REVIEW

Infections in Cancer Patients with Solid Tumors:A Review

Kenneth V. I. Rolston

Received: December 5, 2016 / Published online: February 3, 2017� The Author(s) 2017. This article is published with open access at Springerlink.com

ABSTRACT

Solid tumors are much more common thanhematologic malignancies. Although severe andprolonged neutropenia is uncommon, severalfactors increase the risk of infection in patientswith solid tumors, and the presence of multiplerisk factors in the same patient is not uncom-mon. These include obstruction (most oftencaused by progression of the tumor), disruptionof natural anatomic barriers such as the skinand mucosal surfaces, and treatment-relatedfactors such as chemotherapy, radiation, diag-nostic and/or therapeutic surgical procedures,and the increasing use of medical devices suchas various catheters, stents, and prostheses.Common sites of infection include the skin andskin structures (including surgical site infec-tions), the bloodstream (including infectionsassociated with central venous catheters), thelungs, the hepato-biliary and intestinal tracts,and the urinary tract, and include distinct

clinical syndromes such as post-obstructivepneumonia, obstructive uropathy, and neu-tropenic enterocolitis. The epidemiology ofmost of these infections is changing with resis-tant organisms [MRSA, Pseudomonas aeruginosa,extended spectrum beta-lactamase (ESBL)-pro-ducing organisms] being isolated more oftenthan in the past. Polymicrobial infections nowpredominate when deep tissue sites areinvolved. Conservative management of most ofthese infections (antibiotics, fluid and elec-trolyte replacement, bowel rest when needed) isgenerally effective, with surgical interventionbeing reserved for the drainage of deep absces-ses, or to deal with complications such asintestinal obstruction or hemorrhage. Infectedprostheses often need to be removed. Reactiva-tion of certain viral infections (HBV, HCV, andoccasionally CMV) has become an importantissue, and screening, prevention and treatmentstrategies are being developed. Infection pre-vention, infection control, and antimicrobialstewardship are important strategies in theoverall management of infections in patientswith solid tumors. Occasionally, infectionsmimic solid tumors and cause diagnostic andtherapeutic challenges.

Keywords: Antimicrobial stewardship;Changing epidemiology; Chemotherapy;Infections; Low risk; Obstruction; Radiation;Resistance; Solid tumors; Surgery

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K. V. I. Rolston (&)The Department of Infectious Diseases, InfectionControl and Employee Health, The University ofTexas MD Anderson Cancer Center, Houston, TX,USAe-mail: krolston@mdanderson.org

Infect Dis Ther (2017) 6:69–83

DOI 10.1007/s40121-017-0146-1

INTRODUCTION

The National Cancer Institute has defined solidtumors as non-cystic masses (either benign ormalignant) including carcinomas, lymphomas,and sarcomas. It has been estimated that1,685,210 new cases of cancer will be diagnosedin the United States in 2016, with an estimate ofmore than 14 million new cases worldwide [1].The vast majority will be solid tumors withcancers of the breast, lungs and bronchus,prostate, colon and rectum, and urinary bladderbeing the most common, whereas leukemiaswill account for approximately 4% of new cases.Infections are the most common complicationsseen in cancer patients, and occur as a result ofthe underlying malignancy and of the variousmodalities used for treatment. Despite the factthat solid tumors are far more common, infec-tions in patients with solid tumors have notbeen studied as well as in patients with hema-tologic malignancies [2, 3]. Unlike the latter,most patients with solid tumors are not signifi-cantly immunosuppressed and do not experi-ence prolonged periods of neutropenia. Instead,factors that increase the risk of infection inthese patients include damage to normal ana-tomic barriers, such as the skin and mucosalsurfaces, obstructive phenomena (common inpatients with lung, hepato-biliary, pancreatic,intestinal, prostatic and gynecologic tumors),surgical procedures, chemotherapy, radiation,central nervous system dysfunction, nutritionalfactors, and the increasing use of medical devi-ces (catheters, stents, shunts, and prostheses)[4]. Common sites of infection include the res-piratory tract, the bloodstream (including cen-tral line-associated bloodstream infections), theurinary tract, and skin and skin structures (in-cluding surgical site infections). In recent years,the epidemiology of most of these infectionshas changed with the emergence of resistantorganisms. Consequently, newer therapeuticapproaches need to be developed based on localepidemiologic and susceptibility/resistancedata. Additionally, infection prevention, infec-tion control, and antimicrobial stewardship areimportant and often underrated and neglectedstrategies in this setting [5].

