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Beta streptococcus group b and ciprofloxacin

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MICROBIOLOGY

Group B Streptococcus (GBS) can be found as part of the normal flora in the gastrointestinal and female genital tracts, periurethral area, perineal and perianal skin and even the upper respiratory tract (41). Colonization of the lower digestive tract is most common, seen in 15-35% of males and females of all ages. From the lower digestive tract, bacteria intermittently colonize the genital tract and less frequently the urinary tract. It is only found on the cervix in 6% of pregnant women although this is the site from which the neonate likely acquires the organism (9, 30).

Pregnant women probably vary in extent and duration of Group B streptococcal carriage. Only a small number appear to be heavily and continually colonized during pregnancy but heavy colonization greatly increases the likelihood of vertical transmission and infection in the neonate (48). Intermittent carriage is more common, which well accounts for limitations in the accurate prediction of carriage during labor based on cultures obtained at some time point much earlier in pregnancy. This observation is important in developing guidelines for the prevention of early onset Group B streptococcal disease in neonates based on maternal cultures as discussed below.

EPIDEMIOLOGY

Group B Streptococcus was first reported as a veterinary pathogen causing bovine mastitis long before its human clinical importance was recognized. The first description of Group B streptococcal human disease was in three cases of fatal puerperal sepsis over 60 years ago (23). Since the early 1970s, Group B ß-haemolytic streptococcus (GBS) (Streptococcus agalactiae) has been the leading pathogen causing serious perinatal infection in the USA as well as most developed countries. Control of this infection has therefore become a major priority in pediatrics. Significant advances have been achieved in the areas of diagnosis and management leading to a reduction in mortality from 35-50% in the 1970s to less than half of this initial rate. The incidence of invasive early-onset GBS diseasedecreased by more than 80% from 1.8 cases/1000 live births in the early 1990s to 0.26 cases/1000 live births in 2010; from 1994 to 2010 it is estimated that over 70,000 cases of early onset GBS invasive disease were prevented in the United States (40). The decline stemmed from the increased use of penicillin during labor in women at high risk for transmitting the infection to their newborns.

In recent years it has also been recognized as a significant pathogen in individuals with certain predisposing conditions, particularly advanced age, malignancy, diabetes, HIV, and liver failure, with the risk of disease increasing by as much as 30 fold in these groups (16).

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CLINICAL MANIFESTATIONS

In young, healthy, non-pregnant adults, it is only an occasional pathogen associated with genitourinary infection, pneumonia, bacteremia and soft tissue infection, whereas in pregnant women, it is the second most common cause of urinary tract infection and a frequently isolated bacterium in cases of amnionitis, endometritis and postpartum wound infections. Almost all of these patients have a good outcome with early recognition and adequate therapy. In nonpregnant adults however, most of whom are immunocompromised, fatal outcome is not unusual in spite of appropriate management.

Two distinct clinical syndromes in neonates have been recognized: early onset infection occurring within the first 7 days of birth usually presenting clinically with severe pneumonia, and late onset infection typically peaking at 3-4 weeks of life (range 7 days to 3 months), manifesting as occult bacteremia, meningitis or focal disease such as osteomyelitis, septic arthritis and cellulitis. Virtually all cases of early onset disease are associated with maternal Group B streptococcal colonization while only half of the cases of late onset infection are caused by strains identified in maternal flora.

Most cases of group B streptococcal infection present with bacteremia; additional manifestations are largely age dependent. Early onset group B streptococcal infection in neonates (prior to 7 days of age) most commonly manifests with symptoms of respiratory distress and a chest radiographic appearance suggesting respiratory distress syndrome vs. severe pneumonia. These neonates appear septic with disease often progressing to hypotension and shock. Late onset disease in neonates presents at a median age of onset of 27 days with bacteremia alone or with focal infection such as meningitis, osteomyelitis, arthritis, or cellulitis/adenitis. Disease in infants, children and adults also manifests with bacteremia and rarely with focal infections such as abscesses, necrotizing fasciitis, meningitis, pericarditis, arthritis, osteomyelitis, or epiglotitis. Among pregnant girls and women, bacteremia is a primary finding in two-thirds of all cases but 10% result in chorioamnionitis, 10% in endometritis and septic abortion in 7% of all cases. The case fatality rate for disease in adults is significantly higher than that in neonates (12% vs 4%). Adults 65 years or older have an even higher fatality rate, reported at 15%.

