Which antibiotic will the nurse plan to administer if a patient with bacterial endocarditis has a culture revealing gram

Treatment of Specific Organisms

When the organism is definitively identified, antibiotic treatment must be narrowed accordingly, and validated regimens should be followed (seeTable 67-6). More controversy exists over the treatment of unusual organisms, and consultation with infectious disease specialists is advisable in such circumstances, especially since data from randomized trials provide little evidence about preferable antibiotic regimens.A1

Many regimens recommend consideration of low-dose gentamicin to provide antibacterial synergy with a low risk of toxicity. However, aminoglycoside toxicity is a significant risk in elderly patients and in patients with preexisting renal disease or hearing impairment; even low-dose gentamicin increases the likelihood of a decrease in creatinine clearance by about three-fold. Among the organisms listed inTable 67-6, gentamicin is critical for cure only in enterococcal endocarditis. As a result of these risks and the minimal data supporting its benefit, initial low-dose gentamicin should not be routinely used.

In uncomplicated viridans group streptococcal endocarditis, outpatient therapy with once-daily ceftriaxone is as effective as more complex regimens, provided the patient has been observed in the hospital for the development of complications. The decision to administer antimicrobial therapy in the outpatient setting must, of course, take into account the patient’s social situation, likelihood of compliance, and other risks involved with either an indwelling IV line or recurrent peripheral IV line placements.

Standard therapy for infective endocarditis caused by fully susceptible enterococci includes penicillin or ampicillin plus gentamicin. Although gentamicin is preferred over streptomycin, the choice of a specific aminoglycoside should be based on in vitro susceptibility testing. Nonrandomized data suggest that the duration of aminoglycoside therapy can be limited to 2 to 3 weeks in combination with either penicillin, ampicillin, or vancomycin or that aminoglycoside therapy can be avoided in favor of combination therapy with ampicillin plus high-dose (2 g IV every 12 hours) ceftriaxone. Optimal therapy for enterococci that are resistant to aminoglycosides or vancomycin is not well defined. Endocarditis caused by vancomycin-resistant enterococci may be treated with daptomycin, quinupristin–dalfopristin (7.5 mg/kg IV every 8 hours), or linezolid (600 mg orally or IV twice daily); however, clinical experience with these agents is limited. In this situation, relapse or failure rates are likely to be high, and many cases require surgical intervention (discussed later).

Semisynthetic penicillins, such as nafcillin, are advocated for endocarditis caused by methicillin-susceptibleS. aureus. Cefazolin represents an alternative to semisynthetic penicillins in cases in which the latter are not tolerated or feasible to administer. Although vancomycin is recommended in patients who are allergic to β-lactams, the microbiologic and clinical cure rates are less than that of β-lactam therapy. In a recent randomized trial, daptomycin (6 mg/kg/day for 10 to 42 days, depending on the severity of infection) was as effective as either a semisynthetic antistaphylococcal penicillin or vancomycin for the treatment ofS. aureus bacteremia and right-sided infective endocarditis caused by methicillin-susceptibleS. aureus and MRSA, and this agent is now approved by the Food and Drug Administration for these indications. Ceftaroline, a fifth-generation cephalosporin, can be successful in patients with MRSA bacteremia and endocarditis.

Rifampin or gentamicin can be added to either nafcillin or vancomycin for the treatment of prosthetic valve infection caused by methicillin-susceptibleS. aureus or to MRSA, respectively. Gentamicin is administered for 2 weeks, and rifampin is given for the duration of either nafcillin or vancomycin therapy. Rifampin is never used as monotherapy because of the rapid development of resistance.

Fungal endocarditis is usually a consequence of extensive health care contact. Traditionally, fungal endocarditis was regarded as a primary indication for valvular surgery, and amphotericin B (Chapter 315) was considered the adjunctive treatment of choice. However, many patients withCandida endocarditis can be treated medically with azole-containing antimicrobial agents, with or without amphotericin. The management of fungal endocarditis should always involve the collaboration of an experienced infectious diseases specialist.

