reflectance spectrophotometry has also been used both in clinical setting and in animal model to study hemodynamic changes. Reflectance spectrophotometry measures relative absorbance, which is the difference between a reference substance absorption and the target tissue. Briefly, light is transmitted to the tissue of interest through a micro light guide and the reflected light is analyzed [54]. Reflectance spectrophotometry is applied for physiological and pathological studies to demonstrate the role of blood flow changes such as mucosal perfusion in inflammatory bowl disease, mucosal hemodynamics in chronic hepatitis, gastric mucosal index of oxygen saturation in sepsis patients [55], differentiate middle ear pathological conditions from normal middle ear [56], assess buccal microvascular response in patients with septic shock [57] and microvascular hemoglobin oxygenation [58]. A further development is endoscopic reflectance spectrophotometry where the measuring probe can be passed through the biopsy channel of an endoscope. The probe has two coaxial light guides, one is for incident light and through the other guide reflected light returns to the spectrophotometer. In an anesthetized and mechanically ventilated dog, gastric mucosal oxygenation was assessed by measuring microvascular hemoglobin oxygenation using reflectance spectrophotometry [58].

Direct and indirect monitoring of microcirculation during therapeutic intervention

The available microscopic and spectroscopic techniques to analyze the microcirculation have been applied in a large number of studies to evaluate the influence of a variety of treatment options to improve microcirculation, which is probably associated with survival rate in septic shock patients (extensively reviewed in [20, 59, 60]). These include interventions to improve the global hemodynamic state like fluid substitution in different formulations, red blood cell transfusion, beta-adrenergic agents, vasopressors and vasodilators. Since it becomes increasingly evident that microvascular alterations are often not clearly reflected by global hemodynamic parameter but seem to be the major causes of mortality in sepsis and septic shock [7, 8, 21, 61, 62, 63], current treatment strategies focus on therapeutics that might specifically reverse microvascular malfunctions. These include anticoagulant agents, the Ca2+- channel sensitizer levosimendan, hydrocortisone, magnesium, as well as the local administration of vasodilating agents [59].

Experimental studies on the improvement of microcirculation in animal models

The use of intravital microscopy (IVM) is largely restricted to animal models when investigating the therapeutic intervention on irregularities in microcirculation caused by sepsis. For instance, the influence of various drugs on microcirculatory function was assessed in endotoxemia models of mice, rats, and Syrian golden hamsters [64, 65, 66] or in small rodent like rat, hamster and large mammal such as pig, dog, and sheep models of septic shock [30, 67, 68]). IVM was also applied for monitoring decrease in brain vascular inflammation [69, 70] and protection against cerebral malaria by using exogenous nitric oxide [71]. In another study, using a mouse sepsis cecal ligation and puncture (CLP) model, the glomerular filtration rate was measured by applying a single-bolus fluoresceinyl isothiocyanate (FITC)-inulin clearance method. Blood was collected at different time points to estimate renal function [72]. FITC-labeled dextran was used for intravital video microscopical observation of capillary and vascular space during targeting of sphingosine-1 phosphate receptor in the same sepsis mouse model [73]. IVM using two-photon excitation was used for renal imaging to follow vascular permeability defects and blood flow disruption in endotoxemia rat model. The aforementioned imaging method was further used to show treatment benefit of activated protein C (APC) in endotoxin induced functional defects on renal vasculature [74].

Assessment of liver function

Liver function can be impaired by infection, for instance several viral infections lead to hepatitis. Moreover, during sepsis and severe systemic infections, the liver plays a crucial role, both in protecting from bacterial infection and as a target for organ failure due to dysregulated inflammation [75]. In the pathogenesis of sepsis bacteria, in most cases from the gut lumen, get access to the blood stream and subsequently pass through the liver portal vein. Thus, next to the gut epithelial barrier, the liver plays an essential role in warding off invading bacteria and preventing sepsis. For this reason, patients with pre-existing liver disease like cirrhosis are at high risk to develop systemic bacterial infections and sepsis [76, 77]. During sepsis, the liver injury can occur through pathogens, toxins, or inflammatory mediators. Liver injury during sepsis, like hepatitis, liver steatosis and cirrhosis, is an independent risk factor for mortality [76, 78].