Compliance with Ethics Guidelines

This article is based on previously conductedstudies and does not involve any new studies ofhuman or animal subjects performed by any ofthe authors.

RISK FACTORS FOR INFECTION

As indicated above, several factors increase therisk of infection in solid tumor patients(Table 1). The presence of multiple risk factorsin the same patient is not uncommon, furtherincreasing risk. These factors are discussed indetail below.

Neutropenia

Neutropenia is defined as an absolute neu-trophil count (ANC) of \500 cells/mm3. Themost frequent cause of neutropenia is antineo-plastic chemotherapy. Varying degrees of neu-tropenia also occur after radiation therapy orthe administration of other myelosuppressiveagents (e.g., ganciclovir), and occasionally afterextensive infiltration of the bone marrow byspreading tumor. Unlike patients with hema-tologic malignancies, most patients with solidtumors have normally functioning neutrophils.Additionally, conventional chemotherapyrarely produces severe neutropenia lastinglonger than 7 days. Consequently, the ‘‘at risk’’period is generally short and many solid tumorpatients who develop neutropenic fever areconsidered low risk [6, 7]. Newer treatmentstrategies for low-risk neutropenic patients havebeen developed and include early dischargeafter a short period of hospitalization, or man-agement of the entire episode of neutropenicfever without hospitalization [8–10]. Specificguidelines for the management of febrile neu-tropenic patients with underlying solid tumorshave recently been published [11]. Theseguidelines stress the importance of performingrisk assessment in order to identify low-riskpatients who can be treated in an ambulatorysetting, since hospitalization is associated withseveral drawbacks including iatrogenic errors

70 Infect Dis Ther (2017) 6:69–83

and exposure to healthcare associated, mul-tidrug-resistant microflora. Safety, however, isparamount, and ambulatory/outpatient man-agement should only be implemented if theappropriate infrastructure to support this activ-ity around the clock exists [9, 10].

Disruption of Anatomic Barriers

Normal anatomic barriers such as the skin andvarious mucosal surfaces (oro-pharyngeal, gas-tro-intestinal, respiratory, and genito-urinary)provide an important natural defense mecha-nism against invading pathogens. Cancerchemotherapy often damages mucosal surfaces,thereby increasing the risk of infections causedby organisms that colonize these surfaces [e.g.,viridans group streptococci (VGS), Streptococcuspneumoniae, Stomatococcus mucilaginosus, entericGram-negative bacilli, and anaerobes]. Agentsthat frequently cause mucositis include

5-fluorouracil (5-FC), capecitabine (a pro-drugof 5-FU), cyclophosphamide, ifosfamide, cis-platin and carboplatin. The taxanes (docetaxeland paclitaxel) and vinorelbine have also beenassociated with significant mucositis. Damageto mucosal barriers is also caused by radiationtherapy, surgical procedures, and the use ofmedical devices. Tumors may cause local ero-sion and fistula formation (e.g., broncho-pleu-ral, trachea-esophageal, vesico-vaginal orrecto-vaginal). Protection provided by the skinis also breached by surgical procedures andradiation, and by medical devices such ascatheters and percutaneous endoscopic gas-trostomy (PEG)-tubes [12].

Obstruction of Normal Passages

Obstruction caused by expanding tumors isrelatively common in solid tumor patients.Bronchogenic carcinomas (or metastatic

Table 1 Factors that increase the risk of infection in patients with solid tumors

Risk factor(s)a Additional explanatory comments

Neutropenia Chemotherapy, radiation therapy, bone marrow infiltration with tumor, drugs

(e.g., ganciclovir)

Disruption of anatomic barriers (e.g.,

skin, mucosal surfaces)

Chemotherapy (mucositis), radiation therapy, vascular access catheters, urinary

catheters, percutaneous endoscopic gastrostomy tubes and other medical

devices, surgical/diagnostic procedures

Obstruction due to primary or

metastatic tumor

Airways: post-obstructive pneumonia, lung abscess, empyema, fistula formation

(e.g., broncho-pleural or trachea-esophogeal)

Biliary tract: ascending cholangitis, hepatic and pancreatic abscess

Bowel: bowel obstruction, necrosis, perforation, peritonitis, hemorrhage

Urinary tract: urinary tract infection, renal abscess, prostatitis or prostatic abscess

