Drug-Related Cystitis: An Overview

Abstract

Cystitis is an inflammatory condition of the urinary bladder with infectious or noninfectious aetiologies. Chemical-induced cystitis represents a relatively highly prevalent kind of noninfectious cystitis resulting from therapeutic agents or environmental chemicals. Drug-related cystitis is a type of urotoxicity of drugs, which is a commonly underreported condition leading to impaired quality of patients’ life, discontinuation of medication and non-compliance. Drug-related cystitis can occur in several forms ranging from mild urinary symptoms to gross haematuria, which can be challenging for physicians to treat. Chemotherapeutic drugs, ketamine, tiaprofenic acid and several drugs have been reported to be associated with cystitis until now. Cyclophosphamide (CP) is an alkylating agent that leads to haemorrhagic cystitis with widespread awareness due to its high prevalence in patients under treatment intravenously. However, several currently available drugs have been also reported to induce cystitis, which may be usually ignored. Drug-related cystitis can cause emergency admissions and prolonged hospitalisation, leading to increased medical costs. Some cases of drug-related cystitis are clinically managed with established therapeutic interventions and/or prophylaxis, such as CP-induced haemorrhagic cystitis. On the other hand, standard treatment is currently unavailable for most cases. This chapter will provide current knowledge regarding the drug-related cystitis that should be taken into consideration as a potential adverse effect of drugs by physicians.

1. Introduction

Cystitis is a clinical term that is used to refer to the inflammation of the urinary bladder with various aetiologies related to microbial infection, drugs, environmental chemicals and irradiation [1]. Cystitis may be induced by usage of several drugs, making the patients suffer from urinary symptoms such as dysuria, frequency and urgency in the absence or presence of haematuria [2]. Although the prevalence of drug-related cystitis is quite diverse, alkylating chemotherapeutic agents are the most frequently associated with cystitis [1]. Besides certain drugs with well-described urotoxicity, drug-related cystitis is a commonly underreported condition, resulting in non-compliance, drug discontinuation and prolonged hospitalisation [3]. Chemotherapeutics, ketamine, tiaprofenic acid and several drugs have been reported to cause cystitis until now (Table 1). There is currently no standard to diagnose drug-related cystitis, in which its diagnosis usually relies on cystoscopy and clinical presentation along with the exclusion of other aetiologies such as infection, radiation-induced cystitis and metastasis [1]. There are available approved therapeutic or prophylactic regimens for CP or ifosfamide (IFO)-induced cystitis. However, several cases of drug-related cystitis still lack of standard treatment regimen, leading to a challenge to manage [1, 4]. As a general approach, the discontinuation of suspected drugs and glucocorticoids are used to treat drug-related cystitis [2, 5]. Therefore, clinicians should be aware of drug-related cystitis in patients with urinary discomfort that may be urotoxic side effects of the drugs.

Cyclophoshamide Ifosfamide Ketamine Tiaprofenic acid Penicillins Pencillin G Methicillin Carbenicillin Ticarcillin Piperacillin

Immune checkpoint inhibitors Ipilimumab Atezolizumab Nivolumab Pembrolizumab Sintilimab Bacillus Calmette Guerin

Miscellaneous drugs Busulfan Thiotepa Temozolomide Dacarbazine Doxorubicin Epirubicin Valrubicin Ethoglucid Cisplatin Mitoxantrone Docetaxel Paclitaxel Cabazitaxel Gefitinib Indomethacin

Diclofenac Ketoprofen Naproxen Piroxicam Atorvastatin Empagliflozin Acetylsalicylic acid Dabigatran Allopurinol Danazol Methaqualone Methenamine mandelate

Table 1.

Drugs have been associated with cystitis.

2. Cyclophosphamide and Ifosfamide

Cyclophosphamide (CP) is an alkylating agent that is extensively used for the treatment of lymphomas and solid tumours. Although initially approved for malignancies, CP is now utilised in various autoimmune diseases due to its immunomodulatory effects. CP is a prodrug rapidly metabolised to 4-hydroxycyclophosphamide by hepatic cytochrome P450 (CYP) enzymes in particular CYP2B6 and CYP2C19. 4-hydroxycyclophosphamide coexists with its tautomer, aldophosphamide is cleaved intracellularly to form phosphoramide mustard that is responsible for the cytotoxic effect of CP via cross-linking DNA strands, leading to the inhibition of the proliferation of malignant cells [6, 7].

