56 Urinary concentrations of trimethoprim and
sulfamethoxazole far exceed the minimum inhibitory concentrations (MIC) for most
susceptible urinary pathogens. Therefore, good in-vitro activity, excellent clinical
success which is similar to that of the fluoroquinolones and other alternative agents
in susceptible strains, relatively low resistance rates among common pathogens, and
low cost make TMP–SMX a reasonable choice in V.Q.
guidelines recommend TMP–SMX as an appropriate initial agent of choice in the
treatment of acute, uncomplicated lower UTI in geographic areas where the incidence
of TMP–SMX resistance among E. coli is less than 20%.
Nitrofurantoin is also recommended as an appropriate agent for empirical
treatment of acute uncomplicated cystitis.
20 Nitrofurantoin is almost completely
absorbed after oral administration, but it barely reaches detectable levels in the
plasma because it is rapidly eliminated (half-life, 20 minutes) into the urine and bile;
the resulting high urine levels are 50 to 250 mg/L and are well in excess of the MIC
for most common pathogens causing UTI.
58 Food substantially decreases the rate of
absorption, but it increases the total bioavailability of nitrofurantoin from both the
macrocrystalline capsules and the microcrystalline tablets by about 40%. This effect
lengthens the duration of therapeutic urine concentrations by about 2 hours.
Nitrofurantoin has a spectrum of activity which includes E. coli, some strains of
Pseudomonas, S. saprophyticus, streptococci, and enterococci; on the other hand,
Proteus, Enterobacter, and Klebsiella are more likely to be resistant (susceptibility
59 Nitrofurantoin does not significantly alter the fecal or introital flora,
and the development of resistance in previously sensitive strains does not often
In contrast to ampicillin, TMP–SMX, and other drugs with relatively high
resistance rates, nitrofurantoin has maintained excellent activity against most
uropathogens; susceptibility rates among E. coli currently range from 90% to 99% in
45–49,59 Finally, nitrofurantoin has been shown in comparative
clinical studies to be as effective as TMP–SMX, fluoroquinolones, or fosfomycin in
the treatment of acute uncomplicated cystitis.
20 Nitrofurantoin is thus recommended in
the most recent clinical guidelines as an appropriate choice for treatment of
uncomplicated UTI in patients such as V.Q. (Table 71-3).
Most practitioners in the United States have little experience with fosfomycin
trometamol, but the drug has, nevertheless, been used quite successfully in the
treatment of UTI in many other parts of the world.
acid derivative which has been shown to irreversibly block bacterial cell wall
synthesis through inhibition of early cytoplasmic stages of peptidoglycan
It has bactericidal activity against a broad range of gram-negative and
gram-positive organisms including E. coli and other Enterobacteriaceae,
Pseudomonas aeruginosa, and Enterococcus as well as many multidrug-resistant
pathogens such as methicillin-resistant S. aureus, vancomycin-resistant enterococci,
and ESBL-producing gram-negative bacilli.
44 Fosfomycin is approximately 40%
absorbed after oral administration as granules marketed in a sachet form and is
rapidly and almost completely excreted unchanged in the urine. Fosfomycin achieves
mean urinary concentrations greater than 500 mg/L within 6 to 8 hours after
administration and maintains concentrations greater than 100 mg/L for a duration of
more than 26 hours after a single oral dose.
61 Single 3-g oral doses of fosfomycin
are clinically as effective as trimethoprim and nitrofurantoin, although
microbiological efficacy may be less.
20 Nevertheless, fosfomycin is currently
recommended for treatment of acute uncomplicated cystitis in the 2011 IDSA/ESMID
It should be noted that although fosfomycin is
commercially available in the United States, it is substantially more expensive than
either TMP–SMX or nitrofurantoin.
Summary of Evidence-Based Recommendations for Treatment of Acute
Uncomplicated Cystitis and Pyelonephritis
Recommendations Recommendation Grades
Nitrofurantoin monohydrate/macrocrystals 100 mg PO twice daily × 5 days A-1
TMP–SMX 160/800 mg (1 double-strength tablet) PO twice daily × 3 days A-1
Trimethoprim 100 mg PO twice daily × 3 days is considered equivalent to
TMP–SMX and is the preferred agent in some regions
Fosfomycin trometamol 3 g PO × 1 dose A-1, but appears to have
inferior microbiological efficacy
compared with standard shortcourse therapies with agents
Pivmecillinam 400 mg PO twice daily × 3–7 days (not commercially available
A specific antibiotic is no longer recommended for empirical treatment when
the prevalence of resistance is ≥20%
Fluoroquinolones (ciprofloxacin or levofloxacin) PO × 3 days are highly
efficacious for acute cystitis
Fluoroquinolones should be reserved for other important clinical uses because
of propensity for collateral damage
β-Lactams (including amoxicillin–clavulanate, cefdinir, cefaclor, and
cefpodoxime–proxetil) PO × 3–7 days are appropriate when other
recommended agents cannot be used
Other β-lactams such as cephalexin are less wellstudied but may also be
appropriate in certain settings
β-Lactams generally have inferior efficacy and more adverse effects
compared with other antimicrobials for UTI
Urine culture and susceptibility testing should be performed and initial
empirical antibiotic therapy tailored appropriately based on results
Ciprofloxacin 500 mg PO twice daily × 7 days, ± an initial IV dose of
ciprofloxacin 400 mg, a long-acting parenteral cephalosporin (e.g., ceftriaxone
1 g) or a consolidated 24-hour dose of an aminoglycoside (e.g., gentamicin 5–7
Ciprofloxacin 1,000 mg extended release tablet PO once daily × 7 days, or B-2
Ciprofloxacin 1,000 mg extended release tablet PO once daily × 7 days, or
levofloxacin 750 mg PO once daily × 5 days
If the local prevalence of fluoroquinolone resistance among uropathogens is
>10%, an initial one-time IV dose of a long-acting parenteral cephalosporin or
a consolidated 24-hour dose of an aminoglycoside should be administered
TMP–SMX 160/800 mg (1 double-strength tablet) PO twice daily × 14 days A-1
If TMP–SMX susceptibility is not known, an initial IV dose of a long-acting
parenteral cephalosporin or a consolidated 24-hour dose of an aminoglycoside
Oral β-lactams × 10–14 days are less effective than other available agents B-3
If an oral β-lactam is used, an initial IV dose of a long-acting parenteral
cephalosporin or a consolidated 24-hour dose of an aminoglycoside should be
One of the following antibiotic options may be used initially, based on local
resistance data and tailored based on susceptibility results: IV fluoroquinolone;
IV aminoglycoside ± IV ampicillin; extended-spectrum IV cephalosporin or
extended-spectrum IV penicillin ± aminoglycoside; or IV carbapenem.
