Prospective Comparative Study of Two Protocols of Antibiotic Prophylaxis in Percutaneous Nephrolithotomy

Abstract

Background and Purpose:

Percutaneous nephrolithotomy (PCNL) is considered to be a clean-contaminated surgical procedure, and all patients are recommended to receive antibiotic prophylaxis before the operation to prevent septic events. The aim of the present study is to prospectively compare two different protocols of antibiotic prophylaxis in PCNL.

Patients and Methods:

Seventy-three patients with preoperative sterile urine were randomized into single-dose or short-course antibiotic prophylaxis groups. Patients in the first group (n=36) were given only a single dose of ceftriaxone during induction of anesthesia, while the second group (n=37) were given an oral third-generation cephalosporin after ceftriaxone until nephrostomy catheter withdrawal. For each patient, urine samples that were taken during initial access into the collecting system, as well as some stone fragments, were sent for culture and sensitivity analysis. Moreover, urine samples of the patients were cultured preceding nephrostomy catheter removal. Occurrence of perioperative infection related events was compared in both groups.

Results:

The demographic and treatment-related characteristics of both groups were similar. Peroperative urine samples revealed bacteriuria in one and two patients for the first and second groups, respectively. Fever of >38°C (P=0.52) developed in four (11.1%) patients in the first and six (16.2%) patients in the second group. Positive stone cultures developed in eight patients; of those, three (8.3%) were in the first and five (13.5%) were in the second group (P=0.47). The urine sent for culture on the nephrostomy catheter withdrawal day had positive results in three and two patients for the first and second groups (P=0.54).

Conclusion:

Both antibiotic prophylaxis methods were similar in terms of preventing septic complications. Therefore, we think that a single-dose antibiotic prophylaxis protocol may be safely recommended to patients undergoing PCNL.

Introduction

S urgical antimicrobial prophylaxis is the periprocedural systemic administration of an antimicrobial agent intended to reduce the risk of postprocedural local and systemic infections. Although operating on patients with sterile preoperative urine is thought to be safe, infectious complications are encountered in up to 25% of patients after PCNL,¹ and severe sepsis occurs in about 1% of patients.^2,3 Empiric antibiotic therapy salvages most systemic infections, but patients with renal stones often receive multiple courses of antibiotics after surgery, so the likelihood of resistant organisms increases⁴ Inappropriate antibiotic use increases environmental pressure that favors the emergence of antimicrobial resistant bacteria that can cause postoperative infection, resulting in the administration of more antibiotics, an increase in the cost of care, and a prolonged hospital stay.

Percutaneous nephrolithotomy (PCNL) involves the opening or manipulating of the upper urinary tract and thus is categorized as a “clean-contaminated” complex endourologic surgical procedure, for which the prophylactic use of antibiotics is recommended.^5
–7 There are wide differences in regimes and types of antibiotics for prophylaxis, however. Furthermore, few antibiotic prophylaxis recommendations for PCNL patients are supported by evidence gathered in prospective studies.

Despite universal agreement on the need for application of antimicrobial prophylaxis, the optimum administration period of antibiotics for PCNL remains controversial. In this context, we prospectively compared the clinical efficacy of a single-dose protocol of a prophylactic antimicrobial agent (1 g intravenous [IV] cephtriaxone) with a short-course protocol in PCNL.

Patients and Methods

A total of 73 adult patients with renal stones >2 cm and with preoperative sterile urine who underwent PCNL at our institution were included in this prospective study. These patients were randomized into single-dose (group 1) or short-course (group 2) antibiotic protocols, according to computer generated random numbers. Exclusion criteria were preoperative significant bacteriuria, an indwelling catheter, signs of active infection, and antibiotic therapy within 2 weeks before surgery. Patients with infection stones with an expected significant load of bacteria and patients with anatomic comorbidities were also excluded.