CP still remains one of the most effective drugs to treat various types of malignancies, however, CP is usually associated with a diverse spectrum of complications including gonadal toxicity, nephrotoxicity, hepatotoxicity, pulmonary toxicity, cardiac toxicity, haematological toxicities, secondary malignancies and urotoxicity, which limits its clinical utility [8]. Haemorrhagic cystitis is a potentially fatal complication of CP, which is manifested by irritative voiding symptoms such as frequency, urgency and dysuria accompanied by microscopic or gross haematuria. The urotoxicity of CP is often dose-dependent and the incidence of haemorrhagic cystitis can vary ranging from 2 to 40%, which depends on total dose, the route of administration and duration of the treatment [9, 10]. In adults, the minimum cumulative oral dose of CP required for cystitis was reported as 100 g [11]. Patients receiving high doses of CP intravenously have been reported to be at the highest risk for the development of haemorrhagic cystitis, which mostly occurs within 48 hours of treatment. Late onset of haemorrhagic cystitis occurs rarely up to a month after the discontinuation of the drug. Concurrent use of other urotoxic chemotherapeutics and radiation therapy may increase the risk of haemorrhagic cystitis [10, 12]. Haemorrhagic cystitis arises from the direct effect of acrolein, which is a prominent urotoxic metabolite of CP on the bladder urothelium, leading to urothelial damage and ulceration. Acrolein is a highly reactive unsaturated aldehyde that is renally excreted into the urine and it accumulates in the bladder, which allows direct contact with the urothelium, consequently, damaging the bladder tissue by interacting with various mechanisms involved in oxidative stress and inflammatory response in the bladder [13, 14].

Ifosfamide (IFO) is an oxazaphosphorine derivative used for the treatment of paediatric, adolescent and young adult patients with a wide variety of malignancies, and it exhibits pharmacological effects via alkylating DNA, thus inhibiting DNA synthesis. Like CP, IFO is a prodrug that undergoes biotransformation mediated by CYP enzyme to yield phosphoramide mustard derivatives as active metabolites responsible for cytotoxic effects. IFO is also metabolised to acrolein, leading to haemorrhagic cystitis in the patients receiving IFO with an incidence rate of 20–40% [15, 16].

The clinical management of CP and IFO-induced haemorrhagic cystitis varies according to the severity of cases, thus therapeutic intervention should be selected depending on an individualised basis. Preventative measures remain the mainstay to reduce the risk of bladder inflammation, including hydration via intravenous or oral route and forced diuresis with furosemide if appreciated. Mild cases can be managed in an outpatient setting with hydration and anticholinergic drugs for lower urinary tract symptoms. Generally, intravenous hydration can provide sufficient treatment in cases without blood clots caused urinary tract obstruction [17, 18]. Sodium 2-mercaptoethane sulfonate (mesna) is an approved pharmacological tool used to prevent CP and IFO-induced haemorrhagic cystitis. Mesna acts as a thiol donor and thereby detoxifies the urotoxic metabolite acrolein, which significantly reduces the incidence of haemorrhagic cystitis induced by CP and IFO. Mesna is preferentially administrated intravenously in divided doses during the chemotherapy. Various protocols of administration for mesna have already been applied in clinical use [19, 20]. For the patients, given standard dose IFO (<2.5 g/m²), a total daily dose of mesna is equal to 60% of the total daily dose of IFO, and mesna is administered as three bolus doses are given 15 minutes before, 4 and 8 hours after administration of each IFO dose. In case of oral administration of mesna, a total daily dose of mesna is the same as the total daily dose of IFO. Oral mesna should not be chosen as an initial dose and it can be applied after an intravenous bolus dose of mesna. [18, 21]. Mesna is especially recommended to use intravenously with forced saline diuresis for the patients given high-dose CP (50 mg/kg or 2 g/m²). Continuous bladder irrigation may also be effective to avoid urinary exposures of the urothelium to acrolein and it is vital for the evacuation of all clots from the bladder in the treatment of intractable haematuria. Intravesical applications of formalin, alum 1% (potassium or ammonium aluminium sulphate), sodium hyaluronate, chondroitin sulphate, prostaglandin, and silver nitrate account for alternative options with varying degrees of efficacy [1, 4, 22]. Although hyperbaric oxygen is mainly preferred for radiation-induced cystitis, it may be effective in CP or IFO-induced haemorrhagic cystitis [1, 23]. Amifostine, dexamethasone, N-acetylcysteine, glutathione, pentosan polysulfate sodium, conjugated estrogens, recombinant factor VIIa and aminocaproic acid have also been shown to be beneficial. Refractory severe cases with failure of pharmacological interventions should require surgical procedures including urinary diversion and cystectomy [4, 24]. Although many therapeutic approaches are currently available, they are not able to completely eliminate haemorrhagic cystitis. Thus, more efforts have been recently made for the discovery of novel options with improved efficacy in the treatment of CP and IFO-induced haemorrhagic cystitis [25, 26, 27, 28].