on clinical experience, descriptive studies, or reports of expert committees.
IV, intravenous; PO, orally; TMP–SMX, trimethoprim–sulfamethoxazole; UTI, urinary tract infection.
Alternative agents for the treatment of UTI in V.Q. include the fluoroquinolones
and various oral β-lactam antibiotics.
20 The fluoroquinolones remain highly effective
in the treatment of UTI. However, increasing rates of resistance among common
uropathogens and the potential for significant collateral effects on normal flora
leading to complications such as Clostridium difficile infection have led to recent
recommendations that the fluoroquinolones not be routinely used as preferred agents
in the treatment of uncomplicated UTI such as that present in V.Q.
regarding the use of fluoroquinolones for UTI are discussed in Case 71-2.
Amoxicillin–clavulanate and several oral cephalosporins have been studied for
the treatment of uncomplicated UTI; these studies have shown the β-lactams to be
generally comparable to TMP–SMX, but less clinically or microbiologically
effective than the fluoroquinolones.
20 β-lactams require longer durations of treatment
(see Case 71-1, Question 4), which makes them less attractive from the standpoint of
ensuring patient adherence and may also predispose to higher rates of drug-related
20 Finally, these relatively broad-spectrum agents may be associated
with more frequent emergence of bacterial resistance, including ESBL-producing
20 Thus, the β-lactam antibiotics (with the exception of
pivmecillinam) are currently only recommended for empirical treatment of
uncomplicated cystitis when none of the other agents previously discussed can be
20 Of note, ampicillin and amoxicillin are specifically discouraged
for empirical treatment of UTI because of the high resistance rates previously noted.
V.Q. could be appropriately treated with either TMP–SMX, nitrofurantoin, or
fosfomycin. She has no apparent patient characteristics that would favor the use of
one agent over another. In this case, the most important factor to consider would be
local antibiotic susceptibilities among community-acquired uropathogens,
particularly E. coli. Local costs and availability of the different options would also
be important to consider in V.Q.
Note that the current IDSA/ESMID guidelines do not apply to the empirical
selection of antibiotics for complicated UTI. Complicated infections are often
associated with more difficult pathogens (e.g., P. aeruginosa) and increased risk of
antibiotic resistance; fluoroquinolones are therefore considered preferred agents for
initial treatment of complicated UTI with subsequent antibiotic therapy guided by the
DURATION OF ANTIBIOTIC THERAPY
CASE 71-1, QUESTION 4: V.Q. is started on TMP–SMX for treatment of her infection. What would be the
preferred duration of therapy of antibiotic therapy for V.Q.?
Outpatients with acute, uncomplicated UTI can be treated successfully with a
traditional 7- to 14-day course of oral medications, a shorter 3- to 5-day course of
therapy, or with single-dose therapy.
1–3,5,20,62 The traditional 7- to 14-day course of
antibiotic therapy now is considered excessive for most patients with uncomplicated
infections and is seldom used.
1–3,5,20,62 A 3- to 5-day antibiotic treatment regimen is
just as effective as a 10-day regimen in achieving clinical cures and eradicating
urinary tract organisms, although this is somewhat antibiotic class–specific.
TMP–SMX is recommended as the preferred agent for 3-day treatment regimens; the
fluoroquinolones may also be used in this shorter duration (Table 71-3).
course of nitrofurantoin is as effective as a 3-day course of TMP–SMX for acute
uncomplicated cystitis, and nitrofurantoin is thus currently recommended as a 5-day
63 β-Lactam antibiotics are more appropriately reserved for longer
treatment courses of 3 to 7 days.
20 Longer treatment courses are also used in cases
of treatment failure after regimens of shorter duration, as well as in the treatment of
complicated UTI where longer courses of therapy (7–14 days) are associated with
higher clinical success rates and improved outcomes.
