Pharmacological aspects of the antibiotics used for urological diagnostic procedures.

Pharmacological aspects of the antibiotics used for urological diagnostic procedures Teresita Mazzei1, Sara Diacciati2 1

Department of Health Sciences, Division of Clinical Pharmacology and Oncology, University of Florence, Italy, SODS Oncological Pharmacology, Careggi University Hospital, Florence, Italy

2

Surgical antimicrobial prophylaxis is the use of an antibiotic before, during, or shortly after a urological procedure to prevent postoperative infections such as urinary tract or wound infection. The optimal antimicrobial drug must be microbiologically active against the most frequent potential pathogens and have good pharmacological properties. Correct timing of antimicrobial prophylaxis is the first critical issue in determining treatment efficacy. The antibiotic must be administered before the start of the surgical procedure in order to ensure a high tissue level at the time of microbial contamination. If using an oral antibiotic, this must be administered 1–3 hours before the operation and a parenteral antibiotic should be administered at the induction of anaesthesia. The antibiotics potentially useful for antimicrobial prophylaxis are the beta-lactams, cotrimoxazole, fluoroquinolones, and fosfomycin trometamol. The criteria for choosing the optimal antibiotic include an appropriate antimicrobial spectrum, favourable pharmacokinetic parameters (especially good tissue penetration), and elevated safety or tolerability. The use of cotrimoxazole must be restricted due to increasing chemoresistance. Unfortunately fluoroquinolone-based regimens, once the mainstay of prophylaxis guidelines, are increasingly ineffective due to a constant increase in multidrug-resistant (MDR) Gram-negative bacteria. The same concerns apply with regard to the second and third generation cephalosporins that have problems of resistance and, if administered orally, do not sufficiently penetrate prostatic tissue. An appropriate beta-lactam could be an aminopenicillin combined with a beta-lactamase inhibitor. Fosfomycin trometamol can also be a good potential choice due to its elevated activity against MDR Gramnegative bacteria and its favourable pharmacokinetic parameters, including an elevated penetration into prostatic tissue. Keywords: Urological surgery, Antibiotic prophylaxis, Drug resistance, Fosfomycin trometamol

Introduction In light of the most recent findings, the most important criteria for a rational selection of antimicrobials either for prophylaxis or therapy of any infectious process are the microbiological and pharmacological characteristics of the drug and employment of the proper dosing regimen of the chosen antibiotic. Microbiological characteristics include, first of all, adequate antibacterial spectrum, which consists of good antimicrobial activity against the principal potential pathogens responsible for infection. In addition, the molecule must have adequate antibacterial potency and bactericidal activity.1 The pharmacological criteria involved in selecting an ideal antimicrobial agent for prevention and treatment of surgical infection are closely tied to Correspondence to: Teresita Mazzei, Dipartimento di Scienze della Salute, Sezione di Farmacologia Clinica e Oncologia, Universita` degli Studi, Viale Pieraccini 6, 50139 Firenze, Italia. Email: teresita.mazzei@ unifi.it

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ß 2014 Edizioni Scientifiche per l’Informazione su Farmaci e Terapia DOI 10.1179/1120009X14Z.000000000234

and dependent on the microbiological: the drug must have an adequate spectrum of activity and antimicrobial power against the most important pathogens, according to type of surgery, and must possess certain pharmacokinetic characteristics, which will determine its efficacy. One final but important criterion is the tolerability of the antibiotic and preference should be given to those well-tolerated drugs with the highest therapeutic index.

General Pharmacokinetic Principles: Administration Route, Blood Concentrations, and Tissue Distribution Antibiotics, as pharmaceuticals endowed with ‘selective toxicity’, must above all be able to reach and maintain concentrations necessary and sufficient enough to carry out their antibacterial activity at the infection site.2 The achievement of adequate tissue concentrations is mainly governed and closely

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Pharmacological aspects of antibiotics prophylaxis in urology

Figure 1 Ideal timing for administering antibiotic prophylaxis for surgery.