Zoonotic endocarditis is usually culture negative and most commonly caused byBartonella spp. (Chapter 299),C. burnetii (Chapter 311), orBrucella species (Chapter 294). The treatments of choice for these fastidious pathogens are based on limited data, but documentedBartonella endocarditis is treated with doxycycline for 6 weeks plus gentamicin for the first 2 weeks.

In cases of presumed culture-negative endocarditis in which unusual organisms (seeTable 67-5) and other infections have been reasonably excluded, an empirical course of treatment may be undertaken. The choice of antimicrobial therapy should be influenced by the specifics of the patient’s presentation, and an infectious diseases consultation is recommended.

Continuing Care of the Patient with Endocarditis

In addition to antibiotics, appropriate inpatient care includes surveillance for the development of complications. Widening of the pulse pressure should alert the clinician to the possible development of acute aortic insufficiency (Chapter 66). A careful cardiac examination should be performed on a daily basis to assess for new regurgitant murmurs.

Repeat echocardiography is recommended during therapy for patients with persistent fever, recurrent embolic events, a new murmur, widening of the pulse pressure, or signs or symptoms of heart failure. It is also recommended to screen for periannular complications, especially in prosthetic valve endocarditis. By comparison, repeat echocardiography is not routinely recommended if patients respond adequately to antimicrobial therapy, although serial echocardiography is usually suggested over the ensuing years to screen for long-term valvular dysfunction.

Routine serial ECGs are not recommended. ECG-documented conduction abnormalities are a late sign of perivalvular infections in patients with endocarditis; TEE is the screening method of choice if this complication is suspected.

Any new neurologic findings should prompt a search for evidence of central nervous system (CNS) complications such as embolic events, cerebral hemorrhage, mycotic aneurysm, or brain abscess. Renal function should be closely monitored so that antibiotic doses can be adjusted if necessary. If gentamicin is used for more than a few days, the patient should be alerted to watch for the signs and symptoms of vestibular or otic toxicity. Audiometric testing at baseline and periodically thereafter should be considered in patients at high risk for aminoglycoside-induced ototoxicity, including elderly patients, patients with preexisting renal dysfunction or hearing damage, patients receiving prolonged courses of gentamicin, and patients who also receive other potentially nephrotoxic agents. Serum gentamicin trough concentrations should also be assayed at regular intervals (e.g., twice weekly and more often if renal function is changing) and should be targeted for 1 to 3 µg/mL or less; higher concentrations should prompt either lower or less frequent dosing or both.

Follow-up blood cultures may be indicated toward the end of the first week of therapy in patients whose infective endocarditis is caused by organisms that commonly fail first-line treatment, such asS. aureus or aerobic gram-negative bacilli. Positive cultures in this setting might suggest the need to change therapy, search for metastatic abscesses, or repeat echocardiography, but negative cultures are reassuring.

Patients with infective endocarditis may continue to be febrile for some time after the institution of appropriate antibiotic treatment. About 50% of patients defervesce within 3 days of starting antibiotics, 75% by 1 week, and 90% by 2 weeks. Patients whose endocarditis is caused byS. aureus, aerobic gram-negative organisms, or fungi tend to defervesce more slowly than patients infected with other organisms. Prolonged fever (>1 week after the institution of appropriate antibiotics) should prompt repeat blood cultures. If such cultures are negative, several possibilities should be considered: myocardial abscess, extracardiac infection (e.g., mycotic aneurysm, psoas or splenic abscess, vertebral osteomyelitis, septic arthritis), immune complex–mediated tissue damage, or a complication of hospitalization and therapy (e.g., drug fever, nosocomial superinfection, pulmonary embolism). Appropriate studies might include TEE, CT scan of the abdomen, bone scan, and urinalysis with microscopy (to elicit evidence of interstitial nephritis). IV line sites should be carefully examined for evidence of infection, and indwelling central lines should be changed accord-ing to published guidelines.