Even a single dose of an antibiotic may be effective. Bacteria disappear from the
urine within hours after antibacterial therapy has been initiated.
to defend itself through micturition, acidification, and inherent antibacterial
activity, gives theoretic support to the clinical evidence that a large single dose of an
antibiotic can eradicate a UTI. Fosfomycin trometamol is a perfect example of this
principle: very high urinary concentrations of this bactericidal agent are maintained
for more than 24 hours after a single 3-g oral dose and contribute to the favorable
clinical efficacy observed in comparative trials.
Although not recommended in the current guidelines, single doses of antibiotics
other than fosfomycin are also occasionally used in treating acute, lower UTI in
3 g, ampicillin 3.5 g, nitrofurantoin 200 mg, ciprofloxacin 500 mg, and norfloxacin
20 Again, choice of a specific agent should be based on local susceptibility
patterns, patient allergies, and relative drug costs. Female patients with history or
clinical presentation suggestive of complicated infection (e.g., systemic
manifestations of infection, renal disease, anatomic abnormalities of the urinary tract,
diabetes mellitus, pregnancy), a history of antibiotic resistance, or a history of
not have any of these contraindications, she could theoretically receive single-dose
therapy with an appropriate agent.
The advantages of single-dose treatment of UTI include improved compliance,
reduced cost, proven efficacy in a defined population of patients (i.e., young women
with acute, uncomplicated lower UTI), minimal side effects, and a potentially
decreased incidence of bacterial resistance associated with antibiotic overuse.
However, several concerns also exist regarding single-dose therapy.
sample sizes in most comparative studies were relatively small. Consequently, it is
difficult to determine whether differences in effectiveness or incidence of side effects
therapy has demonstrated that single-dose therapy is significantly less effective in
eradicating bacteriuria than regimens of ≥5 days (83% vs. 93%, respectively, p <
0.001) or ≥7 days in duration (87% vs. 94%, respectively; p = 0.014).
discussed in Case 71-1, Question 3, reduced microbiological efficacy was also
observed with single-dose fosfomycin.
20 Although fewer studies have directly
compared single-dose versus 3-day therapies, numerous studies have shown that 3-
day courses are as effective as courses of longer duration.
therapies have been associated with higher rates of recurrence compared with
5 A 3-day on 5-day course of therapy is therefore
currently recommended by the IDSA/ESMID for uncomplicated cystitis; a large
single dose of fosfomycin is the sole single-dose regimen endorsed by the
Based on the preceding information, and according to current guidelines, a 3-day
course of TMP–SMX, a 5-day course of nitrofurantoin, or a single dose of
fosfomycin would be most appropriate for treatment of V.Q.’s infection ( Table 71-
When using short-course regimens, it is important to counsel the patient that the
clinical signs and symptoms of infection may often not be completely resolved for 2
to 3 days after initiation of therapy. Therefore, symptoms that persist for a short
CASE 71-1, QUESTION 5: Along with TMP–SMX, phenazopyridine is also prescribed because of V.Q.’s
complaints of significant dysuria. Is phenazopyridine appropriate for this patient?
Phenazopyridine, a urinary tract analgesic, occasionally is prescribed alone or
along with an antibacterial agent for the symptomatic relief of dysuria. Although
phenazopyridine at a dose of 200 mg orally three times a day may relieve dysuria, it
is ineffective in the actual eradication of true UTI. Phenazopyridine plus an antibiotic
is not any better than an antibiotic alone; therefore, the drug is not likely of significant
value in V.Q. and should not be routinely recommended. However, although most
patients have resolution of symptoms within 24 to 48 hours after beginning therapy,
certain patients with severe dysuria or delayed response to antibiotic therapy may
benefit symptomatically from a short trial (1–2 days) of phenazopyridine.
for, and duration of, analgesic therapy must be individualized.
Phenazopyridine is an azo dye and may discolor the urine to an orange–red,
orange–brown, or red color that can stain clothes. Other adverse effects of
phenazopyridine occur after acute overdose, or as a result of accumulation in older
patients or in patients with decreased renal function who take the drug chronically. In
vivo, about 50% of phenazopyridine is metabolized to aniline, which can cause
methemoglobinemia and hemolytic anemia. Hemolytic anemia associated with
phenazopyridine occurs primarily in patients with glucose-6-phosphate
dehydrogenase (G6PD) deficiency.
64 Cases of reversible acute renal failure and
allergic hepatitis have also been rarely reported after brief exposure to
INTERPRETATION OF URINE CULTURE AND SUSCEPTIBILITY TEST
CASE 71-1, QUESTION 6: Two days after V.Q. begins treatment for her infection with TMP–SMX, results
of the C&S studies become available and reveal greater than 10
5 bacteria per milliliter of P. mirabilis, which is
Most women with either lower or upper UTI have greater than 10
colonies/mL of urine. However, a major revision in the diagnostic criteria for
symptomatic UTI has been the abandonment of the absolute requirement for growth of
5 bacterial colonies/mL of urine. The criterion of greater than or equal to 100
bacteria/mL results in excellent sensitivity and specificity in correctly diagnosing and
treating women with symptomatic infection.
13 This same criterion should also be
applied to lower UTI when S. saprophyticus is isolated, because UTIs caused by this
pathogen often are associated with low urine bacterial colony counts, suboptimal
growth on commonly used media, and negative findings on nitrite screening.