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LABORATORY DIAGNOSIS

The diagnosis of invasive group B streptococcal infection is established by routine culture techniques and isolation of the organism from normally sterile sites such as blood, urine, cerebrospinal fluid, bone, joint, or from an abscess. Isolation of the organism on surface areas, the genital tract or the gastrointestinal tract only indicates colonization which may or may not be associated with invasive disease. Rapid antigen detection methodology is readily available primarily employing latex particle agglutination methodology. Group B streptococcal antigen can be detected in approximately 90% of CSF specimens and 95% of concentrated urine specimens from patients with meningitis. However, urine assays may be positive in otherwise healthy infants who are heavily colonized with group B streptococci. False positive reactions in CSF are also well reported. Colonization with group B streptococcus can be identified rapidly and reliably by a polymerase chain reaction assay in pregnant women in labor both before and after the rupture of membranes and this test can also be employed for the diagnosis of invasive disease.

PATHOGENESIS

Neonatal acquisition of the organism from the mother’s genital tract takes place predominantly during delivery and 70% of babies born to culture positive mothers will become colonized. Therefore 8-15% of all newborns have the potential for acquiring early onset Group B streptococcal disease (15). When maternal cultures are negative, approximately 5% (range 1-27%) of infants may still acquire Group B Streptococcus as colonizing flora (4). Amongst neonates, the external ear is the site most frequently colonized at birth. The nose, upper respiratory tract, umbilical stump and rectum are also colonized early. Shortly thereafter the adult pattern of rectal carriage is established. There is considerable evidence for hospital based acquisition by newborn infants and subsequent nursery spread is common. However, this appears to originate predominantly from mother-infant contact rather than transmission from hospital personnel. There is also considerable evidence that the neonate my acquire infection from the mother’s breast milk when it is colonized by GBS. Clinical disease is usually after 7 days and by definition late onset (11). For early onset infection, colonization of the neonate in conjunction with low or absent levels of antibody to this organism allow replication in the neonate, entry of the organism into the blood stream and eventual dissemination to other sites.

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SUSCEPTIBILITY IN VITRO AND IN VIVO

Group B Streptococcus is highly susceptible to most classes of antibiotics including penicillins, many first and second generation cephalosporins (excluding cefoxitin), third generation cephalosporins, vancomycin and imipenem (Table 1). Of the third generation cephalosporins, ceftriaxone has the greatest activity. Most strains are also sensitive to erythromycin, chloramphenicol and clindamycin but they are generally resistant to tetracycline. Ciprofloxacin has moderate in vitro activity but has not yet been evaluated for clinical efficacy. Resistance to erythromycin, clindamycin and clarithromycin occurs in 1-3% of isolates, and uniformly to nalidixic acid, trimethoprim-sulfamethoxazole, metronidazole and aminoglycosides.

As compared to group A streptoccoccus, Group B Streptococcus grows more rapidly and requires a longer period of time for killing by beta-lactam antibiotics. In the presence of 1 µg/ml of ampicillin, elimination of group A strains is complete at four hours while sterilization of group B strains does not occur until 20-24 hours even at concentrations of 10 µg/ ml (39). In studies using 50 times the minimal bactericidal concentration (MBC) of ampicillin, killing of Group A strains occurred within 4 hours. In contrast, virtually no killing of group B strains was observed over this time. The relatively slow bactericidal action of ampicillin on this organism may explain the difficulty in treating immunosuppressed hosts.

Synergistic Interaction

Synergy between ampicillin and aminoglycosides in Group B streptococcal inhibition assays has been well documented. Killing occurs at a much more rapid rate when 2 or 10 µg/ ml of gentamicin is added to a cidal concentration of ampicillin. This effect is more marked when the combination contains concentrations of 10 µg/ ml of gentamicin. Monitoring peak serum concentrations of gentamicin to achieve levels this high is therefore indicated. The mechanism of enhanced killing of Group B Streptococcus by the ampicillin-aminoglycoside combination has not been defined; it is postulated that gentamicin enters and acts on cells partially damaged by ampicillin (39). Murine animal models experimentally infected with Group B Streptococcus also demonstrate accelerated clearing of bacteremia when ampicillin and gentamicin are used in combination as compared to ampicillin alone (14).

