Antibiotics in Urology: New Essentials

The need for antibiotics in urology practice

As is true with almost all medical domains, antibioticsare essential therapeutic tools in the armamentariumof urologists; with application in both out-patient andin-hospital care. This is because urinary tract infections(UTIs) are among the most frequently acquiredinfections in both these settings.^1-3    In communitycare set-up, recurrent UTIs are particularly common,especially in women, and warrant strategies for bothprophylaxis and treatment. Accordingly, identificationand elimination of risk factors, which increase therisk of acquiring recurrent urinary infections remainsan important preventive strategy in current clinicalpractice. Often physicians and patients employ nonpharmacologicaloptions for this latter need; butoutcomes are usually not sufficient since many nonantibioticprevention strategies, such as cranberry,vitamin C and methenamine salts, lack strong evidenceto be introduced as routine management options. Thesestrategies frequently fail as an alternative to antibiotics;ultimately making individualized use of antibiotics themost effective method for management of UTIs.¹   Inall, a multimodal approach that focuses on accuratediagnosis and appropriate antibiotic treatment is thusrequired for prevention and treatment of symptomaticUTIs;⁴   and this is applicable to both community andnosocomial settings, where patients are per se proneto develop infections from a myriad of sources.

Classification of UTIs: The first step in UTIs management

Classification of UTIs is generally the first step inmanagement protocol of UTIs. Traditionally, UTIscan be classified by the site of infection (anatomicalclassification, Figure 1), and also based on clinicalsymptoms focusing on these anatomical level (Table 1).Another clinical classification system that is supposedto be an important working instrument to aid targetedtherapeutic decisions is based on the severity of theinfection. It is seen that patients with infections ofthe urinary tract can present with varying levels ofseverity and an exceptionally broad range of clinicalsyndromes, as benign, uncomplicated cystitis to severe,life-threatening urosepsis. Accordingly, UTIs above all can practically be based on the concept of two maincategories, i.e., uncomplicated and complicated UTI(Figure 2).^5,6,7

UTIs as major indications of global antibiotics use

In most countries, about 20% of antibiotics are usedin hospitals and other healthcare facilities, and 80%are used in the community. This demand and usageof antibiotics in humans continues to rise across theglobe, and a significant proportion of this could beattributable to the increases seen in low- and middleincomecountries. The pattern is concerning for Indiaas well, seeing the report from ‘Center for Disease Dynamics, Economics and Policy’ on ‘The State of TheWorld’s Antibiotics’, which shows India as one of thetop global consumers of antibiotics.⁸

UTIs seem to have their significant portion in thisevent, as they are amongst the most frequent bacterialinfections, and therefore responsible for a great amountof antibiotic administration,^1,9    which varies dependenton the type of UTI and antibiotic susceptibility of thecausative pathogens.¹⁰   In fact, the epidemiology clearlyshows the non-reduction of anti-infectious treatmentsuse even in developed nations; with urology beingno exception to this observation.¹¹   The observation,in addition, underlies the urgent need to improveprescription of anti-infectious treatments particularly inurology. In response to this, it is often advocated that inuncomplicated cystitis, antibiotics exclusively reservedfor this indication, such as fosfomycin trometamol,nitrofurantoin and pivmecillinam, should be preferred,in order to reduce antibiotic pressure in this extremelyfrequent entity;¹²    whereas in complicated UTI, a broadbacterial spectrum has to be considered.¹³

Pre-disposing factors for UTIs

In general, it is seen that UTIs are more commonamong women than men, although this differencediminishes with the age and the prevalence is generallysimilar in elderly men and women.¹   In younger women,predominant UTI risk factors are sexual intercourse andthe use of spermicidal contraceptives; though there areseveral other important risk determinants in selectedage groups. These include anatomic and physiologicfactors, such as obstructing lesions and estrogen deficiency; genetic factors, such as blood groupsecretor status; antibiotic exposure; and functionalstatus of the individual.¹⁴   In men, the antisepticproperties of the prostate secretions might be animportant factor to confer some prevention againstrecurrency.¹⁵   Nevertheless, prostate enlargement andurological interventions, such as transrectal prostatebiopsy are per se significant risk factors for UTIsin this gender (men); possibly negating in varyingproportions any favorable gender bias. In fact, ensuinginfections after prostate biopsy are rising due toincreasing rates of the fluoroquinolone resistance,overall significantly affecting the management of UTIin men. In recent years, an increase in febrile infectionrates after transrectal prostate biopsy (from 1% to 4%)has been reported, a major risk determinant for whichseems to be the presence of fluoroquinolone-resistantbacteria.¹⁶