Anticoagulation in individuals with infective endocarditis is controversial. Although new anticoagulation in the setting of native valve endocarditis does not appear to provide a benefit, continuing ongoing anticoagulation may be advisable. Some authorities recommend continuing anticoagulation in patients with mechanical prosthetic valve endocarditis. However, discontinuation of all anticoagulation for at least the first 2 weeks of antibiotic therapy is generally advised in patients withS. aureus prosthetic valve endocarditis who have experienced a recent CNS embolic event; this approach allows the thrombus to organize and potentially prevents the acute hemorrhagic transformation of embolic lesions. Reintroduction of anticoagulation in these patients must be cautious, and the international normalized ratio must be monitored carefully. The best option for patients with other indications for anticoagulation, such as deep vein thrombosis, major vessel embolization, or atrial fibrillation, is less clear and should be decided in a multidisciplinary fashion that balances the risks and benefits for each individual patient.

High-dose (325 mg/day) aspirin does not prevent embolic events and tends to increase the incidence of bleeding in patients with infective endocarditis. Whether a patient should remain on chronic, low-dose (81 mg) aspirin if they develop subsequent infective endocarditis is uncertain.

Complications

The complications of infective endocarditis can be divided into four groups for ease of classification: direct valvular damage and consequences of local invasion, embolic complications, metastatic infections from bacteremia, and immunologic phenomena. Local damage to the endocardium or myocardium may directly erode through the involved cardiac valve or adjacent myocardial wall, resulting in hemodynamically significant valvular perforations or intra- or extracardiac fistulae. Such local complications typically present clinically with the acute onset of heart failure and carry a poor prognosis, even with prompt cardiac surgery. Valve ring abscesses also require surgical intervention and are more frequent in patients with prosthetic valves. Although a conduction defect on ECG may suggest the diagnosis, TEE is the diagnostic technique of choice for detecting paravalvular abscess, valve perforation, or intracardiac fistulae. Frank myocardial abscesses are found in up to 20% of cases on autopsy, andAspergillus endocarditis invades the myocardium in more than 50% of cases. Pericarditis is rare and is usually associated with myocardial abscess. Myocardial infarction (MI), thought to be caused by embolism of vegetative material into the coronary arteries, is seen in 40 to 60% of cases on autopsy, although most cases are clinically silent and lack characteristic ECG changes. However, up to 15% of elderly patients may present with clinical evidence of acute MI, with potentially disastrous complications if the MI is thought to be the primary event and the patient is given thrombolytic therapy. Heart failure is the leading cause of death in infective endocarditis, usually related to direct valvular damage.

Embolic events are less common now than in the preantibiotic era, but about 35% of patients have at least one clinically evident embolic event. In fungal endocarditis, the majority of patients have at least one embolic event, frequently with a large embolus. The presence of large (>10 mm), mobile vegetations on the echocardiogram, particularly when the anterior mitral valve leaflet is involved, predicts a high risk of embolic complications. In addition, patients may have frank infarction of cutaneous tissue from emboli. In addition to the skin, systemic emboli most commonly lodge in the kidneys, spleen, large blood vessels, or CNS. Vegetations of right-sided endocarditis usually embolize to the lungs and cause abnormalities on the chest radiograph, although occasionally such emboli reach the left-sided circulation via a patent foramen ovale.

Renal abscesses are rare in infective endocarditis; however, bland renal infarction is a frequent asymptomatic finding on abdominal CT scanning, seen in more than 50% of cases at autopsy. Similarly, splenic infarction occurs in up to 44% of autopsy-confirmed cases. Such emboli may be asymptomatic but also can cause left upper quadrant pain radiating to the left shoulder, sometimes as the presenting symptom of infective endocarditis. A splenic infarction that progresses to form an abscess can cause persistent fever or bacteremia, so such patients should undergo abdominal CT to search for this complication.

Mycotic vascular aneurysms, which frequently occur at bifurcation points, may be clinically silent until they rupture (which may be months to years after apparently successful antibiotic treatment of infective endocarditis) and have been found in 10 to 15% of cases at autopsy. Whereas peripheral mycotic aneurysms require surgical resection, intracerebral aneurysms can be resected or managed with intravascular techniques (e.g., coils) if they bleed or if they are causing a mass effect. For mycotic aneurysms of the abdominal aorta, endovascular repair may be preferable; but if endovascular therapy is used, long-term antibiotics are generally required.