Mixed flora (more than two organisms) is unusual except in severely debilitated
persons and other complicated infections. Thus, mixed flora in the setting of
uncomplicated infection frequently suggests contamination, and a repeat specimen
Bacterial susceptibility to different antimicrobial drugs is usually determined by
referencing interpretive criteria that correlate with achievable serum concentrations
of those drugs. However, drugs useful in the treatment of UTI are excreted primarily
by the kidney, and urine concentrations of these drugs may be 20 to 100 times greater
than serum concentrations. Therefore, infections caused by organisms that are only
intermediately susceptible, or even “resistant” to the tested concentration of
antibacterial drug, might still be effectively treated with the high concentration of
Although in-vitro susceptibility testing is not always predictive of patient response
to therapy of UTI, studies clearly show that patients infected with a resistant pathogen
are at increased risk of treatment failure.
66 Clinical response to infection
occurred in only 24% to 61% of patients with organisms resistant to TMP–SMX
compared with 83% to 92% of patients infected with susceptible organisms
furthermore, patients infected with TMP–SMX-resistant pathogens were 17 times
more likely to fail therapy compared with patients with susceptible strains.
treated with TMP–SMX, who were infected with drug-resistant organisms, were also
found to have longer median times to symptom resolution (14 vs. 7 days, p = 0.0002),
more frequent return clinic visits within 1 week (36% vs. 6%, p < 0.0001), more
frequent need for subsequent antibiotic therapy (36% vs. 4%, p < 0.0001), and higher
rates of significant bacteriuria after 1 month (42% vs. 20%, p = 0.04).
Although up to 75% of patients with resistant organisms may experience failure of
TMP–SMX therapy, antimicrobial therapy is usually chosen empirically without the
benefit of C&S testing results. Appropriateness of antibiotic therapy is, thus, usually
judged according to subsequent clinical response. If the infecting organism is
susceptible, the urine will usually be sterile for 24 to 48 hours. If a urine specimen
collected 48 hours after initiation of therapy is not sterile and the patient has been
taking the medication properly, the antibiotic may be inappropriate or the focus of
infection may be deeper (e.g., pyelonephritis, abscess, obstruction). If the urine
specimen is sterile and the patient is symptomatically improved, the appropriate
antimicrobial is being used (regardless of susceptibility studies) and the full course
of therapy should be completed. Because V.Q. reports significant improvement in her
subjective symptoms, her 3-day course of TMP–SMX should be completed as
originally ordered and V.Q. should be closely monitored for any evidence of relapse.
A repeat C&S test should be performed in the event that V.Q. reports any new signs
or symptoms which are consistent with antibiotic failure and relapse of her infection,
and a different antibiotic should be selected for treatment at that time.
Appearance, straw-colored and turbid (normal, straw-colored and clear)
Specific gravity, 1.028 (normal, 1.002–1.028)
Glucose, ketones, and bilirubin, all negative (normal, all negative)
Blood and protein, both trace positive by dipstick (normal, both negative)
WBC, 10 to 15 cells/LPF (normal, 0–2 cells/LPF)
RBC, 5 to 10 cells/LPF (normal, 0–2 cells/LPF)
Bacteria, many (normal, 0 to rare)
Epithelial cells, 3 to 5 cells/LPF (normal, 0 to few cells/LPF)
Leukocyte esterase and nitrite tests by dipstick, both positive (normal, both negative)
the past. What is the role of fluoroquinolones in the treatment of I.B.’s community-acquired UTI?
Several fluoroquinolones are indicated for the treatment of uncomplicated or
complicated UTI; these include norfloxacin, ciprofloxacin, and levofloxacin. The
fluoroquinolones are usually administered orally in the treatment of UTI and have
excellent in-vitro activity against most gram-negative organisms, including P.
68 They are also active in vitro against many gram-positive organisms
68 The activity of many fluoroquinolones in vitro is
antagonized by urine (acidic pH, divalent cations); however, this is unlikely to be
clinically significant because urine concentrations are several hundred-fold greater
68 A large number of clinical trials have demonstrated that
fluoroquinolones are very effective in the treatment of acute uncomplicated UTI with
efficacy rates typically greater than 90%.
68 Concerns also exist regarding the overuse of
fluoroquinolones and the promotion of drug resistance among community-acquired
uropathogens. Resistance to fluoroquinolones among organisms causing acute
uncomplicated UTI is usually less than 1% to 2%.
21 Fluoroquinolone resistance may,
however, be more frequent in some geographic areas and in complicated
; recent studies have documented resistance to ciprofloxacin in 2% to
10% of acute uncomplicated infections, whereas it is 8% to 60% in complicated
46–49,69 Furthermore, these quinolone-resistant strains often are resistant to
multiple other antimicrobials.
46–49,69 Concerns also exist regarding the potential for
fluoroquinolones to produce collateral effects on normal flora, these alterations
leading to increased risk of infection because of methicillin-resistant S. aureus and C.
Fluoroquinolones are recommended as appropriate alternatives for patients with
allergies or other contraindications to the use of other first-line agents, or for patients
infected with organisms resistant to multiple antibiotics, such as P. aeruginosa.
Fluoroquinolones are appropriate initial therapy in geographic areas with greater
than 20% resistance of E. coli to TMP–SMX20
; however, many patients in such areas
may be appropriately treated with nitrofurantoin or some other options (Table 71-
20 Finally, the fluoroquinolones are effective in treating patients with structural or
functional abnormalities of the urinary tract and other complicated infections.