Antibiotics available for UTIs

A large number of antibiotics are available for usein patients with UTIs, which work through differentmechanisms: those that act on the bacterial DNA; thosethat inhibit protein synthesis; and those that inhibitpeptidoglycan synthesis. Regardless, all antibioticsbasically require getting into the bacterial cell to affect the pathogen.¹⁷

Antibiotics acting on the DNA

Fluoroquinolones act directly on the bacterial DNA toimpact proliferation of the latter. The target structuresin the bacterial cell are bacterial topoisomerases II and IV, which introduce negative ‘‘supercoils’’ into DNA andachieve a higher order by coiling.¹⁷   Four molecules ofthe quinolone substance combine to form a ternarycomplex together with topoisomerases and DNA,eventually causing breakage of the DNA doublestrand.Fluoroquinolones were recommended as drugsof choice for the empirical treatment of uncomplicatedand complicated UTIs caused by trimethoprimsulfamethoxazole-resistant uropathogens. However,because of their increased use for several other kindsof infections, increasing rates of resistance amongthe most common uropathogens have challengedthis recommendation, especially in the Asia-Pacificregion.¹⁸   Experts are hence concerned about thisoveruse of fluoroquinolones, which has led to increasedprevalence of fluoroquinolone-resistant pathogens,and a propensity for collateral damage with theseantimicrobials. The 2011 Infectious Diseases Society ofAmerica (IDSA) guidelines on the treatment of UTIs infact discourage the use of fluoroquinolones for acute,uncomplicated UTIs.¹⁹

Sulfonamides, such as sulfamethoxazole, lead tothe formation of ineffective forms of tetrahydrofolate(dihydropteroic acid) from para-aminobenzoicacid (PABA) and pteridine by substituting PABA.Physiologically, this tetrahydrofolate is furthercatalyzed to dihydrofolic acid (folate) that is furthercatalyzed into tetrahydrofolic acid by dihydrofolatereductase.Pyrimethamines, such as trimethoprim,exhibit competitive inhibition of the bacterialdihydrofolatereductase, inhibiting the purinesynthesis.17 Trimethoprim-sulfamethoxazole (TMPSMX)was one of the preferred antibiotics for thetreatment of UTIs for many years. However, rising ratesof resistance among uropathogens has discouraged itsuse in many communities.¹⁹

Antibiotics that inhibit protein synthesis

Aminoglycosides act by irreversibly binding to thedistinct parts of the 30S and 50S subunits of thebacterial ribosomes. Consequently, the amino acidtranslocation is inhibited by preventing the bindingof elongation factor G; inhibiting the elongationstage in bacterial translation. Aminoglycosides havebroad spectrum of activity and are given by injectionfor very serious bacterial infections.²⁰   They are oftenused in combination with other antibiotics for broadspectrumcoverage. Gentamicin is the most commonlyused aminoglycoside for severe UTIs.²¹   Nevertheless,aminoglycosides can have very serious side effects, including damage to hearing, sense of balance, andkidneys.²²

Antibiotics that inhibit peptidoglycan synthesis

Beta-Lactam antibiotics inhibit the last stage ofpeptidoglycan synthesis. They bind to penicillinbindingproteins (PBP), which act as enzymes(e.g., transpeptidases, carboxypeptidases, andendopeptidases) in the formation and preservationof parts of the bacterial cell wall. Penicillins inhibit theprocess of cross-linking of the long polysaccharidechains by short polypeptides; and lead to weakeningof the peptidoglycan wall. The glycopeptide antibioticsinhibit the process of transglycosilation of thepeptidoglycan wall.¹⁷

β-Lactam agents are usually considered for UTIswhen other recommended agents cannot be used.They generally have inferior efficacy and more adverseeffects, compared with other UTI antimicrobials,and therefore should be used with caution foruncomplicated cystitis.¹²   It has been observed thatthe resistance of E. coli to ampicillin and amoxicillinranges between 20-40%; therefore, these agents areno longer considered optimal for treatment of UTIsin many patients.²³   Amoxicillin-clavulanate is alsonot very effective for the treatment of UTIs, even inpatients infected with susceptible strains.²⁴   The IDSAguidelines also suggest that amoxicillin or ampicillinshould not be used for empirical treatment given therelatively poor efficacy and the very high prevalence ofantimicrobial resistance to these agents worldwide. ¹²   Pivmecillinam is an appropriate choice for therapy, butits availability is an issue, since the drug is availablein some European countries only. Furthermore, it mayhave inferior efficacy compared with other availabletherapies.