Penicillin Tolerance

Defined as an MBC 16-32 times the MIC, the phenomenon of in vitro tolerance in Group B streptococcal isolates corresponds with delayed bacterial killing, additive rather than synergistic bactericidal activity between ampicillin and gentamicin and possible autolytic enzyme defects in such strains. Penicillin tolerance in vitro has been noted in 4-6% of isolates (31). The clinical importance of this in vitro phenomenon remains ill defined although some experts recommend that all strains of Group B Streptococcus be tested for tolerance before discontinuing the aminoglycoside and that combination therapy be continued for the entire course when tolerance is detected (43). Detection of tolerance is highly dependent on the choice of growth medium employed and the growth phase of the bacterial inoculum (31). Identification of this property is somewhat impractical since in vitrotesting is neither standardized nor available in most hospital laboratories. For patients demonstrating a good clinical response to initial therapy the demonstration of in vitro tolerance would not be an indication for a change either to another class of antibiotics or to combination regimens.

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ANTIMICROBIAL AGENT THERAPY

General

Since Group B Streptococcus remain universally susceptible to penicillins,   penicillin G as single therapy is considered the treatment of choice for established Group B streptococcal infections (29, 33). Primary advantages over an ampicillin-gentamicincombination are its narrower spectrum of antimicrobial activity and lower cost. However, high doses of penicillin G must be used for the treatment of Group B streptococcal disease for two reasons. First, the MIC of penicillin G for Group B Streptococcus is relatively high, 4-10 fold greater (range 0.01-0.4 µg/ml) than that for group A streptococcal strains. Secondly, patients are generally immunocompromised (including neonates), a factor associated with high grade bacteremia and higher concentrations of organisms in tissue, including the cerebrospinal fluid (CSF) where 107-108 organisms/ml have been consistently reported. Since inoculum size greatly influences the in vitro susceptibility to penicillin G, higher doses are likely required to provide bactericidal activity in vivo. This inoculum effect also has been noted with  cefotaxime and  imipenem.

Neonates

Low dosages of penicillin used in the 1970s may in part explain the high rate of relapses initially reported in infants (17, 26, 47, 49). Penicillin was generally given at 100,000units/ kg/day and ampicillin with gentamicin recommended at 200 mg/kg/day and 7.5 mg/ kg/day respectively for a period of 10-14 days. Following these reports, the recommended dosage of penicillin for the treatment of meningitis in neonates was increased from 100,000 to 250,000 units/kg/day. Dosages in neonates of penicillin G as high as 500,000 units/kg/day or ampicillin at 300-400 mg/ kg/ day are recommended by some experts (4). While other treatment resources concur with higher dosages in neonates they also suggest adjusting the dosage based on age (Table 2).

At the present time, the accepted antimicrobial regimen for neonatal sepsis/meningitis of uncertain etiology consists of ampicillin and an aminoglycoside until the organism is identified (8). Once Group B Streptococcus is confirmed treatment can be adjusted to penicillin (or ampicillin) alone.

For the infant with late onset disease where the CSF contains Gram positive cocci in pairs and short chains or a rapid antigen assay for Group B Streptococcus is positive, it would appear prudent to begin therapy with ampicillin and gentamicin or ampicillin and a third generation cephalosporin (ceftriaxone or cefotaxime) since it is essential to eradicate the organisms rapidly from the CSF and the synergistic or additive killing effect of gentamicin combined with ampicillin may prove beneficial in the early course of the infection. In addition Streptococcus pneumoniaeListeria monocytogenes and enterococcus may produce CSF Gram stains similar to that of Group B Streptococcus and ampicillin is the drug of choice for the latter two pathogens. It should also be kept in mind that a third generation cephalosporin plus vancomycin is recommended for pneumococcus.