3. Ketamine

Ketamine is primarily a non-competitive N-methyl-D-aspartate receptor antagonist that has been effectively used as a dissociative anaesthetic in humans and veterinary medicine since 1970 [29]. Ketamine has been also reported to exhibit pleiotropic effects such as sedative, antinociceptive, bronchodilatory, anticancer, antisuicidal, anti-inflammatory and immunomodulatory properties, which provides a wide range of potential therapeutic utility [30]. In recent years, ketamine has gained attention particularly due to its promising antidepressive effects in psychiatric research. In 2019, the S-enantiomer of ketamine in the form of an intranasal spray has recently been approved by the U.S. Food and Drug Administration (FDA) for the treatment of treatment-resistant depression [30, 31]. Apart from its therapeutic benefits, ketamine was reported to be one of the most frequently abused recreational drugs because of visual and auditory hallucinatory effects among drug addicts with its favourable properties such as rapid onset, short duration of action and low market price. Ketamine abuse is being dramatically increased worldwide, making its severe harms to individuals and society [30, 32].

Ketamine is chemically a phenylpiperidine derivate that possesses high lipophilicity, a plasma half-life of 2–4 h, relatively low protein binding and oral bioavailability. It can be applied via multiple routes including oral, intravenous, intramuscular, transdermal, subcutaneous, transdermal, intranasal, rectal and inhalation routes. However, abusers predominantly use ketamine intranasally because of the rapid onset of action and ease of administration. Ketamine is heavily metabolised by the hepatic CYP enzymes to produce an active metabolite called norketamine. Unchanged ketamine and its metabolites are excreted via urine [29, 30].

Chronic ketamine use or abuse has been reported to induce ulcerative cystitis with a broad spectrum of clinical symptoms ranging from polyuria, decreased bladder capacity, urgency, dysuria, nocturia, urinary incontinence and suprapubic pain to gross haematuria. Common histopathological features include the denudation of the urothelium, thickened bladder wall, lamina propria fibrosis and inflammation [33, 34]. The first case of ketamine-induced cystitis was described as an abuser in 2007, and approximately 30% of ketamine abusers have been reported to suffer from urinary problems. The severity of ketamine-associated lower urinary tract symptoms is significantly related to both the duration and the dosage of ketamine [1, 35]. Urological side effects of ketamine can develop when 2 g or more of ketamine is administered at least three times a week for 1 year. Therefore, therapeutic use of ketamine for anaesthesia at low doses (0.5–2 mg/kg) is considered to have no potential risk for cystitis. Urinary symptoms generally resolve after the discontinuation of ketamine, but in limited cases, they may last for up to 1 year after the cessation [36, 37, 38].

The pathogenesis of ketamine-induced cystitis is complicated and involves various mechanisms underlying the urothelial disruption, apoptosis, inflammation and fibrosis in the lamina propria; however, the precise mechanism remains largely unknown. The direct toxic effects of ketamine and norketamine on urothelium have been suggested to contribute to bladder damage [34]. There is currently no approved specific treatment for ketamine-induced cystitis. Currently, the cessation of ketamine is the only effective treatment and urinary symptoms can be improved by some symptomatic approaches including anticholinergic drugs, corticosteroids, intravesical injections of hyaluronic acid and botulinum toxin type A in the management of ketamine-induced cystitis [39].