Indocyanine green clearance

Besides determination of classical biomarkers for liver function from the blood (like bilirubin, alkaline phosphatase, transaminases, gamma-glutamyl-transferase, cholinesterase), the determination of the plasma disappearance rate of indocyanine green (ICG) as a dynamic test is increasingly used as a diagnostic tool to assess the liver function in critical ill patients. This nontoxic, inert, and water-soluble tricarbocyanine dye is exclusively extracted via the liver through selective uptake from the blood by hepatocytes and excretion into the bile. Since ICG is not metabolized and does not show enterohepatic re-circulation, the rate of elimination is assumed to correlate well with the liver function [79, 80]. The hepatic clearance of a compound is determined by the effective hepatic blood flow and the compound-specific extraction rate. Since the ICG extraction rate is high (half life 3–5 min), ICG clearance is highly dependent on the hepatic blood flow, necessitating stable hemodynamic parameters during the measurement. Since the peak absorption of ICG at about 800 nm corresponds to the isosbestic point of hemoglobin (see Fig. 2a, point A), ICG concentration in the blood can be measured by absorption spectroscopy independent of the oxygen saturation of the blood [79, 80]. Moreover, bilirubin absorption has no impact at this wavelength. After injection of a bolus of the dye, ICG plasma concentration shows an initial peak, a second re-circulation peak and an elimination phase (see Fig. 2b). The classical way to determine hepatic ICG clearance is to repetitively take blood samples from the patient for ex-vivo photometric analysis, which is, however, invasive and time-consuming [79], even though it has been applied to monitor the effect of N-acetylcysteine on the liver blood flow in a placebo-controlled study with septic shock patients, showing an increased hepatosplanchnic perfusion after treatment [81]. The elimination of ICG can also be determined via an intravascular fiber-optic sensor that detects relative changes in ICG concentration (COLD system, Pulsion) [82]. Alternatively, the minimal invasive pulse dye densitometry (PDD) allows to detect relative changes in ICG concentration, too. Parameters that can be obtained by these measurements and are frequently given in studies testing liver function in critical ill patients are the elimination rate (ICG plasma disappearance rate - PDRICG) which in healthy individuals is higher than 18 %/min and the ICG retention ratio after 15 min (ICG R15) with normal values below 10% [80]. In PDD, the absorption is measured at two wavelengths using a finger or a nose clip. For calculation of the plasma ICG concentration the wavelength of 805 nm (peak absorption of ICG, minimal hemoglobin absorption, point B in Fig. 2a) is used and related to the hemoglobin concentration (measured at 890 nm or 905 nm, point D in Fig. 2a) [79, 83]. The principle of PDD is similar to pulse oximetry where oxygen saturation is measured non-invasively by a finger clip using the absorption maxima of oxygenized and deoxygenized hemoglobin for calculation. ICG plasma disappearance rate can be measured using PDD by a commercially available device (LiMON, Pulsion).
Fig. 2

Spectral characterization and serum distribution of ICG. Reprinted with permission from [79]. a Absorption spectra of ICG (green), bilirubin (yellow) and hemoglobin (red for oxyhemoglobin and blue for reduced hemoglobin). PDD measures relative ICG concentration at 805 nm (point A) and reference at 905 nm (point C). b Example of a typical ICG indicator-dilution curve in blood. A primary peak, B secondary peak (re-circulation phase), C (hepatic) elimination phase

ICG is not yet used in routine clinics but there are a number of studies showing its prognostic value in critical ill patients with and without liver disease, as well as in patients undergoing liver surgery [79, 82].

Recently, also the patients prognosis and the impact of various treatments on liver function during infections and in septic patients were monitored using this method. The influence of the treatment with the vasodilating agents iloprost and dopexamine on ICG clearance in septic shock patients was determined during the treatment (infusion of the drugs over 24 h) and 1 h after the treatment showing an increase in PDRICG during the treatment and a return to baseline levels after stopping the infusion. The authors conclude that the higher PDR \(_{\text {ICG}}\) might be caused by an improved liver function rather than an increased liver perfusion, since other parameters indicate a constant blood flow through the liver, however further studies are required to clarify this issue [84, 85]. ICG clearance did not change during and after early goal-directed therapy in early septic shock patients, where PDRICG and ICG R15 were assessed with the LiMON device [86]. ICG clearance in patients with sepsis was assessed by the COLD system over several days and shown to be lower in non-survivors than in survivors [87]. The influence of an extracorporal treatment with donor granulocytes on liver function was estimated by measuring the ICG clearance with the LIMON device in a small patients cohort [88]. ICG clearance after treatment initialization was higher in survivors than in non-survivors indicating a prognostic value of this parameter for treatment response. ICG has also been utilized to determine the hepatosplanchnic blood flow in vasoplegic septic patients during treatment with dopamine or norepinephrine by assessing the ICG concentration from blood samples [89].