Older Patients

Although there has been broad experience with the successful treatment of neonatal Group B streptococcal infections much less information is available to guide clinicians in the management of adults with serious invasive Group B streptococcal infections (13, 16, 20) (Table 3). Whereas ampicillin and gentamicin are acceptable as an initial empiric regimen in neonates, even broader coverage may be needed in adults to cover the range of organisms that cause serious infections particularly in immunocompromised individuals. Initial empiric therapy, however, usually includes antimicrobials which have excellent activity against Group B Streptococcus such as cefotaxime (MIC99< 0.06 micrograms/ ml) or ceftazidime (MIC90 < 0.5 micrograms/ml) often in combination with vancomycin (MIC90 < 0.5 micrograms/ ml). These regimens are quite adequate as studies have found no evidence of improved outcome among patients who received ampicillin or penicillin G containing regimens as compared with patients who did not receive these agents.

Diabetes is the single most common underlying condition for severe Group B streptococcal disease in adults. Other predisposing factors include advanced age, liver failure or a history of alcohol abuse, neurologic impairment, malignancy, renal failure, cardiopulmonary disease or heart failure and pulmonary disease. Adults are more likely to die from Group B streptococcal infection than are children. The presence of chronic respiratory, genitourinary or gastrointestinal infections in patients with Group B streptococcal infection suggests that the hospital is the source for the acquisition of bacteremia.

Special Situations

Endocarditis

Both acute and subacute cases of endocarditis have been described. Most occur in younger patients (mean age approximately 18 years). The mitral valve is the most commonly affected (48 percent) followed by aortic (29 percent), mitral and aortic (10 percent) and tricuspid valves (5 percent). Tricuspid valve involvement is frequently seen in intravenous drug abusers. Underlying heart disease is present in more than half of the cases reported with rheumatic heart disease being the most common. Rapid valve destruction necessitating early valve replacement is a characteristic feature of this disease in adults.

The current recommendation for the treatment of Group B streptococcal endocarditis is penicillin (20 million units/day I. V. for 28 days) In the penicillin allergic patient, cefazolin (6 grams/day I. V.) or vancomycin (2 grams/day I. V.) for 28 days may be substituted. Of note is the failure of clindamycin in two presumed penicillin-allergic patients. It has been suggested by some that penicillin should be combined with an aminoglycoside for their synergy but there are currently inadequate data to make such a recommendation. This combination should be used for cases caused by penicillin tolerant or relatively penicillin resistant strains. Prosthetic valve endocarditis requires early surgical intervention as medical therapy alone is usually inadequate (38).

Other Infections

Pneumonia in patients with altered immune function, is often accompanied by pleural empyema. Fatality rates from 30-85 percent are seen even with early and adequate penicillin therapy.

Arthritis and osteomyelitis seems to also occur commonly in diabetics and is generally monoarticular affecting the knee, hip or shoulder. High dose penicillin (8 to 19.2 million units per day for 3-8 weeks) in addition to surgical drainage has been optimal.  Cefazolin and cephradine for 4-6 weeks have also been effective. It is essential to establish an early diagnosis by needle aspiration and culture of joint fluid (4).

Most recently, skin and soft tissue infections have accounted for one third of infections with Group B Streptococcus (4). Cellulitis, foot ulcers, abscess and infections of decubitis ulcers are the most common. Pyomyositis, blistering dactilytis and necrotizing fasciitis have also been reported. Antimicrobial therapy along with drainage affects complete recovery in approximately 90% of these patients.

Other uncommon manifestations of Group B streptococcal infections in adults include meningitis, keratitis, endophthalmitis and urinary tract infections seen in middle aged women with underlying intrinsic alteration of urinary flow or stones. One prospective evaluation attributed 2 percent of all cases of urinary tract infection to Group B Streptococcus (34). The isolates were susceptible to virtually all of the antimicrobials tested except gentamicin. Outcome in most of these cases has been poor, likely related to the well known inability of conventional antimicrobial therapy to eradicate vaginal or enteric colonization. Penicillin remains the drug of choice in the treatment of Group B Streptococcus related urinary tract infections (16).

Parenteral therapy of 10 days duration is recommended for the treatment of bacteremia, pneumonia, pyelonephritis and soft tissue infections. A 14 day minimum duration is recommended for the treatment of meningitis and a 4 week minimum for the treatment of endocarditis or ventriculitis.