Fosfomycin inhibits cell wall synthesis otherthan b-lactam antibiotics.¹⁷   It acts as an analog ofphosphoenolpyruvate and forms a covalent bond withthe active site cysteine residue (Cys 115) of UDP-Nacetylglucosamineenolpyruvyltransferase (Mur A), akey enzyme of the peptidoglycan synthesis process.Fosfomycin is also seen as an appropriate choice fortherapy where it is available, due to low resistance,but appears to have inferior efficacy compared withstandard short-course regimens.¹²   Furthermore,because testing is not routinely performed in manyclinical laboratories, susceptibility data for fosfomycinare also not uniformly available.

Nitrofurantoin: unusual among antibacterials

Nitrofurantoin can be considered unusual amongantibacterials in having multiple sites of attack andmultiple mechanisms of action that possibly conferlack of clinically significant bacterial resistancedevelopment.²⁵   The drug is reduced by bacterialflavoproteins to reactive intermediates, whichinactivate or alter bacterial ribosomal proteins andother macromolecules.²⁶   Because of such inactivations,protein synthesis, aerobic energy metabolism, DNA synthesis, RNA synthesis, and cell wall synthesis areinhibited. A mechanism of action which does notrequire the production of reactive nitrofuran to inmetabolites by bacterial reductases has also beendemonstrated for nitrofurantoin.²⁵   IDSA guidelines recommend nitrofurantoin as an appropriate choice forUTI therapy due to minimal resistance and propensityfor collateral damage. This advocacy is based oncurrent randomized clinical trial data that providestrong support for consideration of nitrofurantoin as an effective agent for treatment of acute cystitis.¹²

The rising concern of antibiotic resistance in uropathogens

Recent epidemiological data clearly confirms that antimicrobial resistance is an increasing problem not only for the hospitalized, healthcare-associated patients, but also for out-patients. Also, the pattern is not limited to particular geographic region, but affects both developed and developing countries, including India.^27,28     In fact, the problem has been identified by the World Health Organization (WHO) as “one of the greatest threats to human health.” The rates of development of bacterial resistance may however vary in different countries.²⁹   In this regard, evidence suggests that rate of bacterial resistance is higher in developing countries compared to the international standards.³⁰

This antibiotic resistance has major implications for urological practice; with rising in bacteria causing UTIs to commonly prescribed antibiotics is increasing both in developing and developed countries. The prevalence of Enterobacteriaceae that produce extendedspectrum β-lactamase (ESBL) or carbapenemase enzymes continues to increase at alarming rates worldwide. Likewise, resistance to other antimicrobial agents including aminoglycosides, sulphonamides and fluoroquinolones is also escalating at rapid rates.³¹   In all, a progressive increase in resistance to broad-spectrum antibiotics, such as 3rd-generation cephalosporins, carbapenems or fluoroquinolones in Enterobacteriaceae, is an alarming situation for the urologists;³²   it has had detrimental consequences not only for treatment but also for prophylaxis of infectious complications after urological interventions.¹   The healthcare impact could be majorly related to an emergence of multidrug resistant (MDR) bacteria in urological practice, which seems to especially contribute to increased infectious morbidity, thereby increasing the financial costs to healthcare system, and making antibiotic resistance an alarming public health concern in urological practice.³³   Responding to these challenges of antibiotic resistance warrant a multifaceted approach, including considered use of current antimicrobial agents, better adherence to basic measures of infection prevention, and research into enhanced therapeutic strategies. Possibly this is the reason why investigators propose that patients at risk of fluoroquinolone resistance should receive carefully selected antibiotics at sufficient concentrations in order to be effective. Box 1 depicts the various mechanisms of antibiotic resistance in uropathogens.¹⁷

Nitrofurantoin: An important antibiotic in current urologic armamentarium

Given that antibiotics classically used for the treatment of uncomplicated UTIs, such as cotrimoxazole, fluoroquinolones, and aminopenicillins, lose their effectiveness because of increasing resistance, there is an urgent need for administration of alternative antibiotics. Besides, use of fluoroquinolones may even cause some serious adverse events (Box 2).³⁴   Ideal substances in such instances are those with low resistance rates used exclusively for this indication.^12,17