Procedure and devices Diagnostic/therapeutic surgery: surgical site infections, wound dehiscence, abscess

formation

Shunts: disseminated infection (bacteremia) shunt-related infections such as

meningitis/ventriculitis, hepato-biliary infections, complicated urinary tract

infections

Prosthetic devices: infected prosthesis, osteomyelitis and/or septic arthritis, local

abscess formation, disseminated infection

Miscellaneous factors Age, nutritional status, prior antibiotic exposure, loss of gag reflex

a Multiple risk factors frequently occur in the same patient

Infect Dis Ther (2017) 6:69–83 71

pulmonary lesions) often cause airwaysobstruction leading to the development ofpost-obstructive pneumonia, which may occa-sionally be the initial manifestation of thesetumors [13]. As obstruction increases, lungabscess, fistula formation, or empyema mayoccur [14]. Biliary tract obstruction in patientswith hepato-biliary and pancreatic tumorsresults in ascending cholangitis and hepaticabscess formation. Ureteral obstruction result-ing in hydronephrosis and complicated urinarytract infection is commonplace in patients withcarcinoma of the cervix and other gynecologictumors. Patients with prostatic carcinoma alsodevelop prostatitis, complicated urinary tractinfections, and occasionally prostatic abscesses.Intestinal tumors can lead to partial or completebowel obstruction, ileus, perforation, peritoni-tis, hemorrhage, and/or abdominal/pelvicabscess formation. In these situations, mixed orpolymicrobial infections are the norm, and theetiologic agents are generally those that colo-nize the site of obstruction.

Procedures and Devices

Surgery, medical procedures, radiation therapy,and the widespread and increasing use of cathe-ters and other devices is often associatedwith thedevelopment of infection [15]. The use of mul-tiple-lumenvascular access catheters has becomecommonplace and greatly facilitates the drawingof blood and the administration of various enti-ties such as chemotherapy, antimicrobial agents,blood and blood products, and fluids. The majorcomplication associated with these catheters isinfection. The organisms causing catheter-re-lated infections are predominantly those thatcolonize human skin. Approximately 70–80%are Gram-positive, with Staphylococcus speciesbeing isolated most often. Gram-negativeorganisms and fungi (mostly Candida spp.) aremuch less common, and 5–10% of these infec-tions are polymicrobial. Urinary catheters areused when obstruction or urinary incontinenceis present.Occasionally, local involvementof theureters or urinary bladder may require the cre-ation of surgical diversions into ileal or colonicsegments. Acute or chronic pyelonephritis,

sometimes progressing to bacteremia (urosepsis),may occur. Theuse of nephrostomy tubesmaybeassociatedwith similar complications [16].Manypatients with central nervous system (CNS)tumors require the placement of shunts in orderto relieve intracranial pressure. When infected,the CNS end of these shunts produce symptomssuch as headache, mental status changes, andmeningismus, whereas the distal ends of theseshunts (which are generally located in thepleuralor peritoneal cavities) give rise to symptoms ofpleuritis or peritonitis. Surgically implantedprosthetic devices are used often in patients withosteosarcoma or other bone/cartilage tumors.Infection is the most common complicationassociated with these devices, and may requireremoval of the device for resolution of theinfection. Patients with head and neck and eso-phageal cancers often require the placement ofPEG-tubes in order to ensure adequate nutrition.Insertion site infections, abdominal wall infec-tions/abscesses, perforationwith peritonitis, andoccasionally bacteremic infections may occur,but are uncommon [12].

Miscellaneous Factors

Patients with CNS tumors often develop partialloss of the gag reflex which predisposes them toaspirate oro-pharyngeal secretions. Neurologicabnormalities resulting in impaired micturitioncan also occur. Radiation can damage ciliaryfunction resulting in aspiration and pneumo-nia. In elderly patients, immunologic deficitscaused by ageing, malnutrition, and cancercachexia may also have an impact on the fre-quency and severity of infection and the overallresponse to therapy. Prior or concurrentantimicrobial usage can result in the selectionof resistant organisms. Antimicrobial steward-ship and strict adherence to infection controlrecommendations and policies are importanttools in limiting the emergence and spread ofsuch infections.

COMMON SITES OF INFECTION

Common sites of infection largely depend onthe location and size of the tumor and/or the

72 Infect Dis Ther (2017) 6:69–83

site and nature of the medical device in use, thesurgical procedure performed, and the site andintensity of radiation (Table 2). Surgical siteinfections are among the most common. Recentdata indicate that the epidemiology of theseinfections has changed significantly. WhilstGram-positive organisms still predominate, theproportion caused by methicillin-resistant S.aureus (MRSA) has increased substantially com-pared to 10–15 years ago. Additionally,Gram-negative and polymicrobial surgical siteinfections appear to be increasing [17]. Thesechanges require modifications to current rec-ommendations for infection prevention andtreatment.