On enrolling, patients received a physical examination and laboratory tests, including blood cell count, blood chemistry, and bacteriologic examination of the midstream urine within 1 week before surgery. A significant bacteriuria was considered 10⁵ cfu/mL urine or more. The stone burden was estimated by two-dimensional measurements on IV urography. The stone burden was measured as the product of the two dimensions on plain radiography. The sum of the largest diameters of all stones was obtained by addition of the maximal length of each stone. Stone surface areas were estimated using an arithmetic calculation formula.⁸ The procedure of this study was approved by the local ethics committee of our institution and informed consent was obtained from all patients.

Patients in the first group (group 1, n=36) were given only a single dose of 1 g ceftriaxone IV during induction of anesthesia 30 minutes before the operation, while the second group (group 2, n=37) were given ceftriaxone plus an oral third-generation cephalosporin until nephrostomy catheter withdrawal.

All PCNLs were performed in the standard aseptic manner and with the patient in the prone position. A nephrostomy tube was routinely left in place after the procedures. All patients had routine urethral catheterization during the operation, and these catheters are removed after the patients were mobilized. For each patient, renal pelvic urine samples and fragmented stones were collected to assess culture and sensitivity. These samples were cultured on eosin methylene blue agar and blood agar. Vital parameters were monitored postoperatively every 2 hours in the first 48 hours, then every 4 hours thereafter until the patient was discharged.

Fever was reported if the patient presented at least once with a temperature ≥38.5°C and shivering. The nephrostomy tube inserted intraoperatively were kept for 48 hours, then clamped and subsequently removed, unless a complication occurred necessitating an extended period of drainage. Additional urine and blood cultures were taken from patients in whom fever developed in the postoperative period, and these paients also received a consultation with the infectious diseases department. Chest radiography was performed in all patients who had supracostal access to rule out thoracic complications. Moreover, urine samples of the patients were sent for culture and sensitivity analysis preceding nephrostomy catheter withdrawal. None of the patients needed secondary interventions before nephrostomy removal.

The end point of this study was a comparison of the prophylactic efficacy of the two regimens against postoperative infection and infection-related events such as fever, bacteriuria, and bacteremia. Power analysis identified a minimum of 52 patients (26 per group) as the total sample size to detect a 50% reduction in postoperative infectious complication rates between the two groups with a power of 80%, at a 5% significance level. With consideration of anticipated patient dropouts, we chose to randomize more patients. The SPSS 16.0 program was used for statistical analysis (SPSS Inc, Chicago, IL). Differences between groups were tested for significance using the chi-square test, t test, and Mann-Whitney U test. The level of statistical significance was defined as P<0.05.

Results

The mean patient age was 44 years (range 18–69 years). There were no significant differences between the two groups with regard to demographics, surgery, or stone characteristics. The degree of pelvicaliceal dilatation of the both groups was also similar Table 1).

Table 1.

Demographic Characteristics, Operative Data, and Comparison of the Results

	Group 1 (n=36)	Group 2 (n=37)	P
Female/male	11/25	10/27
Stone side (R/L)	14/22	13/24
Mean age (years)	43.5	44.7	0.68
Stone surface area (mm²)	517±406	558±521	0.27
Presence of obstruction (%)	19.4	21.6	0.27
Mean creatinine (mg/dL)	0.93±0.23	0.89±0.27	0.65
Supracostal access (%)	16.6	21.6	0.71
Irrigation fluid (lt)	13.2±5.6	12.8±6.5	0.78
Mean operative time (min)	112±32	116±55	0.76
Transfusion rate (%)	8.3	10.8	0.76
Stone-free rate (%)	88.9	91.9	0.66
Nephrostomy withdrawal day	2.8±1.1	3.1±1.8	0.34

Fever of ≥38.5°C (P=0.52) developed in four (11.1%) patients in the first and six (16.2%) patients in the second group. Blood for culture was taken from all patients having postoperative fever, but none of these patients had positive blood culture results. Also, septicemia did not develop in any patient. Analysis of renal pelvic urine samples revealed bacteriuria in one and two patients for the first and second groups, respectively. The results of urine samples sent for culture on the nephrostomy catheter withdrawal day were positive in three and two patients for the first and second groups (P=0.54) (Table 2).