A fluoroquinolone may be considered for I.B. because she has experienced
previous adverse reactions to penicillins and sulfonamides. However, nitrofurantoin
or fosfomycin should be preferentially considered for I.B. based on current
If a fluoroquinolone was deemed appropriate for
I.B. based on other unspecified factors such as availability, cost, or tolerability
issues with other treatment options, the fluoroquinolones are similar in efficacy and
the choice would be based on comparative costs and compliance considerations.
The duration of fluoroquinolone therapy in I.B. would be 3 days.
NITROFURANTOIN-INDUCED ADVERSE EFFECTS
CASE 71-2, QUESTION 2: The decision is made to begin I.B. on nitrofurantoin rather than a
Nausea is a common complication of nitrofurantoin therapy, and the patient’s
adherence with the prescribed regimen may be affected by this side effect. It is not
known whether the mechanism by which nitrofurantoin produces nausea is central or
local. Taking nitrofurantoin with food may reduce nausea either through serving as a
buffer or slowing the rate of absorption and reducing peak concentrations
of the drug. Food, however, may also increase the bioavailability of nitrofurantoin.
Slowing of absorption is particularly beneficial in decreasing the incidence of nausea
and vomiting associated with the microcrystalline product.
macrocrystalline preparation may also reduce adverse effects through slowing rates
of dissolution and absorption, and producing lower serum levels. A disadvantage of
the macrocrystalline form is the cost, which may be 2 to 10 times that of the
microcrystalline form, depending on the product source. Finally, because nausea and
vomiting appear to be dose related and occur more frequently in small persons,
reducing the daily dose of nitrofurantoin may also improve tolerability.
the best-studied and clinically effective dose of nitrofurantoin is 100 mg twice
,which I.B. is currently receiving. I.B. should remain on her current dose;
taking the drug with food and/or switching to a macrocrystalline product should
allow her to successfully finish her course of nitrofurantoin at the recommended
Several hundred cases of nitrofurantoin-induced acute, subacute, or chronic
pulmonary reactions have been reported.
70 Acute toxicity often manifests within
several days of initiating the drug with a sudden flu-like syndrome consisting of
fever, dyspnea, and cough; eosinophilia may also be present. The subacute form
usually occurs after at least a month of exposure; symptoms include fever and
70 Discontinuation of nitrofurantoin results in complete
symptomatic recovery after several weeks; however, permanent fibrotic changes may
persist with chronic pulmonary reactions. Rechallenge with oral nitrofurantoin
results in rapid reappearance of pulmonary symptoms in those who have had an acute
Peripheral neuropathy may also occur during nitrofurantoin therapy and is
characterized by symmetric dysesthesia and paresthesia in the distal extremities,
which progresses in a central and ascending fashion.
within the first 60 days of chronic nitrofurantoin treatment and is rarely seen during
71 Symptom severity is not dose-related and is generally
reversible, although more severe cases may require up to several months to resolve
completely. Renal failure is a risk factor for both neurotoxicity and pulmonary
toxicity, but neuropathy has also been reported in patients with normal renal
FLUOROQUINOLONE USE IN PEDIATRIC INFECTIONS
pending laboratory test results. C&S results, however, are now available and show >10
be most appropriate for continued management of this acute infection in C.S.?
This case illustrates the serious dilemmas caused by antibiotic resistance among
uropathogens. The pathogen isolated from C.S. is resistant to all commonly used,
orally administered antibiotics that have been proved effective in the treatment of
UTI in pediatric patients. Penicillins, cephalosporins, nitrofurantoin, and
sulfonamides are frequently recommended for treatment of pediatric UTI; however,
multiple past treatment regimens and chronic antibiotic prophylaxis make these
agents less suitable for treatment of this new infection in C.S. Although in-vitro
susceptibility testing does not accurately predict clinical response to therapy in all
cases, the risk of treatment failure and poor patient outcome is significantly increased
when agents to which isolates are resistant are administered.
treatment is required; however, few desirable options exist for C.S.
The recommended duration of antibiotic therapy in C.S. would be at least 2 weeks
for the treatment of this complicated and recurrent infection (refer to subsequent
sections of this chapter). Although the organism isolated from C.S. is susceptible to
gentamicin and this drug would be effective, parenteral (intramuscular or
intravenous) administration would be required and the lengthy required treatment
duration makes this far from ideal. Use of aminoglycosides would also be less
desirable because of toxicity concerns. Although ertapenem would also likely be
effective, there is relatively little clinical experience with this agent in the pediatric
population and ertapenem would also require parenteral administration for the
duration of the treatment regimen.
Fluoroquinolones are contraindicated in children and adolescents younger than 18
years of age because of concerns regarding potential musculoskeletal toxicities in
juvenile populations. Although not approved for pediatric use, fluoroquinolones have
been formally studied for febrile neutropenia, infectious gastroenteritis, otitis media,
bacterial meningitis, and other uses in pediatric patients.
fluoroquinolones has substantially increased in children and adolescents, most likely
owing to resistance to other antimicrobials; approximately 520,000 prescriptions
were written for patients younger than 18 years of age during 2002, of which nearly
3,000 prescriptions were for children younger than 2 years.
summarized data related to the safety of fluoroquinolones in children. Although
tendinopathy or other musculoskeletal toxicities have been recorded, these toxicities
have been usually mild, reversible, and occurring at rates comparable to that seen in
72–74 Based on currently available information and in consideration of
antimicrobial resistance, the American Academy of Pediatrics has published
recommendations regarding the use of fluoroquinolones in children and adolescents.