Infections in Pregnant Females

Treatment of chorioamnionitis and intraamnionitic infection in pregnant and postpartum women requires a regimen which will cross the placenta in sufficient quantities to begin fetal therapy.   Ampicillin (2 grams every six hours) and  gentamicin (1.5 mg/kg every 8 hours) or ampicillin (2 grams) plus sulbactam (1 gram) every 6 hours have been recommended (1). Gentamicin is used in higher concentrations in pregnant women because of the high renal clearance associated with pregnancy. Other treatment regimens include combinations of ticarcillin/clavulanic acid or a cephalosporin (e. g.  cefuroxime or cefazolin) plus gentamicin. For penicillin allergic patients vancomycin plus gentamicin or a cephalosporin plus gentamicin are recommended.

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ADJUNCTIVE THERAPY

Supportive care of the critically ill patient with Group B streptococcal disease is identical to serious infections caused by other pathogens. This includes the early recognition and treatment of shock, management of metabolic acidosis and fluid administration. Extracorporeal membrane oxygenation has been utilized as rescue therapy for neonates with overwhelming Group B streptococcal sepsis and pneumonia (28), and granulocyte transfusions in neutrophil depleted patients have been employed (12, 50).  The potential adverse effects of granulocyte transfusions which include graft vs. host disease, transmission of hepatitis and CMV and pulmonary leukocyte sequestration make this therapy still experimental, to be considered only in those individuals who fail to respond to conventional treatment.

Other proposed therapies include granulocyte/macrophage-colony stimulating factor (GM-CSF), GCSF, and intravenous immunoglobulin. Hyperimmune Group B streptococcal immunoglobulin and human monoclonal antibodies to Group B Streptococcus are currently under development. It is clear that deficiency of opsonic antibody and decreased amounts of total serum immunoglobulin contribute to the susceptibility of neonates and immunocompromised patients to Group B Streptococcus. A major factor for early onset GBS disease is low or absent maternal antibody and therefore little or none passively transferred to the fetus (3). It follows that treatment with IVIG may be a useful adjunct to therapy. Studies using immune rabbit serum in an opsonophagocytic bactericidal assay for Group B Streptococcus supported this hypothesis by showing increased killing of Group B Streptococcus when IVIG and complement were combined (23). Similar results have been seen in the type III Group B streptococcal animal challenge model (25). Well designed human clinical trials are needed before any of these therapies can be endorsed.

ENDPOINTS FOR MONITORING THERAPY

Duration of therapy is generally based on published experience, guided by individual clinical response and follow-up cultures. Optimal results have been seen with treatment of bacteremia without a focus or with soft tissue infection parenterally for 10 days, 2-3 weeks for meningitis or pyarthosis, 3 weeks for osteomyelitis and 4 weeks for endocarditis (4). For osteomyelitis and septic arthritis, drainage of the infected site is often an important adjunct to antimicrobial therapy. Based on previous reports of neonatal Group B streptococcal meningitis relapse when treatment was given for only 10-14 days, some experts suggest that at least three weeks of antimicrobial therapy be offered for neonatal meningitis.

Acute phase reactants are useful for monitoring response to therapy in bone and joint infection and as a guide for hospital discharge and discontinuation of antibiotics. Procalcitonin and  C-reactive protein are the first to return to normal, occurring after 3-5 days of appropriate therapy, while the erythrocyte sedimentation rate (ESR) takes longer, generally 7-21 days (45). Discharge from the hospital to home parenteral antibiotic therapy can be planned when the patient is afebrile, the white blood cell count is returning to baseline, and procalcitonin or C-reactive protein are in the normal range. The ESR can be measured after 21 days of therapy and antibiotics discontinued if it is less than 30mm/hr.

Repeat lumbar puncture 24-48 hours into therapy is recommended by some experts in the management of infants with meningitis to confirm response to therapy and sterilization of the CSF. Another lumbar puncture later in the course of therapy is indicated if follow-up CSF cultures were not sterile or if there is no clinical improvement. It should be noted that GBS antigen may be detected in the CSF for a few weeks after adequate treatment of GBS meningitis.