4. Tiaprofenic acid

Tiaprofenic acid is a nonsteroidal anti-inflammatory drug (NSAID) with high potency as a cyclooxygenase inhibitor, which has been globally marketed for the treatment of rheumatic diseases and musculoskeletal disorders [40]. Tiaprofenic acid is rapidly and almost completely absorbed when orally administered. It has a high affinity for plasma proteins and a relatively short half-life (3 to 6 h). After extensively glucuronidated, nearly 60% of tiaprofenic acid is excreted via urine as glucuronide-conjugated metabolites [41].

Tiaprofenic acid-induced cystitis is well-documented and several cases have been published. Tiaprofenic acid was reported to cause usually late onset of urinary tract symptoms manifested by frequency, dysuria, urgency, suprapubic pain, haematuria and urinary incontinence with inflamed oedematous lamina propria as the main histological feature. According to case studies, urinary symptoms are observed to occur in 2 weeks and more than 2 years after the tiaprofenic acid has been started [42, 43, 44]. The aetiology is unclear; however, it can result from the direct toxic effect of tiaprofenic acid on the urothelium and a delayed hypersensitive immune response accompanied by the late onset of the symptoms [3]. It is recommended to stop tiaprofenic acid if urinary tract symptoms develop, which is able to resolve mild cases. More severe cases may require intravesical steroid instillation and surgical interventions such as cystoplasty and urinary diversion. Although the symptoms gradually improve within 6–14 weeks after the withdrawal of tiaprofenic acid, about 10% of cases can have residual symptoms due to persistent changes leading to bladder fibrosis. Tiaprofenic acid use should be avoided in patients with any history of urinary tract disorders [43, 44].

5. Mitomycin C

Mitomycin C is an alkylating chemotherapeutic drug that causes DNA damage by cross-linking DNA strands, thus inhibiting replication and transcription. Mitomycin C is indicated for various solid tumours including breast, gastric, bladder, pancreatic and non-small cell lung cancer [45]. Intravesical mitomycin C instillation is a standard care for non-muscle-invasive bladder cancer, which is highly effective in reducing the recurrence rate of superficial bladder cancer by up to 40%. It is recommended by the American Urological Association and European Association of Urology guidelines that mitomycin C should be applied intravesically at a dose of 40 mg following transurethral resection of bladder tumour [46, 47]. A common complication of intravesical mitomycin C is eosinophilic cystitis that is a rare form of allergic cystitis characterised by diffuse eosinophilic infiltration of lamina propria and muscularis with a spectrum of clinical presentations including dysuria, pelvic pain, haematuria, urinary urgency and urges incontinence [48, 49].

No approved treatment for mitomycin C-induced cystitis is currently available. It usually resolves spontaneously upon withdrawal of mitomycin C. Anticholinergics, antihistamines and alpha blockers can be used for 1–2 weeks in mild cases. If symptoms persist, prednisone (60 mg/day) should be prescribed for 2–4 weeks. Intravesical dimethyl sulfoxide and steroid injection can be applied when the symptoms do not completely improve or still persist due to initial treatments [49].

6. Penicillins

Penicillin is a pharmacological group of beta-lactam antibiotics that are widely used for various infectious diseases with favourable efficacy and safety profile. Penicillins are known to cause many kinds of side effects, however, haemorrhagic cystitis occurs on rare occasions [50].

Penicillin-induced cystitis is associated with deliberating urinary tract symptoms such as pyuria, dysuria, haematuria and frequency, along with predominantly eosinophilic infiltration of bladder. Penicillin G, methicillin, carbenicillin, ticarcillin and piperacillin have been implicated in the development of haemorrhagic cystitis. Urinary symptoms usually occur within 2 weeks after starting penicillin and disappear in few days following the withdrawal of penicillins. The exact mechanism of penicillin-induced cystitis still remains unclear, but it has been suggested that both an immunological mechanism resulting from penicillin-induced immune reaction and direct toxic effect of penicillins or metabolites are involved in bladder damage [4, 50, 51].