Table 2.

Infectious Events

	Group 1 (n=36)	Group 2 (n=37)	P
Fever	4 (11.1 %)	6 (16.2 %)	0.52
Positive renal pelvic urine	1 (2.7 %)	2 (5.4 %)	0.32
Positive stone culture	3 (8.3 %)	5 (13.5 %)	0.47
Positive urine culture(on nephrostomy withdrawal day)	3 (8.3 %)	2 (5.4 %)	0.54
Septicemia	None	None

Positive stone cultures developed in eight patients; of those, three (8.3%) were in the first, five (13.5%) were in the second group, and there was no significant difference between both groups (P=0.47). Of the four patients in whom fever developed postoperatively, only one had positive stone culture results in group 1 and two had positive stone culture results in group 2. The specific pathogens colonizing the stones in group 1 and 2 patients are listed in Table 3.

Table 3.

Types of the Pathogens Isolated from the Stone Cultures

	Group 1	Group 2
Enterococci	-	1
Escherichia coli	-	1
Klebsiella spp	1	-
Proteus mirabilis	1	1
Pseudomonas aeruginosa	-	1
Staphylococcus epidermidis	-	1
Staphylococcus aureus	1	-
Total	3	5

None of the renal pelvic urine cultures grew bacteria between 10² and 10⁴ cfu/mL. Low count bacteriuria was present in urine samples that were taken on the nephrostomy catheter withdrawal day of four patients in the both groups. None of these patients had symptomatic urinary tract infections and considered as contaminated.

Discussion

The optimal antibiotic prophylaxis regime for PCNL has not been widely investigated. There have been very few reports that describe the choice of antimicrobial agents, dose, timing, and duration for PCNL. In one previous study, the need for routine antibiotic prophylaxis was investigated in 107 patients with sterile preoperative urine.⁹ The bacteriologic results of the patients who underwent PCNL without receiving antibiotic prophylaxis demonstrated a 35% rate of postoperative infection.⁸ Of those, 10% presented with febrile urinary tract infections.⁹ These findings were in favor of short-term antibiotic prophylaxis in PCNL.

The efficacy of a single dose third-generation cephalosporin (cefotaxime) prophylaxis was investigated in a group of patients undergoing both PCNL and ureteroscopy (URS).¹⁰ This is the only prospective randomized double-blind study that compared placebo with antibiotic prophylaxis in both PCNL and URS patients. Bacteriuria occurred in 12% of patients in the placebo group and 5% of patients in the antibiotic prophylaxis group.¹⁰ Although patient numbers in the groups were very few for reaching statistical significance, the incidence of bacteriuria was lower in the antibiotic prophylaxis group.¹⁰

A prospective but nonrandomized investigation of 49 patients undergoing PCNL and receiving oral ciprofloxacin, IV ciprofloxacin, or no antibiotic treatment demonstrated perioperative pyelonephritis to occur in 16.7%, 0%, and 40% of patients, respectively.¹¹ In that study, patients continued to receive oral antibiotics 5 to 6 days after surgery, and the conclusion was in favor of antibiotic prophylaxis in PCNL.¹¹