Raman spectroscopic determination of hepatic parameters

Up to now, no standardized laboratory methods exist, that can diagnose the onset of liver failure in critical ill patients [90]. Raman spectroscopy, a vibrational spectroscopic method, holds high potential to assess liver function by determining changes in the complex Raman spectrum of liver cells, tissue and metabolites. The information can be gained in a label- and destruction-free manner with a spatial resolution down to the single-cell level, different cell types can be distinguished based on their Raman spectroscopic fingerprint [91] and even quantitative analysis of intracellular storage molecules, such as retinoids within hepatic stellate cells, is possible [92]. This makes Raman spectroscopy particular interesting for treatment monitoring. First proof-of-concept studies include the Raman spectroscopic monitoring of alterations in the disease state in a murine model of hepatic cirrhosis and recovery [93]. Based on the spectral data, chemical changes associated with liver damage and repair could be recognized on the cellular level providing biomarker-like information of prognosis. If the retinoid content in hepatic stellate cells shall serve as a marker of disease state also non-linear Raman methods, such as coherent anti-Stokes Raman scattering (CARS) can be applied to observe large tissue sections with video rate time resolution [94].

Increased levels of the heme degradation product bilirubin can serve as a biomarker to indicate acute liver failure. Bilirubin and also biliverdin show characteristic Raman spectroscopic fingerprints [95] and thus, can be detected in increased concentration in tissue sections of infected animals with septic liver failure [96]. Using fiber-enhanced resonance Raman spectroscopy (FERS), these degradation products can also be quantified in the clinical relevant range [97] paving the way for monitoring the progress of treatment with label-free FERS from serum samples in the future.

Monitoring treatment of ocular infections

The eye is easily accessible for photonic detection methods. Therefore, there are a variety of photonic techniques to monitor ocular diseases at different locations within the eye. The gold standard to monitor choroidal and retinal vessel structure and perfusion are indocyanine green angiography (ICGA) and fluorescein angiography, which however require the systemic administration of a contrast agent and only provide two-dimensional information [98]. Optical coherence tomography (OCT), by contrast, is label-free and allows the reconstruction of three-dimensional images of the ocular fundus. Briefly, after illumination, reflected light from deeper sample layers is recorded while scattered light is omitted using interferometry to detect the optical pathlength. In optical coherence tomography angiography (OCTA), the same area is repeatedly recorded and by comparing the differences of the images, e.g., the blood flow rate can be determined. A number of ocular infections and their treatment can be monitored by this method, as reviewed in [98]. The use of a number of ocular imaging methods for monitoring therapeutic approaches in ocular tuberculosis, which presents with various manifestations, has recently been reviewed [99]. Fundus autofluorescence imaging is a variant of autofluorescence imaging (AFI, see “Autofluorescence imaging”) where the signal originates from lipofuscin present in retinal pigment epithelium. This method can be used to visualize the border of disease and its progression as shown for acute retinal necrosis caused by a Herpes simples infection[100] or in ocular tuberculosis [99]. Raman spectroscopy in the anterio chamber of the rabbit eye was used to detect and quantify ceftazidime or amphotericin B during endophthalmitis [101], providing a means to determine the individually appropriate drug doses.

Techniques for imaging and detection of infections

Optical imaging of bacteria during infections

The “gold-standard” for in situ imaging of infections has been the radio-detection of fludeoxyglucose (18F) ([18F]FDG) or radio-labeled leukocytes [102]. To directly target and label pathogens in vivo, a contrast agent is coupled to a molecule, which will allow specific detection of pathogens either by binding, uptake, or metabolic activation of the contrast signal [103]. In the past, mainly radionuclides served as contrast agents, which due to their excellent tissue penetration, allow imaging from all regions of the body. Recently, also fluorescent labels are developed for optical imaging. This method allows better resolution but is restricted by the lower tissue penetration of the fluorescent signal, which can be somewhat increased by utilizing dyes that emit in the NIR range of the spectrum. Applied targeting strategies for optical imaging of bacteria have recently been reviewed [102].