Many patients may have evidence of cerebrovascular emboli, which have a predilection for the middle cerebral artery distribution and may be devastating. Most emboli to the CNS occur early in the course of the disease and are evident at the time of presentation or shortly thereafter. Embolic strokes may undergo hemorrhagic transformation, with a sudden worsening of the patient’s neurologic status. Many patients with fungal endocarditis present with an embolic stroke or large emboli that occlude major vessels.

Some complications of infective endocarditis result when bacteremic seeding causes metastatic infection at a distant site. Patients may present with or develop osteomyelitis, septic arthritis, or epidural abscess. Purulent meningitis (Chapter 384) is a rare complication except in pneumococcal endocarditis, although many patients withS. aureus infective endocarditis who undergo lumbar puncture have a pleocytosis. Importantly, the finding of one metastatic complication of infective endocarditis does not exclude the possibility of additional sites of hematogenous infection, particularly inS. aureus endocarditis. Thus, the need for additional diagnostic evaluations should be guided by the patient’s clinical course.

The immunologic phenomena of infective endocarditis are often directly related to high levels of circulating immune complexes. Renal biopsy results nearly always are abnormal in the setting of active infective endocarditis, which classically causes a hypocomplementemic glomerulonephritis (Chapter 113). Histopathologically, the glomerular changes may be focal, diffuse, or membranoproliferative, or they may be akin to the immune complex disease found in systemic lupus erythematosus. In addition, many of the musculoskeletal conditions associated with infective endocarditis, including monoarticular and oligoarticular arthritides, are probably immune mediated. These immunologic phenomena usually abate with successful antimicrobial therapy.

Surgery

Some patients with infective endocarditis require surgical treatment, either to cure the infection or to avoid its complications10,11 (Table 67-8). Most patients with evidence of direct extension of infection to myocardial structures, prosthetic valve dysfunction, or heart failure from endocarditis-induced valvular damage should undergo surgery. In addition, many cases of endocarditis caused by fungi, by aerobic gram-negative bacilli or multidrug-resistant organisms (e.g., vancomycin- or gentamicin-resistant enterococci) require surgical management. Progression of disease or persistence of fever and bacteremia for more than 7 to 10 days in the presence of appropriate antibiotic therapy may indicate the need for surgery; however, a thorough search must first be conducted to exclude other metastatic foci of infection. In a randomized trial of patients with left-sided infective endocarditis, severe valve disease, and large vegetations (>10 mm), early surgery did not significantly reduce all-cause mortality at 6 months but markedly decreased the risk of systemic embolism, including stroke and MI.A2 Surgical management should also be considered for patients with recurrent (two or more) embolic events or those with large vegetations (>10 mm) on echocardiography and one embolic event, although the data in these situations are less convincing. The presence ofS. aureus endocarditis involving the anterior mitral valve leaflet and large vegetations (>10 mm) may be a special circumstance calling for early surgical intervention to reduce the high risk of CNS emboli, especially when mitral valve repair, rather than valve replacement, can be accomplished. Unfortunately, only about 15 to 20% of these latter patients end up being good candidates for valve repair.

After 7 days of preoperative intravenous antibiotics, the risk of infection in an implanted valve is low.11b Delaying surgery in patients with deteriorating cardiac function in an attempt to sterilize the affected valve is ill advised because the risk of progressive heart failure or further complications usually outweighs the relatively small risk of recurrent infective endocarditis after prosthetic valve implantation. Relative contraindications to valve replacement include recent large CNS emboli (>2 cm) or bleed (because of the risk of bleeding in the perioperative period, when systemic anticoagulation is required), multiple prior valve replacements (because of the difficulty of sewing a new valve into tissue already weakened from previous surgeries), and ongoing injection drug use. On occasion, patients haveboth a compelling indication for valve replacement (e.g., acute heart failure) and a recent CNS embolic event. The risk of hemorrhagic transformation of such lesions during cardiac bypass–associated anticoagulation is controversial. However, it appears that the greatest risk of such transformation events is in larger (>2 cm) emboli, especially those that have exhibited a hemorrhagic component. In these latter scenarios, it is prudent to try to delay surgery for at least 2 to 4 weeks to allow organization and resolution of such emboli. However, there appears to be no survival benefit in delaying indicated valve replacement surgery (>7 days) after an ischemic stroke.