These indicate that fluoroquinolones may be considered in special circumstances
including (a) infections caused by multidrug-resistant pathogens for which there are
no other safe and effective alternatives and (b) times when parenteral therapy is not
feasible and no other effective oral agent is available. Treatment of UTI caused by
multidrug-resistant, gram-negative pathogens are specifically mentioned as a
potentially appropriate use for fluoroquinolones in pediatric patients.
Selection of a specific agent for the treatment of UTI in C.S. should be based on
careful consideration of potential risks and benefits of available antibiotic options.
The feasibility, risks, expenses, and inconvenience associated with prolonged (≥2
weeks) parenteral administration of an aminoglycoside or carbapenem are
problematic; however, the ease of oral fluoroquinolone administration must be
carefully balanced against the possible risks of using these agents in C.S. Clearly, no
antibiotic of choice exists for treatment of C.S. and both the providers and the child’s
parents must be involved in development of an acceptable and well-informed
TREATMENT OF LOWER-TRACT INFECTION IN
antimicrobial agent should be prescribed?
The major problem in treating UTI in patients with renal failure is how to achieve
adequate urine concentrations of the drug without causing systemic toxicity. The ideal
drug would be (a) inherently nontoxic, even at high serum concentrations, making
dosage adjustments unnecessary; (b) excreted unchanged in the urine (i.e., not
metabolized); and (c) eliminated by renal tubular secretion rather than glomerular
filtration. Because renal tubular secretion remains active in all but the most severe
cases of renal failure, antibiotics eliminated by this mechanism would reach adequate
urinary levels; however, no such ideal drug exists.
Nitrofurantoin and many sulfonamides are substantially metabolized by the liver
and generally produce low urine levels in uremic patients. The aminoglycosides are
eliminated almost exclusively by the kidneys, but uremic patients are at high risk of
drug-induced toxicities and alternative agents are usually recommended. Penicillins,
cephalosporins, and trimethoprim are partially metabolized by the liver but are also
eliminated by the kidney to a significant extent. These agents are suitable for use in
renal failure according to the criteria described above. Certain fluoroquinolones,
specifically ciprofloxacin and levofloxacin, are highly excreted in the urine through a
combination of filtration and tubular secretion and reach extremely high urinary
concentrations. These agents are also considered safe and effective in the treatment
of UTI in patients with renal failure.
mm Hg, and CVA tenderness. A Gram stain of L.B.’s urine reveals gram-negative rods, and a UA
blood sugars. Which signs and symptoms in L.B. are consistent with pyelonephritis?
It is not always possible to differentiate clinically between upper and lower
urinary tract infections. Symptoms common in lower UTI often are the only positive
findings in upper UTI (i.e., subclinical pyelonephritis).
manifest signs and symptoms of systemic infection consistent with acute bacterial
pyelonephritis, including tachycardia, hypotension, fever, nausea and vomiting,
shaking chills, flank pain, CVA tenderness, hematuria, and WBC casts. In addition,
her diabetes may predispose her to various renal infections, including pyelonephritis,
possibly because diabetic patients have altered antibacterial defense
CASE 71-5, QUESTION 2: Why was L.B. hospitalized?
Most patients with clinical pyelonephritis have relatively mild infection and
usually can be treated as outpatients. The need for hospitalization often is determined
by the patient’s social situation and ability to maintain an adequate fluid intake and
2–5,8,20 Patients who experience significant nausea and/or
vomiting may not be able to maintain adequate hydration and thus may be at higher
risk for cardiovascular complications of infection. Such patients may also require
parenteral therapy initially in order to guarantee adequate initial antibiotic therapy.
Finally, patients such as L.B. with diabetes should be hospitalized because acute
pyelonephritis may predispose her to diabetic ketoacidosis.
Although blood cultures are usually obtained in patients with moderate-to-severe
pyelonephritis, one study found that blood cultures were of low yield in the setting of
acute uncomplicated pyelonephritis; they rarely provided any additional information
not already obtained from the urine culture and were not helpful in the clinical
76 Blood cultures may be positive in up to 25% of patients
with severe or complicated pyelonephritis, however, and they are still recommended
for hospitalized patients such as L.B.
ANTIMICROBIAL CHOICE FOR PYELONEPHRITIS
CASE 71-5, QUESTION 3: Was ampicillin appropriate treatment for L.B.?
Ampicillin is not an appropriate choice for L.B. because diabetic patients (and
patients treated with corticosteroids) are susceptible to colonization with unusual or
more resistant organisms. As with lower tract UTI, pyelonephritis is often classified
as uncomplicated or complicated. L.B.’s infection would be classified as a
complicated infection because of her underlying diabetes.