Bloodstream infections, including thoseassociated with central venous catheters andother vascular access devices, are among themost common infections seen in solid tumorpatients [18]. The spectrum of these infections

is changing with an increased frequency ofGram-negative bacilli, many of which are mul-tidrug-resistant, being reported [18]. The lungsrepresent one of the most common sites ofinfection in patients with solid tumors [19]. Aspreviously mentioned, aspiration pneumonia iscommon in patients with impaired gag reflexand/or ciliary function, whereas post-obstruc-tive pneumonia is common in patients withprimary or metastatic lung cancers. Infectionsinvolving the hepato-biliary and gastro-intesti-nal tracts also occur frequently and are associ-ated with a common set of manifestationswhich may give rise to diagnostic and thera-peutic challenges [20]. Obstructive uropathyand complicated urinary tract infections gohand in hand and are often recurrent and dif-ficult to eradicate. Specific infections/syn-dromes at these sites will be discussed in greaterdetail below.

Table 2 Common sites of infection in patients with solid tumors

Infection site Comments

Bloodstream Often associated with vascular access catheters and neutropenia. Changing epidemiology, with

resistant Gram-negative organisms emerging

Breast Generally related to breast cancer surgery, including reconstruction and implants. Changing

epidemiology with MRSA and Gram-negative organisms common

Bone, cartilage, joints Often surgery- or prosthetic device-related. May require device removal and/or long-term

suppressive therapy

Central nervous system Including ventriculitis, meningitis, shunt-related infections, and post-surgical infections

Skin and skin structure Most often related to surgery, including invasive diagnostic procedures. May be chronic or

persistent in irradiated areas. Poly-microbial infections are common

Respiratory tract Aspiration pneumonia in patients with loss of gag reflex or ciliary function. Post-obstructive

pneumonia (with empyema or fistula formation with progressive disease)

Hepato-biliary pancreatic Ascending cholangitis (±bacteremia); local abscess formation, reactivation of viral infections

(HBV, HCV, CMV)

Upper gastro-intestinal Tracheo-esophageal fistula; percutaneous endoscopic gastrostomy (PEG)-tube-related infection,

gastric perforation with abscess formation or peritonitis

Lower gastro-intestinal,

pelvic

Bowel perforation with peritonitis or abscess formation, neutropenic enterocolitis, Clostridiumdifficile- or CMV-associated colitis; perirectal/peri-anal infection

Genitourinary tract and

prostate

Complicated urinary tract infections; obstructive uropathy; prostatitis; abdominal and/or pelvic

abscesses

Infect Dis Ther (2017) 6:69–83 73

CURRENT MICROBIOLOGYOF INFECTION

Most infections in patients with solid tumorsare caused by the individual patients’ residentmicroflora. Consequently, the distribution ofcausative organisms mirrors the normal micro-flora at a particular site of infection [4, 21].Acquisition of nosocomial or healthcare-asso-ciated pathogens generally occurs several daysafter hospitalization, although, in recent years,the site of care has shifted to a great extent toclinics and out-patient oncology centers,wherein healthcare-associated infections arealso commonplace. Prolonged or multipleantibiotic exposure, which often occurs in solidtumor patients, leads to the selection of resis-tant organisms. Geographic and local (institu-tional) differences in microbiology andsusceptibility/resistance patterns are not infre-quent and must always be taken into accountwhen choosing empiric treatment regimens.

SPECIFIC SYNDROMES/SITESOF INFECTION

Bloodstream Infections

Bloodstream infections occur predominantly inpatients with indwelling central venous cathe-ters and other vascular access devices as well asin patients with significant oral or intestinalmucositis. Bloodstream infections are morecommon in such patients when they developepisodes of neutropenia. Unlike patients withhematologic malignancies, most patients withsolid tumors do not receive antimicrobial pro-phylaxis following chemotherapy. Such pro-phylaxis is directed primarily againstGram-negative organisms. Consequently, in theabsence of prophylaxis, Gram-negative BSIs aremore common than Gram-positive BSIs inpatients with solid tumors. [18]. Escherichia coli,Klebsiella species, and Pseudomonas aeruginosaare the most common Gram-negative speciesisolated [22]. Non-fermentative Gram-negativebacilli are emerging as significant pathogens atsome institutions. These include Acinetobacter

species, Stenotrophomonas maltophilia, Achro-mobacter species, and non-aeruginosa Pseu-domonas species, many of which aremultidrug-resistant [23]. Staphylococci, strep-tococci, and enterococci are the predominantGram-positive pathogens isolated. At manyinstitutions, more than 90% of coagulase-neg-ative staphylococci (CoNS) and more than 50%of S. aureus are methicillin-resistant, and15–20% of Enterococcus species are van-comycin-resistant. A minority of BSIs are fun-gal, caused almost exclusively by Candidaspecies. Anaerobes are seldom isolated fromblood cultures.