dependent on blood levels reached by the antibiotic. This depends mainly on the administered dose and the bioavailability characteristics of the various molecules, which are not administered intravenously.3 In perioperative chemoprophylaxis it is essential that from the beginning of surgery, whether it is a biopsy or surgical excision of an organ, antibiotic concentrations present sufficient to guarantee an antiseptic effect and to impede the bacterial colonization of the operative field – a first step necessary to prevent wound infection and possible sepsis. Therefore, the physiochemical properties of the various antibiotics most indicated for surgical infections must provide rapid tissue penetration. It is also desirable that tissue distribution and half-life of the antibiotic exceed the critical period of postoperative infection, which usually lasts until a few hours after the surgical intervention.4,5 The definition of the correct time of administering the antibiotic is especially important. There is ample evidence in the literature that antibiotic administration too far ahead of surgery risks that the drug is eliminated from the patient at the time of cutaneous and/or bioptic incision, making its concentrations in the operative field too low or even absent. In addition, a late administration, made after the end of the biopsy or surgery (the critical time) can result in lack of impediment of bacterial colonization and adhesion in the operative field, with a resulting wound or local infection (Fig. 1).5 Perioperative prophylaxis of urological procedures, which last less than 3 hours would require antibiotics

with a half-life of about 2 hours, while longer surgery requires antibiotics with longer half-lives or repeated doses of molecules with a shorter half-life. The halflife is not the only pharmacokinetic parameter, which should be considered when evaluating tissue distribution of an antimicrobial agent. There are, in fact, numerous factors, which contribute in various ways to an antibiotic’s ability to penetrate the extravascular compartment (Table 1). Tissue concentrations of an antibiotic essentially depend on characteristics of the drug (drug–protein binding, major or minor lipophilia, and half-life) or the tissue (inflammation, vascularization, and capillary porosity). Tissue levels of a drug are enhanced by an elevated difference of concentration between the vascular and tissue compartments, by good vascularization conditions, porosity of the capillary bed, and tissue inflammation. The amount of antibiotic not bound to protein– plasma distribute into the tissue by simple diffusion through vascular endothelial pores. Therefore, drug– protein binding is important in this context, and it is one of the main factors to affect antibiotic tissue Table 1 Principal factors that determine tissue distribution of antimicrobial agents Drug 2 2 2 2 2

Tissue

Concentration gradient Serum–protein binding Serum half-life Total body clearance Protein–tissue binding


2 Capillary porosity 2 Vascularization 2 Inflammation

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penetration.6,7 Even an antibiotic that is highly protein–plasma bound can have good tissue penetration if its elimination half-life is prolonged (such as ceftriaxone).8 The various characteristics of tissue are mainly represented by degree of capillary porosity and vascularization, and obviously, the presence of inflammation. Acute inflammation generally favours tissue penetration, whereas a chronic infectious process can modify tissue, creating barriers, which then consistently alter the penetration of an antibiotic; the presence of fibrosis or granular scar tissue as well as bacterial detritus and proteic material can all obstruct antibiotic tissue penetration.2,3,9 The degree of tissue vascularization also affects antibiotic distribution, which arrives in tissue through blood circulation. One of the most common questions arising in regard to antibiotic prophylaxis or therapy concerns the administration route. The answer to this question is quite complex since today physicians have a vast choice of antibiotics at their disposal, both oral and parenteral. Choosing the correct administration route must therefore be based on knowledge of various pharmacological, anatomical, physiological, and pathological factors, which influence the drug’s bioavailability and therefore its capacity to reach concentrations adequate to guarantee efficacy in both blood and the infection site. Oral administration, provided that the antibiotic has good bioavailability, is generally safer, less expensive, and more acceptable to the patient, especially when the serum half-life of the drug means that no more than two daily doses are required. In any case, oral antibiotics are more indicated for mild and moderate infections in patients who do not have signs or symptoms of systemic infection, nor pathologies which are not properly controlled by adequate medical therapy.10 Parenteral administration, on the other hand, is determined by four different factors: a patient with reduced capacity to absorb gastrointestinally, a dysphagic or uncooperative patient (i.e. elderly), the lack of availability of oral antibiotics with equivalent activity, specific pathologies, and the severity of the disease. Reduced gastrointestinal absorption can occur in patients with gastrectomy or short bowel syndrome, which are fairly rare, or, most commonly, in the presence of symptoms with gastrointestinal characteristics. The aminoglycosides, carbapenems, glycopeptides, and many cephalosporins are the main classes of antibiotics that do not have oral formulations. When the aetiology or clinical situation indicates one of these antibiotics as first choice, parenteral administration is indispensable. Parenteral administration is also necessary for serious infections and in immunocompromised