After definitive surgical treatment, most patients should receive further antibiotic therapy unless a full course of antibiotics was administered before surgery and there is no evidence of ongoing infection. If the patient received antibiotics for less than 1 week before surgery or the culture from the operative site is positive, the patient should receive the equivalent of a full initial course of antibiotics appropriate for the organism. If the patient received antibiotics for 2 weeks or more and the culture result from the operative site is negative (regardless of whether valve histopathology shows inflammation or a positive Gram stain result), the patient should receive whatever remains of the originally planned course of appropriate antibiotic therapy.

In patients with infective endocarditis related to implanted cardiovascular devices, complete device removal is mandatory, regardless of the pathogen, if the goal is to cure the infection.11c In patients who truly cannot tolerate device removal, chronic antibiotic therapy is the best alternative.12 If a replacement device needs to be implanted, the optimal timing for such a procedure is unclear. However, blood culture results should be negative, and any concomitant local or pocket site infection should be completely resolved.

The duration of antimicrobial therapy after device extraction depends on the device and the infection.13 For lead-related infective endocarditis, which is usually associated with bloodstream infection, 2 weeks of therapy is recommended if there are no infection complications. For infection caused byS. aureus, therapy should be extended for up to 4 weeks.

Nearly 40% of patients with infective endocarditis related to implantable cardiovascular devices have concomitant valve involvement, predominantly tricuspid valve infection, with in-hospital and 1-year mortality rates of 15% and 23%, respectively. Device removal appears to reduce the mortality rate by about 50% (from about 40% to about 20%). In such patients, concomitant 4 to 6 weeks of therapy is recommended.

Introduction

Ticarcillin is a semisynthetic, extended-spectrum, carboxypenicillin antibiotic. It is available as the disodium salt that can be administered parenterally. A beta-lactam antibiotic, ticarcillin is active against gram-positive cocci, including streptococci and staphylococci. However, it is rarely used to treat gram-positive infections since other agents are more active in this regard. Ticarcillin is effective against most gram-negative organisms, including Pseudomonas aeruginosa. In vitro, it is more active than carbenicillin against pseudomonas, but is less active than piperacillin. Gram-positive and gram-negative anaerobic organisms are also susceptible to ticarcillin. Ticarcillin is employed for the treatment of lower respiratory tract infections, skin and skin structure infections, urinary tract infections, and intraabdominal infections. Ticarcillin is sometimes combined with clavulanic acid, a beta-lactamase inhibitor, to eradicate some penicillin-resistant organisms.

Infective Endocarditis

P. aeruginosa accounts for 3% of all cases of infective endocarditis (IE).82 Among non-HACEK pathogens (species other thanHaemophilus species,Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, orKingella species),P. aeruginosa is the second most common gram-negative pathogen causing IE afterEscherichia coli.83 There are no unique clinical characteristics of IE caused byP. aeruginosa, although the presence of ecthyma gangrenosum should raise suspicion. Complications are common, and mortality rates are high, ranging from 36% to 60%.83

Intravenous drug users are the patient population at highest risk forP. aeruginosa IE. The great majority have used tripelennamine and pentazocine with contaminated water or paraphernalia. Patients predominantly present with right-sided endocarditis. Complications are frequent and include sepsis, embolization, and congestive heart failure.84 In this patient population, polymicrobial IE, with bothP. aeruginosa andStaphylococcus aureus, can also occur.84

Left-sided IE in patients without intravenous drug use also occurs, although infrequently. It is predominantly a nosocomial infection occurring after invasive procedures, including cardiac or urogenital procedures. Infected intravascular catheters have also been implicated in IE. Of note, valvular disease is not a necessary predisposing risk factor forP. aeruginosa left-sided IE.85 Splenic abscesses, neurologic sequelae, and ring and annular abscesses are frequent complications.86