Post-obstructive Pneumonia

Post-obstructive pneumonia is defined as infec-tion of the lung parenchyma caused by bron-chial obstruction [24]. In most cases, theobstruction is caused by a neoplasm, andpost-obstructive pneumonia may be the initialmanifestation of malignancy in 40–50% ofpatients with this diagnosis [13]. Fever, cough,sputum production, and weight loss are com-mon. Leucocytosis is also common unlesschemotherapy-induced myelosuppression ispresent. Other symptoms include dyspnea,pleuritic chest pain, and hemoptysis. Symptomspersist and worsen as the degree of obstructionincreases. Since the infection is located belowthe level of obstruction, respiratory samplesfrom above this level are often negative. Inmany cases, Invasive diagnostic proceduressuch as percutaneous lung aspiration/biopsymay be the most accurate way of determiningthe etiology. Microbiologic data are often diffi-cult to interpret, and generally reveal polymi-crobial flora [25, 26]. These include Streptococcusspecies such as S. pneumoniae, beta-haemolyticstreptococci, and viridans group streptococci;Staphylococcus species including methicillin-re-sistant isolates, Gram-negative bacilli such asthe Enterobacteriaceae and Pseudomonas aerugi-nosa, and some anaerobes. Candida species arealso frequently isolated, but their role in thisinfection is unclear. Most patients are treatedwith broad spectrum antimicrobial regimensdirected against the pathogens outlined above.

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Despite such therapy, responses are often slow,and complete defervescence generally does notoccur, with persistent or recurrent infectionsbeing common. Approximately 10–15% ofpatients with chronic or progressive post-ob-structive pneumonia develop serious complica-tions such as lung abscess, hemorrhage,empyema, and fistula formation (bron-cho-pleural or trachea-esophageal). A viciouscycle often ensues, as these complications fre-quently cause delays in the administration ofantineoplastic therapy, which can lead toworsening of the obstruction. Consequently,full attention should be focused on treating thelesion(s) causing obstruction. Several options toaccomplish this are available including low- orhigh-dose-rate brachytherapy, cryotherapy,laser therapy, electro-cautery, and the place-ment of airways stents [27, 28]. Unfortunately,despite these measures, progressive, ultimatelyfatal, disease is the norm [14].

Infections Associated with Breast CancerSurgery

Breast cancer is the most common cancer inwomen worldwide and its frequency has beenincreasing in recent years [1, 29–31]. Most ofthese patients undergo some surgical procedureof the involved breast along with ipsilaterallymph node dissection. Several forms of breastreconstruction are also frequently performed.These include autologous reconstruction usinga transverse rectus abdominis musculo-cuta-neous flap, or a deep inferior epigastric arteryperforator flap [31]. Prosthetic reconstructionusing silicone or saline implants is also widelyused. Although a detailed discussion of thevarious surgical/reconstruction procedures isbeyond the scope of this review, all these pro-cedures are associated with an infection ratethat ranges between 2.5% and 24% [32, 33].Infection is a leading cause of hospital admis-sion in such patients, and can result in devas-tating medical/surgical, psycho-social, andfinancial consequences. Factors that increasethe risk of infection include increased bodymass index, radiation therapy (which alsoretards healing), axillary lymph node

dissection, the use of surgical drains, adjuvantchemotherapy, and possibly tobacco use[34–37]. Staphylococci (CoNS and S. aureus) areinvolved in almost all such infections, with themajority of isolates being methicillin-resistant.However, several recent studies indicate that asmall but significant proportion of these infec-tions are caused by Gram-negative bacilli suchas E. coli, P. aeruginosa, and Klebsiella species[38–40]. Non-tuberculous mycobacterial andpolymicrobial infections are less common butare difficult to manage [41]. With a significantrate of, and changing epidemiology of, infec-tion in this setting, infection prevention hasbecome extremely important. Antimicrobialprophylaxis is an important infection preven-tion strategy. Breast surgery is considered cleansurgery by the Center for Disease Control andPrevention (CDC) and the Surgical CareImprovement Project, and current guidelinessuggest a maximum of 24 h of peri-operativeantibiotics [42]. Agents commonly used forantimicrobial prophylaxis (predominantly first-and second-generation cephalosporin) werechosen several decades ago and do not provideadequate coverage against organisms (MRSA, P.aeruginosa) mentioned above [39, 43]. Severalinvestigators have recommended alternativeregimens based on local epidemiology and sus-ceptibility/resistance patterns [44–46]. Sincemost of the procedures are elective, some rec-ommend screening patients for MRSA and P.aeruginosa and providing targeted prophylaxiswhen these organisms are detected, or usingagents with activity against these organisms inempiric regimens [47–49].