An increasing number of fluorescent dyes that are targeted to bacteria are currently synthesized and have already partly been tested in animal models for in vivo optical imaging including NIR dyes coupled to antimicrobial peptides [104, 105], a dual fluorescence and nuclear imaging probe targeting Gram-positive bacteria via vancomycin-derived self-assembling molecules [106], and an NIR probe to detect biofilm formation on implants [107].

In a mouse endocarditis model with S. aureus infection, a reduction of the fluorescence signal upon treatment with vancomycin was observed [108]. A newly synthesized nanoparticle carrying vancomycin-modified polyelectrolyte–cypate complexes could selectively transfer parts of the NIR fluorophore to MRSA releasing it from ground-state quenching. This theranostic probe was remarkably stable in vivo in a mouse model and might be useful to monitor treatment efficacy [12].

Targeted imaging of bacteria could in future not only serve to diagnose infections, but could also be used in intra-operative surgical guidance for the optimized resection of infected tissue like in necrotizing fasciitis or infective endocarditis and in post-operative examinations [17]. Radiolabeled probes that target bacteria via antimicrobial peptides have already been shown not only to detect bacterial infection sites but also to monitor the eradication of the infection upon treatment with antibiotics in rodent infection models [109, 110]. However, currently no probe is available for targeting and labeling of bacteria for imaging in a clinical setting.

Bioluminescent and fluorescent reporter strains

The use of reporter pathogen strains which exhibit fluorescent or bioluminescent properties allows to follow the development of infection and to monitor the efficacy of antibiotic therapy in animal models and serves as a valuable tool for drug development. For this reason, either intrinsically bioluminescent pathogens are used or genetically modified organisms that express fluorescent or bioluminescent proteins are generated. Bioluminescence photonic imaging (BPI), which in contrast to fluorescence imaging, does not require an external light source for excitation, is a well-established technique [111, 112, 113, 114, 115, 116, 117]. Bioluminescence is an intrinsic property of certain organisms to emit light of a specific wavelength. This is mainly due to the oxidation of a luciferin substrate by a luciferase enzyme [118], which triggers the release of photons. Bioluminescence occurs widely in diverse organisms and more than 30 different independent origins are known for this process. BPI was first reported by Contag and coworkers [119] where bioluminescent Salmonella strains were used to study intraperitoneal infection in mice. Ciprofloxacin treatments resulting in clearance of infection could be followed in vivo. Since then, numerous application have emerged with development of optical systems and combination of bioluminescence reporter systems [120] to monitor a variety of biological processes such as the enzyme-mediated bioluminescent sensor for point of care detection of the biomarker procalcitonin in human serum during bacterial infection[121], catheter-associated urinary track infection in mice where Pseudomonas aeruginosa and Proteus mirabilis were made biolumininescent by inserting a Photorhabdus luminescence luxCDABE operon [122], real-time in vitro visualization of human root canal infection and bacteria clearance due to antibiotic therapy [123], regenerative medicine such as cartilage regeneration [124] and monitoring healing of wound infection [125, 126]. In an animal model with burns infected with a bioluminescent MRSA strain, photodynamic therapy (PDT, see “Photodynamic therapy”) by the application and illumination of a newly developed porphycene dye strongly reduced bacterial load as monitored by bioluminescence imaging [127]. Bioluminescent and fluorescent strains are not just limited to bacteria but are also extended to study fungal burden in order to monitor infection. Jacobsen and colleagues developed a bioluminescent C. albicans reporter strain to monitor in vivo fungal infection in mice and observed that the kidney is the main target. Further, the authors were able to follow treatment efficiency of the antifungal drug caspofungin and fluconazole but observed fungal infection becoming persistent and translocated to other organs such as urinary bladder [128]. In a recent follow-up study, inefficiency of antifungal drugs made of amphiphilic and hydrophobic compounds within the gall bladder and bile duct was shown to be related to the ability of the bile salts to encapsulate antifungals and the formation of micelles, whereas hydrophilic molecules such as sodium azide kept their antifungal properties [129]. These studies, showing the importance of in vivo drug monitoring and following fungal infection, have been excellently summarized recently [130, 131].