7. Immune checkpoint inhibitors

Immune checkpoint inhibitors (ICIs) have made a remarkable advance in the immunotherapy-based treatment of metastatic cancers since 2011 and they are being used increasingly worldwide [52]. ICIs are therapeutic humanised monoclonal antibodies that block receptors and ligands including cytotoxic T lymphocyte antigen-4, programmed death receptor-1 and programmed death ligand-1 involved in the inhibitory signals of T cells, thus allowing for robust activation of immune system and improved antitumor immune response. To date, seven ICIs have been approved for use in humans by FDA in the USA and several clinical trials are currently in progress [52, 53].

Despite that ICIs have provided considerable benefits for cancer patients, they are associated with diverse toxicities named immune-related adverse events (irAEs) resulting from the nonspecific overactivation of the immune system. irAEs represent a broad spectrum of dermatological, gastrointestinal and endocrine side effects and other organ system toxicities ranging from mild to life-threatening, which became a serious challenge for patients with the widespread use of ICIs [54]. Recently, few cases have described that ICIs including ipilimumab, atezolizumab, nivolumab, pembrolizumab and sintilimab are related to immune-related cystitis as an irAE [55, 56, 57, 58]. ICIs-induced cystitis is generally manifested by irritative voiding symptoms and histological features of diffuse redness of bladder mucosa. Immune-related cystitis by ICIs can occur within 6 weeks but can also arise several years after the starting treatment [59]. Emerging evidence indicates that drug withdrawal and treatment with methylprednisolone or prednisolone are effective in the treatment of most cases, but infliximab can be used for steroid-refractory cases of immune-related cystitis [55]. Despite high efficacy of glucocorticoids, there are concerns about the use of glucocorticoids particularly as they are likely to affect negatively the therapeutic outcomes of ICIs due to immunosuppressive effects. Thus, unnecessary use of glucocorticoids should be avoided [58].

ICIs are associated with diverse irAEs of any grade that can develop in up to 30–60% of the patients of which 10–20% consist of severe cases. Among irAEs, immune-related cystitis is considered to be a rare complication of ICIs, therefore, the patients who are being treated with ICIs should be carefully monitored in order to detect early signs and recognise immune-related cystitis [53, 59].

8. Bacillus Calmette Guerin

Bacillus Calmette Guerin (BCG) is an attenuated strain of Mycobacterium bovis, which is primarily used for tuberculosis prevention as a vaccine. Intravesical instillation of BCG is the most effective therapy currently available for superficial bladder carcinoma after transurethral bladder cancer resection [60].

Intravesical BCG is commonly associated with various local and systemic complications ranging from mild to severe. BCG-related cystitis is the most frequent local complication occurring in up to 35% of patients and it is characterised by urination frequency, dysuria, bladder pain, transient haematuria with diffuse thickening of the bladder wall and oedematous mucosa [61, 62]. Cystitis induced by BCG has been shown to occur as a result of chemical or bacterial aetiology. Intravesical instillation of BCG leads to break down glycosaminoglycans layer that covers the urothelium of the bladder, which is the responsible for the initial step in the chemical pathological mechanism of BCG-related cystitis. Urinary symptoms usually develop within a few hours following BCG and generally resolve within 48 hours, demonstrating a hypersensitivity reaction to BCG antigens in the pathogenesis of BCG-related cystitis [1, 61, 62]. Bacterial cystitis due to M. bovis may occur and persist long-term after intravesical BCG administration. Antimycobacterial agents, glucocorticoids and hyperbaric oxygen are useful to improve BCG-related cystitis, in addition, NSAIDs and anticholinergic agents may be proposed to alleviate the symptoms of BCG-related cystitis [63, 64, 65].