Hepato-biliary Infection

Obstruction of the biliary tract as a result ofhepato-biliary or pancreatic tumors results inthe development of ascending cholangitis [50].Less frequently, single or multiple liver absces-ses develop, especially in patients with persis-tent obstruction [51]. These are beingdocumented with increasing frequency due toimproved imaging techniques. As with lungneoplasms and post-obstructive pneumonia,ascending cholangitis may be the initial

Infect Dis Ther (2017) 6:69–83 75

manifestation of local neoplastic disease, andmay lead to its discovery during evaluation.Hepatic abscesses have also been reported afterinvasive procedures for hepatocellular carci-noma, such as the administration of intra-arte-rial chemotherapy [52, 53]. Most of theseinfections are polymicrobial, with entericGram-negative bacilli, Enterococcus species (in-cluding VRE), and anaerobes being predomi-nant [54]. Broad spectrum antimicrobialtherapy and percutaneous drainage are oftennecessary in order to achieve adequate respon-ses. Patients with hepatocellular carcinoma andpancreatic head tumors often develop obstruc-tive jaundice, which can progress to hepaticfailure. In this setting, percutaneous transhep-atic biliary drainage (PTBD) has been used totreat obstructive jaundice [55]. More recently,endoscopic biliary stenting (EBS) is replacingPTBD as the treatment of choice in this setting[56]. Several studies have shown that internalbiliary drainage increases microbial coloniza-tion of stents and the formation of sludgewhich also contains intestinal microorganisms[57]. The frequency of cholangitis appears to beincreased in such circumstances [57, 58].

Infections Involving the Intestinal Tract

The intestinal tract is a common site of infec-tion in patients with solid tumors. Severalwell-recognized syndromes have been describedin such patients, including appendicitis,intestinal perforation with peritonitis and/orlocal abscess formation, Clostridium difficile-as-sociated colitis, cytomegalovirus (CMV) colitis,and typhlitis or neutropenic enterocolitis [20].The clinical manifestations associated withmost of these syndromes are similar, andinclude abdominal symptoms (cramping, pain,tenderness, distension), fever, diarrhea, andintestinal hemorrhage. These manifestationsare not typical nor pathognomonic of any sin-gle entity. Therefore, clinical features, radio-graphic imaging findings, microbiologic,serologic, and histopathologic data need to beconsidered in order to make a specific diagnosis.Conservative medical management (fluid and

electrolyte support, bowel rest, broad-spectrumparenteral antibiotic therapy) is generallyeffective. Surgical intervention is usually nee-ded when complications such as intestinal per-foration or bleeding develop.

In years gone by, neutropenic enterocolitis(NEC) was seen primarily in patients with acuteleukemia receiving intensive cytotoxicchemotherapy with agents such as cytosinearabinoside or idarubicin [59–61]. NEC wasdocumented much less often in patients withsolid tumors. Recent reports have highlightedan association between NEC and therapy withtaxanes (docetaxel, paclitaxel) and vinorelbine[62–64]. These agents are often used to treatsolid tumors such as breast, lung, and ovariancancers. Pre-existing bowel abnormalities suchas diverticulosis/diverticulitis, bowel infiltrationwith the underlying tumor, and prior surgery orradiation may also increase the risk of devel-opment of NEC following cytotoxicchemotherapy. The onset of NEC usually occursin the third week of neutropenia (median17 days) and coincides with maximal mucosaldamage. However, there are reports suggestingearlier or later onset, sometimes even after res-olution of neutropenia. In patients with theabdominal symptoms outlined above, imagingstudies are the most reliable and accurate toolsfor making a diagnosis of NEC. Computerizedtomography (CT) is the imaging option ofchoice [65]. The most characteristic CT findingis bowel wall thickening, usually around 7 mm(range 4–15 mm). An important prognosticfinding is the presence of bowel wall thickeningof[10 mm which is associated with severe dis-ease and poorer outcomes [66]. As mentionedpreviously, general supportive measures such asbowel rest with nasogastric suction and par-enteral nutrition if necessary, along with fluidand electrolyte replenishment, are generallyeffective, with surgical intervention beingreserved for more serious complications.