Fluorescent or bioluminescent reporter strains have also been a valuable tool for developing treatment strategies for tuberculosis, a frequent cause of infection-associated death in humans. Since Mycobacterium tuberculosis is a slow-growing pathogen, monitoring treatment efficacy of newly developed therapeutics in animal models is difficult by standard microbiological methods [132]. Animal models infected with genetically modified fluorescent or bioluminescent reporter strains of Mycobacterium tuberculosis are one strategy to characterize the therapeutic potential of new drugs using fluorescence optical imaging or BPI [133, 134, 135], see Fig. 3 for an example using a fluorescent reporter strain to monitor therapeutic outcome in mice. Another strategy is the development of new probes for optical imaging of this pathogens, which holds great promise for research on new treatment and prevention strategies and might be used for monitoring of infected individuals in clinics, as well. Usage of reporter enzyme fluorescence (REF)-based probes, especially \(\beta \)-lactamase-activated probes, is one strategy to achieve correct localization of the label, since \(\beta \)-lactamase is naturally expressed in Mycobacterium tuberculosis. Using REF substrates coupled to an NIR fluorophore, the therapeutic efficacy of antibiotics in a mouse tuberculosis model could be followed raising the possibility to also use similar REF-based methods for therapeutic monitoring in humans [106, 136].
Fig. 3

In vivo evaluation of anti-TB therapeutic efficacy using a tdTomato-expressing reporter strain of M. tuberculosis. a Images of infected mice treated with rifampicin and isoniazid by daily intraperitoneal injection compared to untreated mice and noninfected mice. b Images of lungs harvested from mice sacrificed at day 0, 2, and 6 post infection. Images are reproduced from [134]

Autofluorescence imaging

Autofluorescence imaging (AFI) is achieved using a portable device such as the PRODIGI imaging device, MolecuLight Inc, TOPCON medical system Inc for real-time detection of bacteria in chronic skin infections without the need of contrast agents. These devices are hand-held and are easily portable to bedside investigations. AFI technique utilizes the porphyrins produced by the bacteria which absorb light and have emission in the red region with a peak at about 635 nm. This emitted light is detected by illuminating with 405-nm excitation wavelength to localize the bacteria. AFI helps to detect bacteria in and around wounds and helps sampling of pathogens from the wound area with a swab for clinical investigations thus enabling to monitor treatment in patients with diabetic foot ulcers [137, 138, 139]. AFI has also been applied for determination of the appropriate time for wound closure at the incision site after device transplantation and detecting presence of infection causing bacteria [140].

Photodynamic therapy

In PDT, a nontoxic photosensitizer (PS) is used to locally generate active molecular species like singlet oxygen (1O2) by illuminating a defined region of the body with a specific wavelength of light and, thus, to locally destroy harmful material. PDT has been most widely applied in cancer therapy, however there are also emerging other applications including the treatment of infections [141]. PS are usually designed to accumulate at the site of interest (i.e., at deteriorated cells or bacteria). Since PS are mostly fluorescent or luminescent in the NIR range, they can also be used for visualization of the corresponding target by specifically detecting their fluorescence or luminescence signal and, thus, serve as theranostic agents [142]. Labeling and inactivation of Gram-positive bacteria [143], selective binding of a PS to a drug-resistant Gram-positive strain [144], performing PDT in combination with a polyethylenimine-ce6 photosensitizer for inactivation of methicillin-resistant Staphylococcus aureus [145] and photodynamic inactivation of \(\beta \)-lactamase expressing bacteria using a fluorescence resonance energy transfer (FRET)-based luminescence probe [146] have recently been achieved. The cationic phenothiazinium (5-ethylamino-9-diethylaminobenzo[a]phenothiazinium chloride) and (5-ethylamino-9-diethylaminobenzo[a]phenoselenazinium chloride) PS were characterized for their anti-mycobacterial activity [147]. Such labeling approaches might in the future be applied for selective destruction of bacteria in skin infections as well as for monitoring their distribution during treatment [144] .