E. coli remains the predominant pathogen in complicated pyelonephritis, but other
gram-negative organisms (e.g., Klebsiella, Proteus, Pseudomonas) are found
2–5,8 Because L.B. is acutely ill and has gram-negative organisms in her
urine, she should be treated with an antibiotic that has a better spectrum of activity
against gram-negative organisms. Because of high rates of ampicillin resistance
among common uropathogens, ampicillin and amoxicillin are inappropriate for the
empirical therapy of UTI, including pyelonephritis.
recommendations for the initial oral management of acute pyelonephritis are shown
i n Table 71-3. Because L.B. is to be hospitalized, broad-spectrum antibiotics
appropriate for initial therapy would include parenteral third-generation
cephalosporins (e.g., ceftriaxone), IV fluoroquinolones (e.g., ciprofloxacin,
levofloxacin), extended-spectrum penicillins, such as piperacillin–tazobactam, or
2–5,8,20 Aminoglycosides may be used empirically as either monotherapy
or in combination with various β-lactams: in combination with ampicillin to provide
better activity against suspected enterococci, or together with cephalosporins or
piperacillin–tazobactam to provide enhanced gram-negative activity.
a specific regimen is based on local susceptibility patterns and should be tailored as
needed on the basis of C&S test results.
It is not always necessary to initially treat
patients with antipseudomonal therapy; thus, agents such as ceftriaxone with
relatively less activity against
Pseudomonas are often appropriate as initial therapy in patients such as L.B.
Because most hospital laboratories can report C&S results within 48 hours, these
antibiotics can be replaced with more specific ones if appropriate.
SERUM VERSUS URINE CONCENTRATIONS
therapeutic success be determined?
In patients with pyelonephritis and infection of the renal parenchyma, adequate
tissue concentrations of antimicrobial agents are needed. Therefore, antibiotics that
achieve bactericidal concentrations in serum and kidney tissues as well as in the
77 Patients requiring hospitalization should be treated with
parenteral antibiotics until fluids can be taken orally and the patient is
symptomatically improved and afebrile for 24 to 48 hours.
followed with a course of oral antibiotics for a total duration of antimicrobial
therapy of approximately 14 days; less severe infections not requiring hospitalization
are usually treated with 7- to 14-day courses, depending on the specific agent
20 Although it is customary to observe the patient in the hospital for 24 hours
after switching from parenteral to oral antibiotics before discharge, this is probably
2–5,8 Specimens for C&S testing should be obtained on the second
day of therapy (to rule out treatment failure), 2 to 3 weeks after the completion of
therapy, and again at 3 months.
For patients who have relapsed after 14 days, retreatment for 6 weeks usually is
curative. There have been reports of successful retreatment of relapsed infection with
; however, longer courses are recommended.
ORAL THERAPY FOR PYELONEPHRITIS
CASE 71-5, QUESTION 5: Would oral therapy have been appropriate for the initial treatment of acute
Patients with mild, acute pyelonephritis (no nausea, vomiting, or signs of sepsis)
can be treated with oral antibiotics such as fluoroquinolones for 5 to 7 days, or with
2–5,20 Oral fluoroquinolones are preferred agents for initial
empirical therapy of acute pyelonephritis in patients not requiring hospitalization
because of lower rates of resistance among common uropathogens compared to
TMP–SMX, and higher rates of clinical and microbiological efficacy compared to βlactams.
20 Fluoroquinolones may be particularly useful for patients potentially
infected with resistant organisms because of their excellent in-vitro activity against
gram-negative organisms and high kidney tissue concentrations (2-fold to 10-fold
68 However, fluoroquinolone resistance and risk of inappropriate
initial therapy may be more common in certain geographic areas. If fluoroquinolone
resistance among E. coli exceeds 10%, treatment for acute pyelonephritis should be
initiated with an intravenous dose of extended-spectrum cephalosporin or an
aminoglycoside until C&S test results are known (Table 71-3).
amoxicillin–clavulanate, cefuroxime, cefpodoxime proxetil, or cefdinir also can be
used in this setting, but the most recent guidelines suggest that oral β-lactams are less
Patients such as L.B. with evidence of bacteremia (e.g., fever, shaking chills) or
sepsis (e.g., hypotension) should be hospitalized and treated with parenteral
(see Table 71-4). L.B.’s frequent vomiting and potential inability to
be successfully treated with oral antibiotics would also make initial therapy with
parenteral antibiotics more favorable. Although L.B. will be initially treated with
parenteral antibiotics, early switch to oral therapy after as few as 1 to 4 days of
treatment is recommended; clinical outcomes with oral antibiotics are similar to
those achieved with continued parenteral therapy (i.e., 5 days or longer).
RECURRENT URINARY TRACT INFECTIONS
especially useful at this time?
Recurrent infections develop in approximately 20% to 30% of women with acute
80 Repeat C&S data should help determine whether this infection
represents a relapse or a reinfection. Relapse refers to a recurrence of bacteriuria
caused by the same microorganism that was present before initial therapy. Most
relapses occur within 1 to 2 weeks after the completion of therapy and are caused by
persistence of the organism in the urinary tract. Relapses often are associated with an
inadequately treated upper UTI (e.g. medication non-adherence), structural
abnormalities of the urinary tract, or chronic bacterial prostatitis.
Reinfection implies recurrence of bacteriuria with a different organism than was
present before therapy. Reinfections can occur at any time during or after the
completion of treatment, but most appear several weeks to several months later.
Approximately 80% of recurrences are caused by reinfection.
generally caused by introital colonization with Enterobacteriaceae from the lower
; of these, E. coli is the most common. Certain E. coli strains have
been shown to adhere to vaginal epithelial cells and, in women with recurrent UTI,
adherence of these organisms to epithelial cells is increased.
symptom-free for 8 weeks suggests that this is a reinfection, rather than a relapse.