Risk factors associated with C. difficile colo-nization and disease include antibiotic usage,proton-pump inhibitors or H2 blockers, previ-ous hospitalization, and antineoplasticchemotherapy [67]. Up to 6% of patientsreceiving cisplatin therapy for ovarian carci-noma develop C. difficile-associated colitis [68].

76 Infect Dis Ther (2017) 6:69–83

Such therapy should subsequently be avoidedsince relapse or recurrent infection can occur[69]. Recent data suggest that vancomycin issuperior to metronidazole therapy for moderateto severe infection. Fidaxomicin, a new macro-cyclic agent, is similar to vancomycin withregards to clinical response, but produces moresustained responses and fewer relapses [70–72].Fecal microbiota transplantation has beenshown to be efficacious in patients with multi-ple recurrences [73].

CMV disease has not been well studied insolid tumor patients. Although infrequentlyreported, CMV testing is not routinely per-formed in such patients, consequently reacti-vation of CMV or active disease is probablyoften unrecognized and underreported. Oneretrospective analysis reported that at least 50%of patients with solid tumors with a positiveCMV polymerase chain reaction also had clini-cally relevant CMV disease requiring antiviraltherapy [74]. Although gastrointestinal CMVdisease is uncommon in patients with solidtumors, it is associated with high morbidity andmortality [75].

Hepatitis

Hepatitis virus infections (both hepatitis Bvirus, HBV, and hepatitis C virus, HCV) arerelatively common worldwide. Recent estimatessuggest that more than 350 million individualsglobally have HBV infection and 130–170 mil-lion are infected with HCV [76–78]. In oncologysettings, HBV reactivation rates vary between30% and 80% depending on the HBV serologicstatus and the specific chemotherapy regimen[79]. Whilst reactivation can be asymptomatic,it can lead to severe hepatitis, liver failure anddeath [80]. It often leads to delays in antineo-plastic chemotherapy which can result inincreased tumor-related mortality. Patients withsolid tumors who are hepatitis B surface antigen(HBsAg)- or hepatitis B core antibody(HBcAb)-positive are at risk for HBV reactivationafter the administration of cytotoxicchemotherapy. The CDC recommends univer-sal screening of individuals prior to the

administration of cytotoxic chemotherapy orimmunosuppressive therapy [81]. A recent sys-tematic review and meta-analysis of HBV reac-tivation and prophylaxis during chemotherapyfor solid tumors concluded that, in patientswith chronic HBV receiving such chemother-apy, the risk of reactivation was similar to othertypes of immunosuppressive therapy, and thatthere was strong support for HBV screening andantiviral prophylaxis prior to initiating suchtherapy [82]. Other studies/groups have con-firmed these findings [83, 84]. Preferred agentsfor HBV prophylaxis include lamivudine, ente-cavir, and tenofovir. Additionally, monitoringof viral load and hepatic transaminases is rec-ommended for patients who do not have activeHBV infection and are not receiving prophy-laxis [85].

HCV reactivation in cancer patients has notbeen as well studied as HBV reactivation. Theoverall prevalence of HCV infection in cancerpatients ranges from 1.5% to 32% [86, 87].However, very little is known about its naturalhistory, prophylaxis, treatment, and outcomesin this patient population. HCV-positivepatients with cancer have a higher risk ofdeveloping cirrhosis, progress to fibrosis morerapidly, and have poorer virologic responses[88]. Increased mortality has been reported inpatients with cancer who have HCV infectioncompared to those who do not [89]. Addition-ally, increased risk of reactivation has also beenreported in patients receiving targeted therapies[90]. Although treatment and outcomes data incancer patients are limited, in the general pop-ulation HCV therapy can cure infection, pre-vent reactivation, delay progression to cirrhosis,and reduce overall mortality [91, 92]. Guideli-nes recently issued by the National Compre-hensive Cancer Network state that all patientsreceiving chemotherapy or immunosuppressivetherapy should be screened for HCV [85].Although no specific treatment guidelines forcancer patients exist, HCV therapy in this set-ting has been shown to be feasible and to pre-vent or decrease progression of liver disease. Analgorithm for the management of patients withcancer and HCV infection has recently beenpublished [86].