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patients, either as in- or out-patients, since an injected drug provides elevated blood and tissue concentrations more rapidly than what is guaranteed by oral administration.11 Intramuscular administration, which is used much more frequently in Italy than in other countries such as UK and USA, has characteristics that are in between intravenous and oral administrations. The bioavailability of the drug is rapid but not immediate, as in intravenous administration. Antibiotics in aqueous solution are absorbed in relation to their concentration and the rate of haematic flow in the injection site.11 Nevertheless, intramuscular administration can be particularly useful when there are difficulties of venous access (vein preparation, maintenance of the catheter permeability, high risk of local infection, etc.) or logistical/organizational problems. Regardless of which administration route is used, the main object is to provide prophylactic or therapeutic efficacy through attainment of antibacterial concentrations superior to the minimal inhibitory concentration (MIC) of the potential pathogens in the infection site. There are many reports in the literature regarding antibiotic tissue concentrations, which are possible to achieve with normal therapeutic doses, moving from the cutaneous district to the muscles, heart, brain, uterus, prostate, gall bladder, etc. These reports usually describe methodologies involving homogenized surgical samples that can be characterized by different contents of blood or inflammation. Both these factors can influence antibiotic concentrations with values that must be interpreted on the basis of physico-chemical parameters of the drug. Intracellular fluid can also be a factor that dilutes concentrations of antibiotics such as the betalactams, which are diffused only in the extracellular compartment. On the other hand, the more lipophilic or amphoteric molecules such as the fluoroquinolones can theoretically achieve higher tissue concentrations due to their optimal capacity to diffuse in intracellular fluid itself. Literature publications regarding the distribution of antimicrobial agents in prostatic tissue report highly variable data, depending on type of patient studied, the drugs, administration route, and time of sampling. Patients are often undergoing prostatic adenoma resection and consequently the sampled tissue is not uniform, but comprises interstitial fluid, prostate gland extracellular fluid, smooth muscle cells, prostatic secretions, and blood.12,13 Interpretation is therefore complex, especially because of the lack of studies of pharmacokinetic–pharmacodynamic correlations. In other words, in all the publications, there are no data regarding proof that a higher or lower tissue concentration corresponds to a better or worse clinical


Enterobacteriaceae Enterococci Staphylococci Enterobacteriaceae

Ureteroscopy of proximal or impacted stone or percutaneous stone extraction

Transurethral prostatectomy (TURP)

2014

TMP6SMX 5 cotrimoxazole *Literature date uncertain.

Transurethral resection of bladder tumour (TURB)

Enterobacteriaceae Enterococci Staphylococci

Ureteroscopy for uncomplicated distal calculi

Enterobacteriaceae Enterococci

Enterococci



Enterobacteriaceae Enterococci Staphylococci Enterobacteriaceae Enterococci Staphylococci

Enterobacteriaceae Anaerobes*

Pathogen

SWL with stent or nephrostomy tube

Surgical, endoscopic procedures, lithotripsy (SWL) Shockwave lithotripsy (SWL)

Ureteroscopy

Cystoscopy Urodynamic tests

Diagnostic procedures Transrectal biopsy of the prostate

Procedure

No

All patients

All patients

No

All patients

No

No

No

All patients

Prophylaxis

II and III Generation cephalosporins Aminopenicillin/beta-lactamase inhibitor TMP6SMX II and III Generation cephalosporins Aminopenicillin/beta-lactamase inhibitor

TMP6SMX II and III Generation cephalosporins Aminopenicillin/beta-lactamase inhibitor TMP6SMX II and III Generation cephalosporins Aminopenicillin/beta-lactamase inhibitor TMP6SMX II and III Generation cephalosporins Aminopenicillin/beta-lactamase inhibitor Floroquinolones TMP6SMX II and III Generation cephalosporins Aminopenicillin/beta-lactamase inhibitor Floroquinolones TMP6SMX

TMP6SMX II Generation cephalosporins

Fluoroquinolones Trimethoprim6sulphamethoxazole (TMP6SMX) Metronidazole?* TMP6SMX II Generation cephalosporins

Antibiotics

Table 2 Recommendations for perioperative antibiotic prophylaxis in urology (European Association of Urology)15

Consider in high-risk patients and large tumours

Low-risk patients with small prostate probably do not need prophylaxis

Short course Length to be determined Intravenous administration recommended at operation

Consider in patients at risk

Patients at risk

Consider in high-risk patients

Consider in high-risk patients

Single-dose efficacious in low-risk patients Consider prolonging therapy in high-risk patients

Comments

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Table 3 Cotrimoxazole concentrations in prostatic tissue16,17

Antibiotics Sulphamethoxazole

Trimethoprim

Number of patients treated and sampling time (hours)

Dose (mg) and administration 400 i.m. multiple 800 oral single 800 oral multiple 80 i.m. single 160 oral single 160 oral single

6 5 8 6 5 8

(4) (4) (4) (4) (4) (4)

outcome.13,14 Notwithstanding this, these studies are considered indispensable by both pharmacologists and clinicians because of their probable value in attributing to the absolute significance of tissue distribution, which is sometimes definable as scarce, adequate, or decidedly good. Scarce prostatic penetration can create serious doubt about the therapeutic indications for some categories of antibiotics, even if they possess an appropriate spectrum of activity and potency. Given the above mentioned background, it would be useful in this review, from a pharmacological point of view, to discuss the principal molecules suggested in the most recent European guidelines for prophylaxis of the main urological diagnostic procedures and indicated in Table 2.