Three previous studies compared different antibiotic prophylaxis regimens in patients undergoing PCNL. In the first study, norfloxacin and cefuroxime were reported to be equally effective for preventing infectious complications in 70 patients.¹² The second one included 81 patients with preoperative sterile urine. Patients were given IV ofloxacin or IV ofloxacin plus oral ofloxacin until nephrostomy tube removal.¹³ The authors reported no significant difference between single-dose and short-term antibiotic prophylaxis protocols in terms of infectious complications.¹³ In the more recent third study, the effect of sulbactam-ampicillin and cefuroxime prophylaxis in preventing systemic inflammatory response syndrome (SIRS) was compared in 198 patients.¹⁴ In that study, patients were further randomized to three subgroups according to the duration of antibiotic treatment: Single-dose prophylaxis, additional dose 12 hours after the first dose, and continuous antibiotic treatment until nephrostomy tube removal. Similar postoperative positive culture rates between sulbactam-ampicillin and cefuroxime prophylaxis groups were reported. The incidence of SIRS was also not significantly different between the main and subgroups of patients. The authors concluded that single-dose antibiotic prophylaxis with either antibiotic was sufficient in preventing SIRS.¹⁴

In the present series, the overall rate of postoperative bacteriuria was 8.3% and 5.4% in the single-dose and short-course antibiotic prophylaxis groups. The comparison of the findings of these studies cited above, as well as the present series is summarized in Table 4.

Table 4.

Results of Previous Studies on Antibiotic Prophylaxis in Patients Undergoing Percutaneous Nephrolithotomy

Author	n	Study design	Antibiotics	Postoperative bacteriuria
Charton⁹	107	Retrospective	No ABP	35 %
Fourcade¹⁰	49	Prospective randomized	Placebo vs	5 %
		double blind	Cefotaxime	12 %
			Intravenous ciprofloxacin	0 %
Darenkov¹¹	46	Prospective	Oral ciprofloxacin	16.7 %
			No ABP	40 %
Cutajar¹²	70	Retrospective	Cefuroxime vs	11 %
			Norfloxacin	2.8 %
Dogan¹³	81	Prospective randomized	Single dose ofloxacin	6.9 %
			Continuous ofloxacin^a	2.6 %
			Ampicillin-Sulbactam vs
Seyrek¹⁴	198	Prospective randomized	Cefuroxime	43.3 %^b
			(single dose, 2 doses and continous dose^a)	56.7 %^b
Tüzel	73	Prospective randomized	Single dose cephtriaxone	8.3 %
			Cephtriaxone + oral cephalosporin^a	13.5 %

ABP=antibiotic prophylaxis.

Until nephrostomy tube withdrawal.

Systemic inflammatory response syndrome rates.

Briefly, in the current literature, there are three kinds of studies about antibiotic prophylaxis in PCNL. One study assessed patients without having any antibiotics,⁹ two studies compared antibiotic treatment with placebo or no antibiotics,^10,11 and the other three studies compared different antibiotic prophylaxis regimes.^12
–14 We do not think that the investigations comparing antibiotic prophylaxis with placebo would be reproducible because of ethical concerns. Urosepsis after PCNL may occur despite sterile preoperative urine because of the release of preformed bacterial endotoxins and viable bacteria after fragmentation of stones during the procedure.¹⁵ Moreover, 32% of calcium oxalate stones were reported to be infected in one study.¹⁶ Septic shock with up to 66% to 80% mortality may be seen in about 1% of patients after stone manipulation.^17,18 These factors may place the patients who do not receive preoperative antibiotics at risk for mortal septic complications. Thus, we think that conducting qualified prospective comparative studies investigating the optimal antibiotic prophylaxis method in patients undergoing PCNL would be more valuable. The present study was designed in this context.

A proper antibiotic for prophylaxis should be effective and well tolerated, and its spectrum should cover the range of pathogens usually found in infections after PCNL. Because different types of microorganisms are isolated from the urine, renal pelvic, and stone cultures after PCNL, a prophylactic antibiotic should cover gram-negative and gram-positive bacteria, and it should have a high renal excretion rate. Antibiotic prophylaxis recommendations for stone surgery that has been described by the latest clinical guidelines recommend trimethoprim±sulfamethoxazole, first, second, and third generation cephalosporins, aminopenicillins, aminoglycoside + metronidazole or clindamycin, and fluoroquinolones in complex endourologic interventions, such as PCNL.^5,6

Clindamycin or aminogylicoside + clindamycin or metranidazole are generally alternatives to penicillins and cephalosporins in patients with penicillin allergy. Fluoroquinolones should be used sparingly and better reserved for treatment rather than prophylaxis.⁵ Gram-negative specific antibiotics such as aminoglycosides, alone or in combination, may also be appropriate for antimicrobial prophylaxis in PCNL. Their use, however, can be limited because of potential nephrotoxicity and ototoxicity (mainly irreversible) resulting in a narrow therapeutic margin.