VACCINES

No vaccines are yet available commercially for the prevention of Group B Streptococci but candidate products are currently being investigated.

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PREVENTION

Early Onset Disease in Neonates

Once Group B streptococcal invasive disease became a major concern, in the early 1970s, a number of strategies for controlling neonatal infection were examined (1,32, 35, 36, 53).  These can be divided into the following approaches: 1) active immunization of young or pregnant women, 2) passive immunization with intravenous immunoglobulin (IVIG), 3) treatment of Group B streptococcal carriers, 4) early antibiotic treatment of all neonates, and 5) chemoprophylaxis during labor.

Immunization of Women

One fairly consistent finding with Group B streptococcal invasive disease is absence of type specific IgG antibody in the neonate (5). It has been shown that maternally acquired IgG antibody in the neonate persists for two months. Since the presence of such antibody simply reflects passive transfer from the mother, its absence in the mother represents the focus for correction. There are two strategies which are presently being investigated: active immunization of antibody negative pregnant women (7, 51) and passive immunization with specific antibody. The latter strategy has only been investigated in animal models and appears to have limited clinical applicability.

Most promising are studies examining maternal active immunization with Group B streptococcal vaccines as a method for preventing neonatal invasive disease. Vaccination of nonimmune women during their third trimester of pregnancy with a vaccine containing the Type III polysaccharide of group B streptococcus was initially reported in 1988 (7). Low or unprotective antibody concentrations were defined as < 2 µg/ ml. Fifty-seven percent of recipients responded with a rise in titer from 1.3 to 7.1 mg/ml four weeks after vaccination and 80 percent of the infants of successfully immunized mothers retained protective levels of antibody until one month of age. Therefore this vaccine would be expected to protect a maximum of only 50% of babies potentially at risk. These early studies were therefore encouraging but indicated that a more immunogenic vaccine would have to be developed before considering large trials to evaluate the safety and efficacy of this strategy. A conjugate antigen which covalently links Group B Streptococcus Type III polysaccharide to a protein carrier is the likely solution and candidate vaccines are currently being develop (52). However, maternal antibody does not cross the placenta in adequate concentrations until 32 weeks gestation. At this age antibody concentrations are only 50% those of full term neonates thereby suggesting that successful maternal immunization may still be inadequate for preventing disease in the very prematurely born.

Prophylaxis Against Group B Streptococcus Carriers

Eradication of maternal Group B streptococcal colonization was a strategy first investigated two decades ago (22, 24, 27). Well designed clinical studies utilized oral antibiotics to treat colonized mothers during the second or third trimester of pregnancy. In these initial trials, relapse occurred commonly and was thought to be a consequence of colonization of sexual contacts. Subsequent studies therefore included treatment of partners but results were essentially unchanged; recolonization was still observed in two-thirds of study cases prior to rupture of membranes and onset of labor (24). These experiences suggested that prevention of neonatal disease might best be accomplished by eradicating Group B Streptococcus during the immediate antepartum period.

Prophylaxis of Neonates at Birth

Early administration of penicillin to prevent Group B streptococcal disease in neonates has been investigated in a number of clinical studies, but results were variable. Two encouraging reports demonstrated efficacy of penicillin prophylaxis although neither focused on high risk populations of neonates (18, 42, 44).  In the latter study, the incidence of severe infection caused by non Group B streptococcal pathogens was increased, thereby negating clinical benefits of intervention.

A more recent study included an appropriate concurrent control group among neonates weighing 2000g or less (37).  One thousand one hundred eight-seven high risk premature neonates had blood and surface cultures obtained and were randomized to no treatment or to receive 100,000 U/kg of crystalline penicillin G intramuscularly immediately after birth and every 12 hours for 72 hours. Treatment in this series did not prevent early-onset streptococcal disease nor reduce excess mortality associated with infection.

Intrapartum Prophylaxis

Intrapartum administration of intravenous penicillin or ampicillin to Group B Streptococcus colonized mothers has been shown to decrease vertical transmission of the bacterium and to prevent neonatal disease (46). This occurs whether the mother is lightly or heavily colonized and has been documented in both low risk and high risk neonates. These factors only vary the incidence of disease in untreated pregnancies and therefore the relative benefits of intervention.