Cotrimoxazole This antibiotic is a preconstituted combination of trimethoprim – a diaminopyrimidine – with sulphamethoxazole in a fixed ratio of 1:5. The combination widens the antibacterial spectrum of the two single components, endowing the drug with a synergistic bactericidal effect. The growing incidence in the world and, consequently also in Italy, of bacterial resistance by the principal pathogens such as Escherichia coli and the Enterobacteriaceae (§20– 30%) discourages the use of this drug in the field of urology for either prophylaxis or therapy for the main types of infection, even with its considerably adequate pharmacological profile. Sulphamethoxazole reaches high blood levels with a plasma peak between 40 and 60 mg/L, whereas those of trimethoprim are instead between 1 and 2 mg/L. The half-life of both molecules is similar, varying between 7 and 12 hours for sulphamethoxazole and between 8 and 15 hours for trimethoprim, as is the elimination route, which is primarily urinary. This attribute allows for urinary concentrations, which are useful for therapy (190 mg/L sulphamethoxazole and 75 mg/L trimethoprim). The recommended dose in adults is 800 mg of sulphamethoxazole and 160 mg of trimethoprim every 12 hours either orally or intravenously. Prostatic tissue concentrations have been studied in a small number of patients and are highly variable. Notwithstanding these limitations, they can be

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Mean serum concentration (range) (mg/L) 17.8 26.2 65.9 0.40 0.98 2.39

(12.1–32.2) (2.3–32.9) (40–108) (0.22–0.51) (0.4–1.3) (0.7–3.0)

Mean tissue concentration (range) (mg/L) 5.19 7.11 34.9 1.55 2.84 5.54

(3.2–6.51) (0.45–13.4) (19–64) (0.81–2.5) (0.47–5.0) (4.1–27)

Ctiss/Cs (%) 29 27 53 387 290 232

considered appropriate from a pharmacological point of view (Table 3).16,17 Cotrimoxazole is moderately well tolerated by patients. Its side effects are mainly cutaneous rash (5.9%) with an extremely rare incidence of exfoliative dermatitis, Stevens–Johnson syndrome and toxic epidermal necrolysis (Lyell syndrome).

Beta-Lactam Antibiotics The beta-lactam antibiotics (penicillins, cephalosporins, carbapenems, and monobactams) are the antimicrobial agents, which are generally most commonly used. These are time-dependent bactericidal molecules, with a linear haematic pharmacokinetics, generally brief elimination half-life (1–2 hours, with the exception of some cephalosporins), mainly renal elimination and a volume of distribution of about 20 L, indicative of extended penetration only in the extracellular tissue compartment (Tables 4–6). The penicillins that are most prescribed today in urology are those combined with a beta-lactamase inhibitor, which greatly increases their antibacterial spectrum. The most commonly used is amoxicillin with clavulanic acid, which should be dosed at 1000 mg every 8–12 hours in adults. The preconstituted combination of ampicillin and sulbactam, administered only parenterally (intramuscularly or intravenously) is another important combination antibiotic. Piperacillin combined with tazobactam is a drug that is indicated for more serious infections and therefore is not recommended for short-term prophylaxis. Its serum half-life is about 1 hour, and so it needs to be administered every 6–8 hours (Table 4).17,18 Table 7 summarizes the concentrations of some penicillins and oral cephalosporins in prostatic tissue.17,19–24 Ampicillin has moderate distribution in the prostate, reaching values of about 4 mg/L after multiple administration of only 500 mg, a dose, which today is considered inadequate. In fact, the dose, which should be administered to adults is 1 g every 8 hours. On the other hand, none of the oral cephalosporins of the first (cefalexin), second (cefaclor), or third generations (cefpodoxime) reach adequate prostatic concentrations. Their tissue distribution is quite scarce, with levels rarely exceeding 1 mg/L. These

29.1–34

Tazobactam (500)

0.78–0.8

0.960.1 1.04 0.99 0.75–0.91

1.760.3

T1/2 (hours)

0.26

0.2160.05 0.16 0.10 0.21

0.2160.03

Vd (L/kg)