The American Heart Association recommends, as per expert opinion, that medical treatment ofP. aeruginosa IE should include an extended-spectrum penicillin (ticarcillin, piperacillin) and ceftazidime or cefepime in full doses in combination with high-dose tobramycin (8 mg/kg/day IV or IM in once-daily doses) with peak concentrations of 15 to 20 µg/mL and trough concentrations of less than or equal to 2 µg/mL. This combination should be given for at least 6 weeks. Use of ciprofloxacin in combination with an aminoglycoside should be used with caution because ciprofloxacin resistance can occur during therapy. Other regimens that have been successful in a small number of patients include the combination of imipenem and an aminoglycoside.87

Case reports have also shown success with other combinations of antimicrobial agents. Among two renal transplant recipients with no valvular heart disease who developedP. aeruginosa nosocomial IE, 6 weeks of therapy with imipenem and ciprofloxacin was successful in the first patient and 2 weeks of imipenem and amikacin followed by 6 weeks of imipenem alone was successful for the second patient (amikacin was stopped early owing to nephrotoxicity). Both patients’ conditions were stable at 6 months of follow-up.88

Pharmacokinetic Data

Ticarcillin-clavulanate is available for intravenous administration in a 30:1 ticarcillin-clavulanate ratio [1,472,473]. Like piperacillin, ticarcillin is eliminated via glomerular filtration and renal tubular secretion. Approximately 60% to 70% of ticarcillin is excreted unchanged in urine during the first 6 hours after administration. However, only 30% to 40% of clavulanic acid is excreted unchanged in the urine while the remainder undergoes nonrenal metabolism. Ticarcillin is approximately 45% protein bound whereas clavulanic acid is approximately 25% protein bound. Ticarcillin penetrates well into bile and pleural fluid.

PK data for ticarcillin-clavulanic acid has been assessed in 64 preterm and term neonates; however, the ratio of ticarcillin/clavulanate was not consistent between reports [477–480]. In a study of 24 newborns (25 to 39 weeks of gestation) who received 80 mg/kg ticarcillin and 3.5 mg/kg clavulanate, the ticarcillin peak serum concentrations (mean 183 μg/mL, range 100 to 400) and half-life (mean 4.5 hours, range 1.2 to 9.5) are similar to those observed after administration of ticarcillin alone [480]. The ticarcillin and clavulanate half-lives were shorter in term infants (ticarcillin 2.7 hours, clavulanate 1.4 hours) than in preterm infants (ticarcillin 4.2 hours, clavulanate 2.6 hours) [479]. Similar results were reported for the one PK study that evaluated the commercially available product with a 30:1 ratio of ticarcillin:clavulanate [478].

Ticarcillin and clavulanate have different PK profiles. Ticarcillin is renally eliminated and clearance improves with renal maturation and chronologic age. Alternatively, clavulanate is eliminated through nonrenal mechanisms and is more rapid [454]. Ticarcillin accumulates in young neonates due to renal immaturity; however, clavulanate does not and therefore the ticarcillin:clavulanate ratio observed in older patient is not likely maintained in neonates. Simulation of ticarcillin and clavulanate exposure using a population PK model [478] suggested that a lower dose (50 mg/kg ticarcillin) administered more frequently (i.e., every 6 hours) was needed to maintain both ticarcillin and clavulanate levels. The significance of altered ticarcillin:clavulanate ratios is unclear [481] since we do not know the optimal duration or concentration for serum clavulanate.

Endocarditis Due to Enterobacteriaceae orPseudomonas Species

Approximately 2% of contemporary IE cases are caused by aerobic gram-negative bacilli.227 Health care contact and cardiac devices seem to have largely replaced injection drug use as the primary risk factors for acquisition of IE due to these bacteria. The prognosis is especially poor with left-sided cardiac involvement. Certain combinations of penicillins or cephalosporins and aminoglycosides have been shown to be synergistic against many of these strains and usually are recommended.334 For IE caused by most strains ofE. coli orProteus mirabilis, a combination of a penicillin, either ampicillin (2 g IV every 4 hours) or penicillin (20–24 million units IV daily), and an aminoglycoside, usually gentamicin or a broad-spectrum cephalosporin, is suggested. Third-generation cephalosporins are extremely active againstE. coli in vitro, and some (e.g., ceftriaxone) have proved effective in experimental animal models ofE. coli IE,701 even when long dosing intervals were used. This group of agents merits further evaluation in humans for IE due to susceptible gram-negative bacilli.