9. Miscellaneous drugs

CP and IFO are alkylating agents that are well-known to be causative drugs for haemorrhagic cystitis. It has been demonstrated that other alkylating agents such as busulfan, thiotepa, temozolomide and dacarbazine can also potentially induce cystitis that could be clinically managed with the discontinuation of the drug and continuous bladder irrigation [66, 67, 68, 69]. Chemotherapeutic agents are also employed for intravesical therapy to treat bladder cancer due to its lower risk potential for recurrence and adverse effects. Intravesical administration of doxorubicin, epirubicin, valrubicin, ethoglucid, cisplatin and mitoxantrone has been reported to cause bladder damage [2, 70]. Especially, gross haematuria can occur in 20% of patients when doxorubicin is combined with mitomycin C, leading to discontinuation of the therapy [71]. On rare occasions, taxanes are also associated with haemorrhagic cystitis. Cabazitaxel, docetaxel, solvent-based and albumin-bound paclitaxel have been reported to induce haemorrhagic cystitis that resolved after the drug withdrawal or bladder irrigation [72, 73, 74]. The patients treated with cabazitaxel were previously exposed to pelvic radiation in most cases of cystitis, suggesting that radiation recall syndrome induced by cabazitaxel may be implicated in cabazitaxel-related cystitis [74]. However, cabazitaxel-related haemorrhagic cystitis was even seen in a patient without a history of radiation therapy [75]. Gefitinib is an oral epidermal growth factor receptor tyrosine kinase (EGFR) inhibitor that has been widely used as a first-line treatment of advanced non-small cell lung cancer with proven efficacy after standard chemotherapy [76]. Gefitinib-related cystitis has been rarely reported and the precise mechanism is yet to be defined. But it was speculated that the EGFR signalling pathway affected by gefitinib could mediate the alterations in the bladder [77].

NSAIDs are one of the most widely used drugs to treat a broad range of diseases due to their antipyretic, analgesic and anti-inflammatory properties. Despite being commonly available without a prescription, NSAIDs have potential safety concerns because of numerous adverse effects in long-term use. Tiaprofenic acid seems to have a higher risk of cystitis, however, other NSAIDs like indomethacin, diclofenac, ketoprofen, naproxen and piroxicam have been reported to be associated with cystitis [3, 78].

Statins are the inhibitors of the hydroxymethylglutaryl-CoA reductase enzyme that catalyses the crucial step of cholesterol biosynthesis and they are highly effective drugs in hyperlipidaemia. Statin use was found to be significantly associated with interstitial cystitis [79]. Moreover, haemorrhagic cystitis was reported in a patient receiving atorvastatin in the 2nd week of the treatment and haematuria disappeared within 1 week after the withdrawal of atorvastatin [80]. The mechanisms of statin-related cystitis are largely unclarified; however, statins have been shown to induce chronic inflammation in the urothelium [79].

Emphysematous cystitis is a relatively rare form of complicated urinary tract infection commonly seen in elderly females with diabetes, which is characterised by gas within the bladder wall and lumen due to gas-producing bacteria [81]. It has been reported that sodium-glucose cotransporter-2 inhibitors such as empagliflozin may increase the risk for emphysematous cystitis in diabetic patients [82].

Acetylsalicylic acid and dabigatran have been related to haemorrhagic cystitis with unknown aetiology [83, 84]. In addition, it should be noticed that anticoagulants and antiplatelet drugs can exacerbate bleeding in the patients’ receiving drugs that induce haemorrhagic cystitis [85].

Other drugs have been associated with cystitis include allopurinol, danazol, methaqualone, methenamine mandelate, tacrolimus and tranilast [86, 87, 88, 89, 90].

10. Conclusions

Cystitis is considered to be unusual for being a side effect of drugs, except with some chemotherapeutics. Therefore, drug-related cystitis is likely to be a less recognised and underestimated condition that leads to impaired quality of patients’ life, discontinuation of medication and non-compliance. To date, several drugs have been reported to induce cystitis. Although CP or IFO-induced cystitis can be treated with well-established pharmacological approaches, there is no currently approved treatment for another drugs-related cystitis. However, discontinuation of suspected drugs and glucocorticoids have been proven to be effective in most cases. Infliximab may also be indicated for steroid-resistant cystitis. Moreover, surgical interventions should be employed in severe cases. Patients taking drugs who suffer from urinary problems should be advised to seek prompt medical attention. Physicians should be also aware of the potential association between drug use and cystitis in patients with clinical presentation of cystitis.