Emerging vibrational spectroscopic methods for detection of infection

In addition to established optical imaging methods (see “Optical imaging of bacteria during infections”, “Bioluminescent and fluorescent reporter strains” and “Autofluorescence imaging”), new, vibrational spectroscopy-based methods are emerging that enable a detection of the infection-causing pathogen directly form the patient’s sample in a label-free manner [148]. Although these spectroscopic techniques are currently limited to in vitro investigation of clinical samples (such as body fluids or surgical samples), the high potential of the technology to monitor load of infection and in addition reveal physiological changes during infectious diseases and their potential reversal upon treatment is demonstrated in a huge number of prove-of-concept studies [149, 150]. Vibrational spectroscopic methods, in particular Raman spectroscopy, can reduce the pathogen detection times from more than 24 h in established microbiological routine to less than 1 h, as no biomass enriching steps are required. If patient’s urine samples are analyzed, the result can be available after only 35 min [151]. Raman spectroscopic analysis can also be applied to identify bacteria from sputum samples [152] or ascetic fluid [153], to name just a few. Other examples have been recently reviewed [148]. In order to record a Raman spectrum, a single bacterial cell is sufficient [154, 155, 156, 157]. Thus, the method could be further developed to monitor bacterial load in body fluids under antibiotic treatment to assess almost real-time treatment efficiency. For the detection of intracellular pathogens, such as those causing persistent infections, currently new spectroscopic imaging approaches are under development, e.g., for the characterization of intracellular S. aureus [158] or the detection of the malaria pigment hemozoin in early ring stages of Plasmodium falciparum-infected erythrocytes [159]. As an infection is causing host response and thus changes in body (e.g., in the blood), Raman spectroscopy can be utilized also to indirectly detect an infection by recording the spectroscopic fingerprint of patient’s serum samples. In this way, it was possible to differentiate critical ill patients with infection (sepsis) and sterile inflammation [160]. Indirect detection of bacterial antigens, e.g. for cholera, was achieved by making use of surface enhanced Raman spectroscopic (SERS) immunoassays [161]. Also, infrared absorption spectroscopy, another form of vibrational spectroscopy, has been demonstrated as a useful tool in detecting infections of viral or prion origin [162, 163, 164, 165], raising the possibility to screen for therapeutic interventions.

Antibiotic therapy

Personalized medicine - antibiotic susceptibility testing (AST)

With the increasing number of resistant bacteria, rapid isolation of pathogens from patients and their identification as well as testing of their antibiotics susceptibility becomes crucial to avoid the use of broad-spectrum antibiotics as well as treatment with inefficient drugs. The gold standard is cultivation of bacteria giving results only after 24 h or longer. A number of spectroscopic investigation show very promising results in giving results on both pathogen species and antibiotic resistance within a few hours. Spectral changes between sensitive and resistant pathogens upon incubation with antibiotics can be detected after a very short incubation time by Raman spectroscopy [166] making this technique a very promising method to detect antibiotic resistance. Using a dielectrophoresis-based system, Enterococci [167] or E. coli [168] could be concentrated on a chip and their susceptibility to vancomycin or ciprofloxacin was determined by Raman spectroscopy within 3 1/2 hours. Also infrared spectroscopy has been shown to have potential in detecting antibiotics resistance of E. coli [169].

Urinary tract pathogens have been shown to be isolated and tested for their antibiotics susceptibility using an immunosorbent ATP-bioluminescence assay on a microfluidic device within 3–6 h [170].

Also, morphological changes that occur under pathogen exposure to antibiotics (reviewed in [171]) can be used to develop fast antibiotics susceptibility test as demonstrated for different pathogens and antimicrobial agents recently [172].

Therapeutic drug monitoring (TDM)