Patients with reinfection should be investigated for modifiable predisposing factors
such as use of a diaphragm with or without spermicides. Patients with frequent
reinfections should also be evaluated for risk factors such as anatomical
abnormalities, undiagnosed glucose intolerance or diabetes, or other factors.
CASE 71-6, QUESTION 2: Pending the C&S test results, what therapy should be instituted in T.W.?
T.W. has a history of recurrent infections and now probably has a reinfection.
Because reinfection is not caused by failure of previous therapy, TMP–SMX may be
a reasonable choice once again. The probability that a resistant organism will be
responsible for the infection increases when the interval between infectious episodes
is short. If several months elapse between each episode of antimicrobial therapy,
normal fecal bacterial flora become reestablished and the risk of infection with
resistant pathogens is reduced.
Parenteral Antimicrobial Agents Commonly Used in the Treatment of Urinary
Penicillins Ampicillin 2–4 g 8 g Every 4–6
Piperacillin–tazob9acgtam 18 g Every 4–6
Cefazolin 1.5–3 g 6 g Every 8–12
More effective than second- or thirdgeneration cephalosporins against
Intermediate between first- and thirdgeneration cephalosporins against
C gram-negative organisms. efuroxime 2.25 g 4.5 g Every 8 hours
Cefotaxime 3–4 g 8 g Every 6–8
Better coverage than first- and
second-generation cephalosporins
against gram-negative organisms.
Ceftazidime and cefepime are most
effective against Pseudomonas. All
generations of cephalosporins are
ineffective against Enterococcus
faecalis and methicillin-resistant
Ceftriaxone 1 g 2 g Every 12–24
Ceftazidime 1.5–3 g 6 g Every 8–12
Ceftaroline has activity against
methicillin-resistant staphylococci.
Ceftaroline 0.6 0.6 g Every 12
1 g 2 g Every 6 hours The most broad-spectrum coverage
of any antibiotics listed. Ertapenem
not active against Pseudomonas.
Resistance may develop especially
with Pseudomonas. Toxic in some
Meropenem 1.5–3 g 3 g Every 8 hours
Ertapenem 0.5–1 g 1 g Every 24
Monobactam Aztreonam 1–2 g 6–8 g Every 8–12
Active against gram-negative aerobic
pathogens, including Pseudomonas
Aminoglycosides Gentamicin 3 mg/kg 5–7
bacteria including Pseudomonas.
Associated with possible eighth nerve
toxicity in the fetus. Amikacin should
be reserved for multiresistant
Quinolones Ciprofloxacin 400–800 800 mg Every 12 Use for resistant organisms. Change
mg hours to oral Therapy when indicated.
(see Chapter 62, Principles of Infectious Diseases)
The alteration of fecal flora caused by the sulfonamides makes these drugs poor
choices for repeated use in cases of frequent reinfection, especially when C&S
results are unknown. The development of bacterial resistance also may limit the
usefulness of these agents for chronic antimicrobial therapy.
because her most recent infection was 12 weeks ago and the UTI prior to that was 5
months earlier, TMP–SMX would again be a reasonable choice at this time.
CASE 71-6, QUESTION 3: If T.W. exhibited an adverse reaction to TMP–SMX, what are some other
Nitrofurantoin is highly effective against E. coli with relatively low rates of
resistance (<10%) in most geographic areas. It does not significantly alter the fecal
or introital flora, and the development of resistance in previously sensitive strains
81 Therefore, it is generally a useful agent for the treatment
of recurrent E. coli, S. saprophyticus, and Enterococcus infections.
The fluoroquinolones also are useful in this setting, especially in geographic areas
with high rates of TMP–SMX resistance.
78 Their widespread use should not be
encouraged for reinfections as in T.W. in light of their high cost and concern
regarding selection of resistant organisms.
80 Cephalosporins (e.g., cefuroxime,
cefpodoxime proxetil) and trimethoprim have also been recommended as alternative
Antibiotic Selection for Treatment of Relapse
CASE 71-6, QUESTION 4: Greater than 10
5 bacteria per milliliter of P. mirabilis, sensitive to ampicillin and
TMP–SMX, are cultured from T.W.’s urine. One week after completing her second course of TMP–SMX
this still a reasonable medication for T.W. at this time?
Because the P. mirabilis cultured during the last recurrence was still susceptible to
TMP–SMX, this agent would again be a reasonable choice until C&S test results are
obtained. Alternatively, use of a different agent (e.g., nitrofurantoin, fluoroquinolone)
could be considered because the relapse occurred within 1 week of completing the
previous treatment and resistance may have developed.
treatment failure, including failure to adhere to previously prescribed medication
regimens, should also be investigated in patients with apparent recurrent infections.
CASE 71-6, QUESTION 5: How long should antibiotic therapy be continued in T.W. for her relapsed
The duration of therapy for relapsing infections usually is 14 days. In patients who
relapse after a second 2-week course of therapy, treatment for 6 weeks should be
If relapse occurs after a 6-week course, some experts recommend
longer courses of 6 months to 1 year.
1–3 These prolonged courses should be reserved
for children, adults who have continuous symptoms, or adults who are at high risk for
experiencing progressive renal damage. Asymptomatic adults without evidence of
obstruction should not receive these longer courses. T.W. should be treated for at
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