T1/2 (hours) 1a 0.77b 1.760.6 3.060.4 2.7 2.5

Mean serum concentration (peak or range) (mg/L)

15a 11b 7–10c 1.7–2.9d 2.6 15

4.8–6.4a Cl50.94, Clcrz0.28 1.360.2 3.460.6 0.7–1.1

0.2060.04 0.3060.03 0.760.07 0.21–0.24

Clearance (mL/minute kg)

74.363.7a 71.265.8b 96610 4167 46 70

1150 15.7–305 60 200

900

Normal dosage (adults)1

250–500 mg IR every 8 hours 750 mg MR every 12 hours 250–500 mg every 12 hours 400 mg every 24 hours 200–400 mg every 12 hours 200–400 mg every 12–24 hours


2250–4500 mg (P: 4 or 2 g/T: 0.25 or 0.5) i.v. every 6–8 hours

1500–3000 mg i.v./i.m. every 6–8 hours

1000 mg (A: 875 mg C: 125 mg) oral every 8–12 hours

Mean urinary concentration (peak or range) (mg/L)

204

91.10664.95 56.86638.88 209

381

Mean urinary concentration (peak or range) (mg/L)

Urinary elimination (%)

50–60

43614 71 71 50–60

8668

Urinary elimination (%)

5.86

Vd (L/kg)

0.17

3.661.0 0.25 0.17 0.21

2.660.4

Clearance (mL/minute kg)

1 Ref. 18. aAfter 500 mg, I.R. (Immediate Release). bAfter 750 mg, M.R. (Modified Release). cCefuroxime axetil, prodrug. dMean values after single oral dose of 200 mg (capsule) in healthy volunteers. eProdrug at a dose of 200 mg.

Cefuroxime axetil Cefixime Cefpodoxime proxetile Ceftibuten

Cefaclor

Antibiotics (dose mg)

Table 5 Principal pharmacokinetic parameters of the oral cephalosporins17

Ref. 18.

2.8 93.5 49.6 264.4–277

Clavulanate (125) Ampicillin (500) Sulbactam (500) Piperacillin (4000)

1

i.v.: 46612 oral: 5


Amoxicillin (875)


Table 4 Principal pharmacokinetic parameters of the oral and parenteral penicillins combined with a beta-lactamase inhibitor17

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Ref. 18. aFollowing a single dose of 1 g i.v. or i.m. in healthy adults. bThe active metabolite, dexacetilcefotaxime, amounts to 1664% of excreted portion; T1/252.260.3 hours following an i.v. dose of 1 g. Mean Cmax after single i.v. dose (25-minute infusion) of 30 mg/kg, or single dose of 1 g i.m. in healthy adults. Dexacetilcefotaxime has peaks of 14.766.2 mg/L at 0.960.5 hours after i.v. dose. Accumulation after four doses per day not observed. dMean values from various studies, where 1 g bolus i.v. or i.m. administered in healthy volunteers. eMean values of a single 1 g i.v. dose (30-minute infusion) or i.m. twice daily at stable state in adults. fAfter single 1 g i.v. dose.

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antimicrobial agents are therefore not recommended for preoperative or prebioptic prophylaxis and even less in postoperative infection therapy. Instead, both aztreonam and the main parenteral cephalosporins of the first (cefazolin), second (cefuroxime), and third generations (cefotaxime, ceftriaxone) penetrate the prostate very well, mainly due to contemporarily very high concentrations in blood (Table 8).17,25–29 The reason for the high plasma concentrations of all the parenteral cephalosporins is due to the dosage recommended in adults, which varies from 1 to 2 g every 8–12 hours, which provides for levels often superior to 100 mg/L (Table 6). Their half-life is 1–2 hours, with ceftriaxone reaching 7– 8 hours, meaning it can be administered every 24 hours. Ceftriaxone is the only molecule among these that also has good biliary elimination (Table 6). This sentence has been altered slightly for clarity. Please check that the amendments are correct and retain your intended meaning. All the parenteral cephalosporins can be used for prophylaxis of urological surgical procedures, which are clean-contaminated or contaminated (higher risk of infection and longer duration of surgery). When surgery is prolonged, it is advised that a second dose of antibiotic be administered 4 hours following the first dose, with the exception of ceftriaxone, which has a long half-life. These antimicrobial agents can also be used for therapy in urology if the causative pathogen is not a producer of extended-spectrum beta-lactamases (ESBLs). The data reported in Table 9 are rather discouraging, relating to the low concentrations of the two carbapenems, imipenem and meropenem, in prostatic tissue. The explanation for this may be due to the low number of patients studied and the single-dose administered with a too early sample time. There are no data in the literature regarding prostatic tissue distribution of penicillins, either combined or not with a beta-lactamase inhibitor. The beta-lactam antibiotics are very well tolerated. The only adverse event, which is clinically relevant is risk of sensitization to the drug even to the point of allergic reaction such as anaphylaxis. True anaphylactic reactions are very rare, equal to 0.004–0.005 for every 10 000 patients treated with penicillin or cephalosporin.