The best designed and most convincing prospective, randomized, controlled clinical trial focused on pregnant women colonized with Group B Streptococcus and showed that intrapartum prophylaxis with intravenous ampicillin resulted in preventing at least 50% of the early onset Group B streptococcal infections in their patient population (10). A metaanalysis of seven additional trials which included studies of carriers with and without risk factors estimated a 30-fold reduction in early onset Group B streptococcal disease with similar chemoprophylaxis (45).

Collectively these data strongly support maternal intrapartum chemoprophylaxis and this approach for preventing Group B Streptococcus has been endorsed by the American Academy of Pediatrics and by the American College of Obstetricians and Gynecologists. Two strategies are equally acceptable, one directed by culture results obtained at 35-37 weeks gestation (Figure 1) and the other based on maternal risk factors (Figure 2).

For chemoprophylaxis based on cultures, all pregnant women should be screened at 35 to 37 weeks gestation for Group B Streptococcus, using a single swab specimen from the lower vagina and anorectum and employing appropriate selective broth medium for transport and solid media for final recovery. Results of this culture should be recorded and readily available at the time the mother begins labor.

There are two exceptions to the requirement that colonization is a prerequisite for treatment. These are maternal Group B streptococcal bacteriuria during her pregnancy or a previous neonate with invasive Group B streptococcal disease, either early or late onset. The former circumstance is appropriate since bacteriuria is strongly predictive of heavy genital colonization and previous history of GBS neonatal disease is known to be an independent variable highly associated with subsequent neonatal Group B streptococcal sepsis.

Until an effective Group B streptococcal vaccine is developed, selective intrapartum chemoprophylaxis should be routinely employed. The preferred intrapartum chemoprophylactic regimen is intravenous penicillin G, 5 million units initially and 2.5 million units every 4 hours until delivery (Table 4). Clindamycin or erythromycin may be used for women allergic to penicillin.

Management of infants whose mothers received at least two doses of intrapartum antibiotics is based on gestation and clinical assessment (Figure 3). This algorithm is not an exclusive course of management but should be modified to include variations that incorporate individual circumstances or institutional preferences. A full diagnostic evaluation implies a complete blood count (CBC) and differential, blood culture, and chest radiograph if the neonate has respiratory symptoms. Lumbar puncture need only be performed at the discretion of the physician. Duration of therapy will vary depending on blood culture and CSF results and the clinical course of the infant. If laboratory results and clinical course are unremarkable, duration of therapy may be as short as 48 hours. The term limited evaluation for the neonate whose mother received less than 4 hours of intrapartum chemoprophylaxis implies that a CBC with a differential and a blood culture are the only investigations needed. Neonates less than 35 weeks gestation with suspected sepsis should have a complete sepsis evaluation and empiric antibiotics pending results of cultures and clinical status during this observation period. Cultures require 48 hours of incubation prior to being reported as negative. Asymptomatic newborns >35 weeks gestation can be followed without antibiotic therapy if clinically normal. Some experts recommend obtaining surface and gastric cultures for Group B Streptococcus in these infants. Symptomatic neonates at any gestation should undergo a sepsis work-up followed by broad spectrum antimicrobial therapy, usually ampicillin plus gentamicin or ampicillin plus a third-generation cephalosporin.

Pediatricians are encouraged to develop their own management protocols if they disagree with any aspects of the present algorithm.

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Tables

Table 1.  MIC50 and MIC90 Antimicrobial Susceptibility Concentrations for Group B Streptococci