Monitoring the serum concentration of drugs is especially indicated when the therapeutic range of the respective drug is small or when elimination is highly variable between patients. For drugs indicated in the treatment of infections, this mainly applies to aminoglycoside antibiotics [173] and some antifungal agents [174]. Moreover, in critical ill patients, pharmacokinetics (PK) and pharmacodynamics (PD) may be severely altered due to changed plasma protein binding, volume of distribution, acid-base balance or elimination rate caused by kidney or liver failure [175]. Altered PK/PD may lead to overdosage and, thus, adverse drug effects as well as to underdosage leading to reduced treatment efficacy and possible development of pathogen resistances. Nowadays, TDM is well established for certain types of antibiotics like aminoglycosides where immunoassays are used routinely. Chromatographic methods, often coupled to mass spectrometry or tandem mass spectrometry may give more accurate results and can also be used for drugs where no immunoassays are available like \(\beta \)-lactam antibiotics [175]. Though giving precise results and offering the opportunity for simultaneous detection of different pharmacological substances, these methods require more sophisticated and expensive equipment and highly trained personal to perform the analysis which is not available in every hospital [176]. There are a number of newly emerging photonic techniques currently being developed that aim to meet the need for an inexpensive, fast and easy-to-handle test that can be performed at the patients bedside. Roughly, two strategies can be applied for fast therapeutic drug monitoring: the use of in vivo biosensors to detect the drug concentration within the body [177] and point-of-care ex vivo methods utilizing small volumes of body fluids, which can be analyzed with cheap equipment and are easy to handle.

Currently, photonic techniques being developed for ex vivo analysis of drug concentrations mainly include approaches based on surface-enhanced Raman spectroscopy (SERS) [178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190], fiber-enhanced Raman spectroscopy (FERS) [191, 192, 193] surface plasmon resonance (SPR) [194, 195] or bioluminescence and bioluminescence resonance energy transfer (BRET). However, many of them were only shown to work in principle in water or buffer (detection of the concentration of the infusion solution) or for the determination of antibiotic contaminations in food [196]. The application of these techniques to real patient samples may be hampered by the presence of a number of absorbing and competing molecules in the serum and their applicability has certainly to be proven under real clinical measurement settings.

Most innovative assays for therapeutic drug monitoring cover agents used to treat cancer and other severe diseases that require the use of aggressive medication with a narrow therapeutic index. For instance, the cytostaticum methotrexate and several other drug have been shown to be detectable using a bioluminescence resonance energy transfer (BRET) assay with sensor proteins and small sample volumes spread on paper to omit the influence of contaminating biomolecules on the bioluminescence signal [197]. Similar approaches might be developed for testing the serum concentration and the effects of antimicrobial agents in the future. An in vivo approach was reported to monitor the concentration of lithium, a drug used in bipolar disorders with narrow therapeutic range, in real time in mice using photoacoustic imaging [198].

An optofluidic biosensor integrated into a microneedle was demonstrated to detect the antibiotic vancomycin using a replacement of a horseradish peroxidase-coupled vancomycin and TMB as substrate by measuring the absorbance at 635 nm of [199]. Though not yet tested with real patient samples, this system holds the potential, integrated into a portable device, to collect and analyze extremely small samples of interstitial fluid. Recently, a vertical-flow membrane-based system using an inkjet-printed surface enhanced Raman sensor has been described to be able to detect the antifungal drug flucytosine in the presence of serum using a portable spectrometer[178]. The aminoglycoside antibiotic tobramycin could be detected by SERS using functionalized nanoparticles in diluted human serum in doses that might allow detection of this drug in physiological concentrations from patient serum samples [200]. SERS-based approaches combined with lab-on-the chip microfluidic devices (LoC-SERS) require minimal sample volume and have in principle been shown besides the detection of methotrexate [180], to be applicable for quantifying of the fluoroquinolone ciprofloxacin in spiked river water [183] as well as levofloxacin used for treating urinary tract infections in artificial human urine [184]. Nitroxoline possessing antibiotic and antimycotic activity, which due to increasing occurrence of pathogens resistant for classical treatment in the urinary tract is now frequently applied to these infections, in spite of some severe gastrointestinal side effects demanding monitoring of therapeutic concentrations. In spiked urine samples nitroxoline was quantifiable in clinical relevant concentration using Loc-SERS [182]. Also the aminoglycosides kanamycin and moxifloxacin were shown to be detectable from the urine using plasmon resonance light scattering or SERS assays [201, 202] suggesting a use in TDM of these drug using urine samples. Another study suggests that tobramycin can be detected in serum by a localized surface plasmon resonance (SPR) approach [194]. Also the detection of the aminoglycoside amikacin using SPR was developed, however so far only shown within a buffer solution. Since the sensitivity is quite high, the authors suggest that a high dilution of blood samples is possible minimizing adverse effects from the serum [195]. None of these approaches has found its way into clinical routine, yet.