Fluoroquinolones The fluoroquinolones are widely used for the treatment of many moderate and serious infectious pathologies. Their antimicrobial activity is concentration-dependent (as opposed to being time-dependent as are the beta-lactams), and they have a long postantibiotic effect. The pharmacodynamic parameters predicting clinical cure in hospitalized patients and

c

2.260.02 1.160.3 1.660.1 7.361.6 2.1 (1.3–2.4) i.v.: 2376285a i.m.: 4269.5a i.v.: y150c i.m.: 20.5c i.v.: 119–146d i.m.: 29–39d i.v.: 168e i.m.: 114e 6567f Cefazolin Cefotaximeb Ceftazidime Ceftriaxone Cefepime


1

every every every every every i.m. i.m. i.m. i.m. i.m. or or or or or i.v. i.v. i.v. i.v. i.v. mg mg mg mg mg 1000–2000 1000–2000 1000–2000 1000–2000 1000–2000 4000 i.m. 90–3261 i.m. 69, 159–185.5 504–995 81.7, 163.9 80616 80–90 8464 49613 80 0.9560.17 3.760.6 Cl51.05, Clcrz0.12 0.2460.06 1.8 (1.7–2.5)

Clearance (mL/minute kg) Vd (L/kg) T1/2 (houra)

0.1960.06 0.2360.06 0.2360.02 0.1660.03 0.26 (0.24–0.31)

Mean urinary concentration (peak or range) (mg/L) Urinary elimination (%) Mean serum concentration (peak or range) (mg/L) Antibiotics (dose mg)

Table 6 Principal pharmacokinetic parameters of the parenteral cephalosporins17 30

8 hours 8–12 hours 8–12 hours 12–24 hours 8–12 hours




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that prevent bacterial resistance are represented by the Cmax/MIC.12.2 ratio and an AUC/MIC5100–125 for the Gram-negative bacteria.32–36 It has been demonstrated both in vitro and in vivo that the fluoroquinolones have antimicrobial activity, which is synergistic with other antibiotics, especially the beta-lactams. For this reason, they are quite efficacious and manageable as combination therapy in patients with serious infections, gradually substituting the role previously played by the aminoglycosides. The main pharmacokinetic parameters of the most commonly used fluoroquinolones are reported in Table 10.17 Ciprofloxacin, when administered as 500 mg orally every 12 hours, has peak serum levels of 3 mg/L, whereas these concentrations double after one 400 mg intravenous dose. Elimination is mainly renal, providing high urinary levels of the drug. Levofloxacin achieves peak concentrations of 4.5 mg/ L with primarily renal clearance. Table 11 shows the studies in the literature regarding prostatic tissue distribution of ciprofloxacin and levofloxacin administered orally or intravenously.17,37–39 Concentrations


are often superior to contemporary plasma levels, which means between 3 and 4 mg/L for ciprofloxacin and notably superior for levofloxacin at 19 mg/L. There are no reports in the literature about prostate penetration of prulifloxacin. Ciprofloxacin and levofloxacin both have a good pharmacokinetic profile and would otherwise be suitable for prophylaxis for diagnostic urological procedures if there were not high levels of resistance in the principal bacterial pathogens, which makes their use strongly unadvisable. The fluoroquinolones are generally well tolerated, with the most frequent adverse events being gastrointestinal, cutaneous, and of the central nervous system. Nausea and vomiting are the most frequently experienced gastrointestinal side effects with an incidence of 3–5%. Diarrhoea (2%), abdominal pain, and dyspepsia (1.7%) are less frequent but in recent years, cases of pseudomembranous colitis have been reported. The central nervous system side effects are moderate such as migraine or vertigo (1%) but can be more serious (,1%) with

Table 7 Concentrations of oral penicillin and cephalosporins in prostatic tissue2,17,19–24

Antibiotics Ampicillin Cefaclor Cefpodoxime Cefalexin *

Dose (mg) and administration 500 500 500 200 500 500

oral oral oral oral oral oral

multiple multiple multiple single single multiple


Mean serum concentrations (range) (mg/L)

Mean tissue concentrations (range) (mg/L)

12 12 5 8 12 17

8.9 (1.0–20.5) 6.7 (3.0–10.2) 1.87 (0.6–5.0) 1.72 (0.72–2.77) 4.48 (0.17–16.55) 6–10 (0–715)

4.0 3.7 0.74 0.68 0.88 ,5

(2–3) (2–3) (2) (3) (2–7)* (0.75–2)

Ctiss/Cs (%)

(0.6–6.9) (1.0–9.3) (0.24–1.94) (0.41–1.23) (0.09–3) (0.5–10)

45 55 39 37 20

Patients with infection.