Antimicrobial Agent   MIC (microgram/ml)  Range MIC50            MIC90
Ampicillin          0.12-0.25 0.25 0.25
Cefamandole     < 0.03-0.5         0.06 0.12
Cefoxitin 0.5-8.0 4.0 4.0
Cefuroxime <0.03-1.0 0.06 0.06
Cephradine 0.25-4.0 2.0 2.0
Cephalexin 0.5-8.0  4.0 4.0
Cephalothin 0.06-0.5 0.25 0.25
Ceftriaxone 0.06-0.12 0.12      0.12     
Cefotaxime       0.02-0.12 0.12      0.12     
Cefoperazone 0.12-0.5 0.25      0.5
Ceftazidime       0.12-0.5 0.25      0.5
Clindamycin      <0.03-0.25        0.06      0.06     
Carbenicillin      0.5-1     1 1
Chloramphenicol 1.0-4.0  2.0        4.0
Colistin 8.0->32.0 >32.0    >32.0
Doxycycline 0.12-32.0          16.0      16.0     
Erythromycin    <0.01-0.25        0.06 0.06
Gentamicin        1.0>32.0 16.0      16.0     
Kanamycin       8.0->32.0          >32.0    >32.0   
Lincomycin       0.03-0.25          0.12      0.12     
Methicillin 0.5-16.0 2.0        2.0       
Minocycline      0.25-32.0 16.0      32.0
Mezlocillin 0.12-0.25          0.12      0.25
Moxalactam 2-8       8 8
Neomycin 4.0>32.0 32.0      >32.0
Nalidixic Acid   >32.0    >32.0    >32.0   
Nitrofurantoin    8.0-32.0 16.0      32
Penicillin <0.01-0.12        0.06      0.06     
Piperacillin        0.25-0.5 0.5 0.5
Sulfa-trimethoprim 1.2/0.06-9.5/0.5 4.8/0.25 4.8/0.25
Ticarcillin 1-2 2 2
Tetracycline 0.12->32.0        32.0 32.0
Vancomycin      0.5-2.0  0.5 0.5

Table 2.  Antimicrobial Regimens Recommended For Treatment of Group B Streptococcal Infections in Neonates and Young Infants

Site of Infection  Age  Drug Dose Per Day (Intravenous)  Duration
Bacteremia without meningitis All Ampicillin plus gentamicin 150-200mg/kg  7.5 mg/kg  Initial treatment before culture results (48-72 hr) 
    Penicillin G 200,000 units/kg Complete a total treatment course of 10 days 
Meningitis   < 7 days Ampicillin 200-300 mg/kg/day in 3 divided doses Initial treatment until CSF is sterile 
    Gentamicin 5 mg/kg in 2 divided doses   
  < 7 days Penicillin G 250,000-400,000 u/kg/day in 3 divided doses Complete a minimum total treatment course of 21 days 
  > 7 days Ampicillin 300-400 mg/kg/day in 4-6 divided doses Initial treatment until CSF is sterile  
    Gentamicin 7.5 mg/kg in 3 divided doses   
  > 7 days Penicillin G 500,000 u/kg/day in 4 divided doses Complete a minimum total treatment course of 21 days 
Septic arthritis   All Penicillin G 200,000 units/kg 2-3 wk
Osteomyelitis All Penicillin G 200,000 units/kg 3-4 wk
Endocarditis All Penicillin G 400,000 unit/kg 4 wks-6 wks

Table 3.  Treatment of Group B Streptococcal Infections in Adults

Diagnosis Antibiotic (Dose) Alternative Dose forPenicillin-Allergic Patients Duration
Bacteremia, soft tissue infections  Penicillin G (10-20 million units/day)  Vancomycin 10 days
 Meningitis  Penicillin G (20-30 million units/day)  Vancomycin 14-21 days
 Osteomyelitis  Penicillin G (10-20 million units/day) Vancomycin  4 weeks
 Endocarditis  Penicillin G (20-30 million units/day) with an aminoglycoside for 2 weeks  Vancomycin with an aminoglycoside  6 weeks

Table 4. Recommended Regimens for Intrapartum Antimicrobial Prophylaxis for Perinatal Group B Streptococcal Disease

Recommended

Penicillin G, 5mU IV bolus, then 2.5mUs IV every 4 hours until delivery

Alternative

Ampicillin, 2gIV bolus, then 1 g IV every 4 hrs until delivery 

If penicillin-allergic :

 

Recommended 

Clindamycin, 900 mg IV every 8 hrs until delivery

Alternative

Erythromycin, 500 mg IV every 6 hrs until delivery

Note: If patient is receiving treatment for amnionitis with an antimicrobial agent active against group B streptococci (e.g. ampicillin, penicillin, clindamycin, or erythromycin), additional prophylactic antibiotics are not needed.


Source: http://antimicrobe.org/b240.asp


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