A combination of a third-generation cephalosporin and an aminoglycoside (either gentamicin or amikacin) is recommended forKlebsiella IE. IE due to carbapenem-resistantKlebsiella has been successfully treated with a combination of colistin and gentamicin in one case report. Certain β-lactam/β-lactamase inhibitor combinations (e.g., piperacillin-tazobactam,702 but not ceftriaxone-sulbactam703) are active in vivo in experimental models ofKlebsiella IE in animals induced by TEM-3–producing isolates and merit further evaluation in combination with an aminoglycoside in humans with this disease. The specific aminoglycoside used is a crucial variable and cannot be predicted totally from MIC data alone, because pharmacodynamic characteristics differ markedly in animal models of IE caused by gram-negative aerobic bacilli.704,705 EndovascularSalmonella infections, including IE, also may respond to third-generation cephalosporins (see later discussion).706 Left-sided IE due toS. marcescens is often refractory to medical therapy alone.432

P. aeruginosa is a rare but potentially devastating cause of IE in at-risk populations. Medical therapy may be successful inP. aeruginosa IE involving the right side of the heart in 50% to 75% of cases. If the disease is refractory to antibiotics, tricuspid valvulectomy or “vegetectomy”707 without valve replacement is indicated.708 Although valve replacement often is necessary for a cure of left-sided IE due toP. aeruginosa,709 medical therapy alone occasionally is curative.256,430 Studies in animals with experimentalPseudomonas IE710 offer a partial explanation for these disparate results: the penetration into vegetations and the time during which antibiotic concentrations exceeded the MBC were significantly greater with tricuspid vegetations than with aortic vegetations for ceftazidime and tobramycin.

TICARCILLIN-POTASSIUM CLAVULANATE

Ticarcillin combined with potassium clavulanate was approved for use in 1985. It extends the spectrum of activity of ticarcillin to include β-lactamase–producing strains of staphylococci (but not methicillin-resistant strains), H. influenzae, M. catarrhalis, E. coli, Klebsiella, Proteus, Providencia, N. gonorrhoeae, and B. fragilis.63 Ticarcillin-clavulanate also often is active against multidrug-resistant Stenotrophomonas maltophilia. Enterococci are moderately resistant to this agent. Because clavulanic acid does not inhibit Bush group 1–inducible chromosomal β-lactamases, Citrobacter, Enterobacter and Serratia spp., as well as de-repressed mutant strains of P. aeruginosa that are resistant to ticarcillin because of inducible cephalosporinases, also are resistant to ticarcillin-potassium clavulanate. Ticarcillin-potassium clavulanate is approved for use in children older than 3 months of age for lower respiratory, skin and skin structure, urinary tract, bone and joint, and intra-abdominal infections caused by susceptible pathogens.34 Treatment of febrile neutropenic adult patients with ticarcillin-clavulanate combined with an aminoglycoside has been shown to be effective.

TICARCILLIN

Ticarcillin is a semisynthetic penicillin with pharmacologic and toxic properties virtually identical to those of carbenicillin. Its in vitro activity is similar to that of carbenicillin, with the exception that ticarcillin is more active against P. aeruginosa.189

Mean peak serum concentrations of 189 μg/mL are seen 1 hour after administration of 75-mg/kg intramuscular doses to low-birth-weight infants younger than 7 days of age and of 125 to 160μg/mL to older neonates (see Table 37–6).193 The half-life and plasma clearance during the neonatal period are similar to those for carbenicillin.193,194

Comparative clinical studies of carbenicillin and ticarcillin have not been conducted to identify an advantage of one drug over the other. As noted previously, in the United States, carbenicillin is no longer available. Use of ticarcillin alone or combined with clavulanate (Timentin) is preferred in patients with P. aeruginosa infections because of its greater in vitro activity against this organism. Although the quantity of sodium per gram is larger for ticarcillin than for carbenicillin, the lower dosage schedule for ticarcillin that is recommended for neonates and young infants provides a smaller amount of sodium per dose of drug, which conceivably could be advantageous in infants with cardiac or renal disease. The dose is 75mg/kg administered every 12 hours to infants younger than 1 week of age, and every 8 and every 6 hours to older infants weighing 2000g or less and more than 2000g at birth, respectively.