Table 8 Concentrations of monobactams and parenteral cephalosporins in prostatic tissue2,17,25–29

Antibiotics Aztreonam Cefazolina

Cefuroxime Cefotaxime Ceftriaxone *

Dose (mg) and administration 1000 i.v. single 2000 i.v. single 1000 i.m. or i.v. single or multiple 1500 i.v. single 2000 i.v. single 1000 i.m. multiple 2000 i.v. single




Ctiss/Cs (%)

8 (0.8–3) 14 (0.5)* 38 (6 20)

31.4 (18–46.3) 139.1 (6 39.68) 14614

8.0 (1.7–12.1) 34.6369.75 22 (0.9)

25 25 37

33 25 7 5

99.6 45.2 19.5 106.4

(1) (1.5) (1–2) (1.5)

(40–210) (30–72) (11–30) (73–158)

20.1 22.9 2.8 41.4

(6–35) (4–50) (1–4) (11.7–75.4)

20 51 15 39

Patients with infection.

Table 9 Concentration of carbapenems in prostatic tissue17,30,31

Antibiotics Imipenem Meropenem

Dose (mg) and administration




Ctiss/Cs (%)

500 i.m. single 500 i.v. single 500 i.v. single

10 (2) 10 (2) 8 (0.5)

8.9 (7.4–10.4) 32.5 (30–65) 13.3

2.75 5 2.3

31 15 15.6


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Table 10 Principal pharmacokinetic parameters of the fluoroquinolones17



T1/2 (hours)

Vd (L/kg)

Ciprofloxacin

oral: 2.561.1a i.v.: 6.7b

oral: 3.360.4a 2.260.4 i.v.: 4.2b

Levofloxacin

oral: 4.560.9c i.v.: 5.760.8d

oral: 761c i.v.: 6.760.7d

Prulifloxacin

y2 mg/L

10

1

Mean urinary Urinary concentration Clearance elimination (peak or range) (mL/minute kg) (%) (mg/L) 5065

200a 350b

oral: 1.3660.21c oral: 2.560.45c i.v.: 1.560.23d i.v.: 2.860.5d

61–87

521–771

–

20

7.660.8

–

a

b

110

Normal dosage (adults)1 500–750 mg oral every 12 hours 200–400 mg i.v. every 8–12 hours 250–500 mg oral/i.v. every 24 hours 600 mg

c

Ref. 18. After oral 500 mg dose twice daily for 3 or more days. After i.v. dose of 400 mg. After single oral dose of 500 mg. No significant accumulation with one daily dose. dAfter single i.v. dose of 500 mg.

tremors, insomnia, mental confusion, psychic alterations, hallucinations, and convulsions. These effects are due to inhibition of gabaergic receptors. Some fluoroquinolones can cause phototoxicity, cardiac arrhythmia, or QT interval alterations. Other rarer complications (,1%) include tendonitis or spontaneous tendon rupture, mainly of the Achilles tendon and bilateral in half of the cases. These side effects can be exacerbated by other risk factors in the patient such as corticosteroid use, chronic renal insufficiency, intense physical exercise, and age over 60 years.

Fosfomycin Trometamol Fosfomycin is an antibiotic derived from fosfonic acid and its bactericidal activity works through blockage of the first steps in the synthesis of the bacterial wall by inhibiting piruviltransferase enzyme.40,41 Fosfomycin has a broad spectrum of activity, including both Grampositive bacteria such as Staphylococcus aureus, S. epidermidis, and enterococci as well as the Gramnegative germs. It is active against E. coli (including ESBL producers), Proteus mirabilis, Klebsiella pneumoniae, Enterobacter spp., Serratia spp., Shigella, Salmonella spp., and Neisseria meningitidis. It is moderately active against Pseudomonas aeruginosa. After a 3-g oral dose of fosfomycin, blood peaks vary from 22 to 32 mg/L with about 40% bioavailability and