In the present series, cephalosporins were chosen because of their effectiveness against the disease relevant bacterial flora characteristics of the operative site and their high urinary concentrations. In addition, they are among the antibiotics that are recommended to use for prophylaxis in PCNL, by the current guidelines.^5,6 There are great variations worldwide regarding bacterial distribution and bacterial susceptibility to different antibiotics, however. Thus, local knowledge about the pathogens' profile and susceptibility pattern is of paramount importance in setting up a rational antibiotic policy. We think that those antibiotics that best prevent infection after PCNL need to be identified by further investigations.

The duration of use of prophylactic antimicrobial agents should be kept as short as possible, not only to avoid the induction of bacterial resistance, but also so as not to waste medical resources. Inappropriate antibiotic use increases environmental pressure favoring the emergence of antimicrobial resistant bacteria; this can cause postoperative infections resulting in the administration of more antibiotics, an increase in the cost of care, and prolonged hospital stay.¹⁹ Excessive use of a particular drug is not desirable because many endogenous and iatrogenically transmitted bacteria are gaining resistance to such drugs. Currently, there is very little evidence-based information about the rational length of antibiotic prophylactic regimens for PCNL patients. Our findings are in agreement with two prievious investigations that showed no difference between single-dose and short-term prophylaxis protocols in terms of postoperative fever and infection.^13,14 On the other hand, the host and its potential risk factors, the environment, local bacterial profile, as well as the factors related to the procedure's complexity and duration would certainly affect the individual patient's postoperative infection risk. Thus, perioperative prophylaxis may be prolonged if there are such risk factors.

In regard to study limitations, the number of subjects included should be taken into consideration. In particular, the lack of statistical significance between two groups in the present study might be attributed to the inclusion of the limited number of patients. The incidence of infectious complications in PCNL patients is rare under antibiotic prophylaxis. With relatively small patient numbers, it may be difficult to detect a statistically significant difference, especially when the occurrence of adverse events is infrequent. Further studies including larger numbers of patients are warranted to overcome this ubiquitous problem.

In a previous systemic review, it was suggested that antibiotic prophylaxis would not be advantageous when results of culture of preoperative voided urine are negative.²⁰ Recent studies, however, have shown that urine cultures are low predictors of upper urinary tract colonization, and the renal pelvic urine and stone cultures are better predictors of infection.²¹ Because of this, some investigators suggest obtaining routine stone cultures during PCNL in dictating the proper antibiotic therapy, especially in patients at risk of SIRS.¹⁵

Conclusions

With regard to the duration of prophylaxis, two previous prospective studies found that single-dose antibiotic use was associated with the same incidence of septic events compared with antibiotic prophylaxis until the time of nephrostomy tube withdrawal.^12,13 We evaluated the efficacy of single-dose antibiotic prophylaxis (1 g cephtriaxone IV) with short-course antibiotic prophylaxis in a prospective randomized trial. We also confirmed that short-course prophylaxis with ceftriaxone was not superior to single-dose prophylaxis in terms of decreasing the rate of postoperative infection or fever. Based on our data, single-dose prophylaxis can be considered an effective, well tolerated, and the preferred manner of perioperative antibiotic prophylaxis. Therefore, a single-dose antibiotic prophylaxis protocol can be safely recommended to patients undergoing PCNL.

Footnotes

Disclosure Statement

No competing financial interests exist.

Abbreviations Used

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