The co-administration of clavulanic acid with ticarcillin significantly enhances the antibacterial activity of the latter drug against several organisms, including some ticarcillin-resistant strains of E. coli, Klebsiella pneumoniae, P. mirabilis, and staphylococci.195,196 Clavulanic acid is a β-lactam with weak antibacterial activity, but it has the property of being a potent irreversible inhibitor of several β-lactamases produced by gram-positive and gram-negative bacteria.197 Information regarding the use of this compound in newborns is limited. Pharmacokinetic data obtained in three newborns with gram-negative infections treated with a ticarcillin–to–clavulanic acid weight ratio of 25:1 included peak serum concentrations and half-life values similar to those observed after administration of ticarcillin alone.198 This drug combination is potentially very useful in the treatment of neonatal infections. We have prescribed ticarcillin-clavulanate either alone or, more commonly, with an aminoglycoside for infants with nosocomial gram-negative enteric infections, with satisfactory safety and effectiveness.

Ticarcillin

Ticarcillin (see Fig. 20-7) is no longer available as a single agent. It is susceptible to hydrolysis by class A β-lactamases and is used as a fixed combination of ticarcillin-clavulanate. It is less active than aminopenicillins against penicillin-resistant streptococci and relatively inactive against enterococci but is more active against many gram-negative species, including Pseudomonas aeruginosa. Serum levels of 260 µg/mL are achieved after a 3-g intravenous dose.54 Ticarcillin is excreted by renal tubules. Probenecid delays renal excretion and increases serum concentrations. Tissue distribution is similar to that of ampicillin, but cerebrospinal fluid concentrations are inadequate for treatment of meningitis. Its half-life is approximately 70 minutes, and it accumulates in the presence of renal failure. Greater accumulation occurs if there is combined hepatic and renal dysfunction. Hemodialysis and continuous venovenous hemofiltration reduce plasma concentrations. Side effects are similar to those seen with penicillins and in addition can interfere with platelet function because it binds to the adenosine diphosphate receptor site on platelets and prevents normal contraction.55 Thus, bleeding may occur in the presence of high serum levels and in the presence of renal failure.

Ticarcillin—(Ticar; Timentin)

β-Lactam Antimicrobial plus β-Lactamase Inhibitor Combination

Timentin, (ticarcillin/clavulanate), Zosyn (piperacillin/tazobactam), and Unasyn (ampicillin/sulbactam) are all combinations of two β-lactam drugs. The first β-lactam drug, the true antibiotic, effectively binds to the target site in the bacteria and results in the death of the organism, assuming that the second β-lactam drug neutralizes the organism’s β-lactamase. The second β-lactam drug has poor intrinsic activity as an antibiotic but still displays high affinity to and may bind irreversibly to and neutralize the β-lactamase enzyme the organism has produced. This agent is also known as a β-lactamase inhibitor. The combination adds to the spectrum of the original antibiotic when the mechanism of resistance is a β-lactamase enzyme. Not all β-lactamase inhibitors have an equal ability to inhibit all β-lactamases. Timentin and Zosyn have no significant activity against Pseudomonas beyond that of ticarcillin or piperacillin because their β-lactamase inhibitors do not effectively inhibit the β-lactamases of Pseudomonas. In general, the β-lactamase inhibitors present in the antibiotics Timentin, Zosyn, and Unasyn do not inhibit the adenosine monophosphate 3′5′ (AmpC), type 1 chromosomal β-lactamases present in Enterobacter, Serratia, and Citrobacter. They do, however, inhibit enzymes present in a number of other pathogens, including the β-lactamases often present in strains of H. influenzae, Bacteroides fragilis, and S. aureus.