an elimination half-life mean of about 5 hours42 (Fig. 2). Fosfomycin does not have strong protein– plasma binding and is eliminated mainly in urine through glomerular filtration.43 Urinary concentrations reach a maximum of 4,400 mg/L within 4 hours after administration of a single 3-g dose in healthy adults and decrease in the following hours, but remain higher than levels needed to be bactericidal against the most common urinary pathogens for at least 36– 48 hours. This high and persistent concentration in urine contributes to the primary indication for this drug, which is for uncomplicated urinary tract infections.44–46 However, fosfomycin’s activity is not limited to urinary infections. In terms of tissue distribution, fosfomycin penetrates extracellular fluid very well, diffusing in many tissues and organs including cephalorachidian fluid.43 Its penetration into prostatic tissue is extremely rapid, reaching very high concentrations: 3 hours after administration, 20 mg/L are achieved, equal to about 90% of contemporary blood concentrations (Table 12). After 12 hours, prostatic levels are still potentially antibacterial, equal to about 5 mg/L.47 These data, published by Italian authors, have recently been confirmed in numerous patients (26) by Australian researchers, who have studied fosfomycin’s global pharmacokinetic profile (urinary plasmatic and prostatic tissue concentrations) following

Table 11 Concentrations of fluoroquinolones in prostatic tissue3,17,37–39

Antibiotics Ciprofloxacin

Levofloxacin


Dose (mg) and administration 100 i.v. single 500 oral single 500 oral multiple 1000 oral single ER 1000 oral single ER 500 oral multiplez 500 i.v. single

25 8 8 7 6 20

ER: extended release; *Peak concentration;

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(0.33) (2–5) (6) (1) (3) (1)

**

AUCprostatic

SUPPL

1



Ctiss/Cs (%)

1.2 (0.9–1.8) 2.0 (1.1–2.3) 1.5 (1.0–2.4) 2.1 (0–2.98) 3.1 (1.25–4.4) 6.5*

3.0 (1.1–4.6) 2.64 (1.1–5.5) 3.6 (1.1–9.5) 4.75 (3.15–7.17) 4.3 (1.6–6.4) 19*

250 132 240 226 138 2.96**

tissue/AUCserum.



Figure 2 Fosfomycin trometamol: mean serum and urinary concentrations after a single 3-g dose.42

its administration to patients for TURP prophylaxis48 (Table 13). Prostatic tissue was sampled about 10 hours after a single dose of the antibiotic and a mean of 6.5 mg/L was confirmed, with the highest concentrations in transition zone tissue (8.366.6 mg/ L) and lower but still effective concentrations in the peripheral zone of the organ (4.464.1 mg/L). Fosfomycin has been demonstrated to be fully capable of reaching therapeutic prostatic tissue levels if used for prophylaxis before an invasive urological diagnostic procedure such as transurethral prostatic biopsy. These concentrations are able to impede colonization, adhesion, and growth of potential pathogens, including those that are resistant to other classes of antibiotics such as the fluoroquinolones, beta-lactams, and cotrimoxazole.

After more than 30 years of use in both adult and paediatric patients, fosfomycin’s tolerability and safety are well founded. The most common side effects are gastrointestinal, with diarrhoea being the most frequent. The other most commonly reported adverse events are nausea, vomiting, dyspepsia, migraine, vertigo, and vaginitis.49

Disclaimer Statements Contributors The contributors to the article are the two authors. Funding None. Conflicts of interest Professor Mazzei collaborates with the following Pharmaceutical companies:

Table 12 Concentrations of fosfomycin trometamol in prostatic tissue after a single oral dose of 3 g in six patients47 Serum (mg/mL)

Prostatic tissue (mg/g)

Prostatic tissue/serum (%)

25.6363.66 6.7560.82

20.7862.35 4.9260.89

91 74

3 hours after administration 12 hours after administration

Table 13 Mean concentrations of fosfomycin after administration of a single 3-g dose to 26 patients undergoing transurethral prostatectomy (TURP)48 Fosfomycin concentrations

Plasma (mg/L) Urine (mg/L) Prostatic tissue–transition zone (mg/g) Prostatic tissue–peripheral zone (mg/g) Prostate (mg/g)

Time after dose (hours:minutes)

Mean

SD

Mean

SD

11.4 571 8.3 4.42 6.5

7.6 418 6.63 4.10 4.9

9:25 9:41 9:58 10:08 10:03

2:29 2:30 2:33 2:35 2:34


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Cubist, Novartis, Pfizer, Roche, Zambon. Diacciati has no conflict of interests.

Dr

Ethics approval Since it is a review article, ethics approval was not necessary.

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