To pave the way for standard clinical applications and to compete with the current clinical methods in TDM, new approaches have to fulfill certain requirements: 1) They should work with real patient samples like body fluids with minimal sample preparation requirements. Alternatively they might work without the requirement of taking samples, i.e., by measuring drug concentrations in vivo by transcutal analysis of signals, however, none of the current approaches is really addressing this possibility. 2) Results should be available fast, i.e., within a few minutes to adjust the dosage of patients in time. 3) To avoid time-consuming sample transport to specialized facilities, small and easy-to-handle systems that can be used at the patient’s bedside are required. 4) The cost for analysis has to be minimized and should not exceed that of the approaches currently in use. 5) Newly developed approaches should offer the possibility for simultaneous detection of different drugs and at best also the rate of free and bound drugs. Future will show, which of the photonic approaches currently under development will find its way into clinical routine, but we expect some photonic developments to find their place in point-of-care monitoring of the concentration of antimicrobial agents from patients samples or in vivo under clinical conditions.

Monitoring the bodies response to the application of drugs, i.e. the eradication of infection using specific biosensors is another promising field that might find its way into clinical routine in the future. So far, an approach to detect the level of the fungal cell wall components \(\beta \)-glucans from serum using an electrochemical signal has been reported [203].

Conclusions and outlook

Photonic technologies are an emerging field for monitoring treatment efficacies in infectious diseases. However, many applications are still restricted to the investigation of animal models since they require to introduce labels which do not have clinical approval, yet. Label-free techniques that utilize intrinsic properties of the investigated material like bacterial autofluorescence or hemoglobin absorbance circumvent the need of clinical approval.

The impact of systemic responses to infections leading to organ failure, sepsis, and septic shock can be monitored by a number of photonic technologies that determine the functionality of organs like the liver or assess hemodynamics of the microcirculation. Using these technologies can help to evaluate treatment strategies for their capacity to treat and prevent sepsis-associated organ dysfunctions.

Though photonic techniques yield an excellent spatial and temporal resolution and a high sensitivity when it comes to imaging diseased areas, techniques which are solely relying on light in the UV, visible or IR spectrum suffer from a low capacity to penetrate tissue which, in general decreases with decreasing wavelength. Therefore, for diagnosis of infection-associated transformations and injuries in deeper layers detecting treatment response technologies that allow deep tissue imaging preferably with the high resolution of optical imaging are required. New emerging photonic techniques like photoacoustic imaging [204] are very promising to meet these requirements: They are currently tried in animal models and will likely find their way in the diagnosis and treatment monitoring of infections leading to a individualized medicine which adopts therapeutic strategies on the individual patients response to certain treatments. For imaging infections, the use of dual optical-nuclear probes might enable to identify the site of infection by PET or SPECT and than use optical techniques for detailed monitoring of surgery or drug response [102, 106].

Notes

Acknowledgements

Financial support by the BMBF via the Integrated Research and Treatment Center “Center for Sepsis Control and Care” (CSCC, FKZ 01EO1502) and via the Forschungscampus InfectoGnostics (FKZ 13GW0096F), the DFG via the research group FOR 1738 “Heme and heme degradation products” and via the Core Facility Jena Biophotonic and Imaging Laboratory (JBIL, FKZ: PO 633/29-1, BA 1601/10-1), as well as the European Union via HemoSpec (FP7-ICT-2013-CN-611682) and the Leibniz Society via the Leibniz ScienceCampus InfectoOptics (SAS-2015-HKI-LWC) is highly acknowledged.

Compliance with ethical standards

Disclosure of conflicts of interest

The authors state no conflict of interest.

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Astrid Tannert
    • 1
    • 2
  • Anuradha Ramoji
    • 1
    • 3
  • Ute Neugebauer
    • 1
    • 2
    • 3
    • 4
    • 5
  • Jürgen Popp
    • 1
    • 2
    • 3
    • 4
    • 5
  1. 1.Leibniz Institute of Photonic TechnologyJenaGermany
  2. 2.Jena Biophotonics and Imaging LaboratoryJenaGermany
  3. 3.Center for Sepsis Control and CareJena University HospitalJenaGermany
  4. 4.Institute of Physical ChemistryFriedrich Schiller University JenaJenaGermany
  5. 5.InfectoGnostics Research Campus JenaJenaGermany

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