Nitrofurantoin is one of such antibiotics well filling the therapeutic gap here owing to its demonstration of efficacy with minimal drug resistance; this makes it an attractive option for uncomplicated UTIs (Figure 3).¹²   This favored acceptance is based on susceptibility data showing trends in favor of the nitrofurantoin. For instance, in a study evaluating antibiotic susceptibility patterns of the most frequently isolated uropathogens from UTI patients attending a tertiary care center in South India, Gram-negative pathogens in both inpatients and outpatients departments showed least resistance to nitrofurantoin (Table 2).³⁵      Indian studies from some other regions have also noted resistance levels of urinary E. coli isolates to be least with nitrofurantoin.^36-38   As follows, nitrofurantoin might be considered the best choice for uncomplicated UTIs, due to its low frequency of use and its high susceptibility rate in common UTI pathogens.³⁹   Nevertheless, the consideration still necessitates judicious use of antibiotics to curb the menace of antibiotic resistance.

Treatment of complicated and upper UTIs

Treatment of complicated and upper UTIs has become increasingly complex due to the rising prevalence of MDR Gram-negative bacteria. Therefore, considering the local resistance patterns, while selecting an antimicrobial therapy, remains a universal needful strategy, particularly for E. coli since this microbe is responsible for considerable number of pyelonephritis cases. Several treatment options, including ceftolozane + tazobactam, ceftazidime + avibactam, ciprofloxacin, fosfomycin, levofloxacin, TMP-SMZ, and nitrofurantoin, are available for the treatment of complicated and upper UTIs (pyelonephritis),⁴⁰   which may be selected and tailored based on the clinical profile of the patient, disease course, and the antibiogram. Often, these patients with upper UTIs may require in-patient management.⁴¹   Moreover, the duration of therapy is typically higher than individuals with lower tract symptoms, and may range from 10 to 14 days.⁴²

New therapeutic strategies

The increasing prevalence of antibiotic-resistant uropathogens is likely to limit the effectiveness of current antibiotic arsenal, highlighting the need for a better understanding of these infections and development of new therapeutic strategies.^43,44     This search for antibiotics is driven by new information on potential therapeutic targets; including ability of bacteria to attach to and invade the bladder mucosa, and to form biofilms. Many emerging treatments are aimed at blocking adhesion of bacteria to the urothelium, and thereby preventing the establishment of troublesome intracellular reservoirs. For instance, type 1 pili (or fimbriae), which are multiprotein filamentous adhesive structures encoded by virtually all uropathogenic E. coli, are generally indispensible for colonization of the urinary tract, and promote development of intracellular bacterial communities. Accordingly, as type 1 pili are important colonization factors, the therapeutic potential of inhibiting the assembly or function of these adhesive organelles has received considerable attention, paving way for ongoing efforts at development of new antimicrobial approaches, such as use of pilicides and mannosides. Type 1 pili also promote biofilm formation, which is an important factor for persistence infections, causing relapses. Therefore, several new therapeutic approaches, with inherent intent to inhibit bacterial virulence and biofilm formation, are being evaluated; such as catheters coated with hydrogels or antibiotics, nanoparticles, iontophoresis, biofilm enzyme inhibitors, liposomes, bacteriophages, quorum sensing inhibitors, and low-energy surface acoustic waves.⁴⁵   Additionally, attempts are on to identify new vaccine candidates for individuals who suffer from recurrent or chronic UTIs.

Conclusion

Urinary tract infections are amongst the most frequently encountered infections in both community and hospital settings. The prevalence is usually higher in women than in men, but this gender difference diminishes with increasing age. Several antibiotics are available for use in patients with UTIs, but increasing prevalence of antibiotics resistance is a concern in the urologic practice. Especially, antibiotics classically used for the treatment of uncomplicated UTIs, such as cotrimoxazole, fluoroquinolones, and aminopenicillins, are losing their effectiveness because of increasing resistance, raising need for alternative antibiotics. Nitrofurantoin is one such alternative, close to being an ideal antibiotic with low resistance. Several new treatments, based on novel information on therapeutic targets, are also being evaluated to offer relief to individuals who suffer from recurrent or chronic UTIs. Nevertheless, till their wide application in clinical practice, it seems rationale to propose that nitrofurantoin still holds good for the treatment of most uncomplicated UTIs.

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