Infect Dis Ther (2017) 6:69–83 77

Obstructive Uropathy/ComplicatedUrinary Tract Infections

Obstructive uropathy is common in patientswith solid tumors [16]. The resultant urinarystasis leads to bacterial colonization and canprogress to the development of complicatedurinary tract infection and urosepsis. Acute orchronic ureteral obstruction (most often uni-lateral but occasionally bilateral) is a complica-tion of advancing retroperitoneal or pelvicmalignancy. Prompt decompression of theobstruction is required. Ureteral stents havebeen used for the management of ureteralobstruction in this setting. Silicone or poly-urethane stents are most often used but may beassociated with significant failure rates. Metallicstents have also been evaluated and are con-sidered to be effective [16, 93–95]. Alternatively,obstructions can be dealt with the placement ofpercutaneous nephrostomy tubes. The use ofstents and nephrostomy tubes is associated witha significant rate of pyelonephritis [16]. Organ-isms causing these infections include Staphylo-coccus species, Enterococcus species, E. coli, P.aeruginosa, S. maltophilia, Klebsiella species, andCandida species [16]. Eradication of such infec-tions is difficult to accomplish and recurrentinfections are the norm. Long-term suppressive

antibiotic therapy may be necessary in patientswho develop frequent bouts of urosepsis.

INFECTIONS MIMICKING CANCER

Occasionally, certain infections produce clinicalmanifestations and/or radiographic images thatcannot be readily distinguished from thoseproduced by neoplasms. When such lesions aredetected, the most common suspicion is that ofmetastatic or recurrent neoplasm, but, in asmall proportion of patients, are caused by aninfection. These lesions also need to be evalu-ated promptly and a specific etiology estab-lished, since the management of recurrentneoplastic disease is totally different from thatof infection.

SUMMARY

Patients with hematologic malignancies oftendevelop infections, especially during episodes ofneutropenia. Since this is a relatively homoge-nous group of patients compared to patientswith solid tumors, it has been well studied.Several societies have developed and publishedguidelines for the management of neutropenicpatients [8, 9, 85, 96]. Infections also represent a

Table 3 Infection-related clinical syndromes commonly seen in patients with solid tumors

Clinical syndrome Comments

Post-obstructive pneumonia Frequent in patients with primary or metastatic lung lesions. Sometimes the initial

manifestation of malignancy. Complications include lung abscess, fistula formation, or

empyema. Treatment failures common

Obstructive uropathy Common in patients with genitourinary and prostatic tumors. Complicated urinary tract

infections and multidrug-resistant organisms are frequent

Reactivation of viral

infections

Hepatitis B virus and hepatitis C virus, usually following chemotherapy or

immunosuppressive therapy. Screening for all patients scheduled to receive chemotherapy is

recommended as is HBV prophylaxis for patients with HBV infection

Clostridium difficileassociated disease

Multiple risk factors (antibiotics, chemotherapy, local anatomical factors). Recurrent

infections/relapses common. Newer therapies (fidaxomicin, fecal microbiota

transplantation) have been developed

Neutropenic enterocolitis Associated with taxanes (docetaxel and paclitaxel), vinorelbine, and other agents producing

severe mucositis

78 Infect Dis Ther (2017) 6:69–83

significant problem in patients with solidtumors and this is a much more heterogenousgroup. These infections are quite different fromthe infections seen in patients with hemato-logic malignancies, especially those with neu-tropenia, and have generally been less wellstudied. Many of these infections are related tothe tumor itself, due mostly to obstruction ordisruption of natural anatomic barriers. Othersare related to various treatment modalities(chemotherapy, radiation, surgery, targetedtherapies). Recent data regarding many aspectsof such infections are scant. This review pro-vides an update and discusses in detail syn-dromes such as NEC, post-obstructivepneumonia, breast cancer surgery-relatedinfections, and reactivation of hepatitis virusinfections, which have either become morecommon or are being newly described/studiedin solid tumor patients (Table 3). The changingepidemiology of infections, with the emergenceof resistant organisms has been highlighted,and the role of infection control in preventingthe spread of such infections, as well as the roleof antimicrobial stewardship in preserving theuseful life of antimicrobial agents, has beenstressed. Very rarely, certain infections maymimic cancer. These conditions need to be dif-ferentiated promptly so that appropriate ther-apy can be delivered.

ACKNOWLEDGEMENTS

No funding or sponsorship was received for thisstudy or publication of this article. All namedauthors meet the International Committee ofMedical Journal Editors (ICMJE) criteria forauthorship for this manuscript, take responsi-bility for the integrity of the work as a whole,and have given final approval for the version tobe published.

Disclosures. Kenneth V. I. Rolston hasnothing to disclose.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not involve any new studies of human

or animal subjects performed by any of theauthors.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

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